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Chen PJ, Chen CC, Chang SC, Chang YY, Lin BW, Chen HH, Hsieh YY, Hsu HC, Hsieh MC, Ke TW, Kuan FC, Wu CC, Lu WC, Su YL, Liang YH, Chen JB, Huang SY, Huang CW, Wang JY. Outcomes of upfront primary tumor resection in patients with synchronous RAS wild-type metastatic colorectal cancer. Am J Cancer Res 2024; 14:5863-5873. [PMID: 39803657 PMCID: PMC11711521 DOI: 10.62347/dlwi1455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/03/2024] [Indexed: 01/16/2025] Open
Abstract
This multicenter study explored the survival benefits of upfront primary tumor resection (PTR) followed by first-line cetuximab plus chemotherapy in real-world patients with RAS wild-type metastatic colorectal cancer (mCRC). Treatment options for mCRC include chemotherapy, targeted therapy, immunotherapy, and surgery. The efficacy of upfront PTR in managing mCRC remains unclear. In this retrospective study, we evaluated the outcomes of upfront PTR in 582 patients with synchronous RAS wild-type mCRC who received cetuximab plus chemotherapy as first-line treatment between November 2016 and August 2020. Of these patients, 364 (62.5%) underwent upfront PTR (PTR group) and 218 (37.5%) did not (non-PTR group). Relevant data were collected from 14 medical institutions in Taiwan. No significant differences were discovered between the PTR and non-PTR groups in median overall survival (37.9 vs. 31.7 months; P = 0.079) or progression-free survival (13.70 vs. 13.29 months; P = 0.62). Compared with patients who did not undergo metastasectomy, those who underwent this surgery exhibited significantly longer median overall survival (29.2 vs. 54.18 months; P < 0.001) and progression-free survival (12.8 vs. 15.60 months; P = 0.013). Our findings suggest that upfront PTR may not improve oncological outcomes in patients with synchronous RAS wild-type mCRC. Cetuximab-based targeted therapy plus chemotherapy appears to be suitable as first-line treatment for these patients. This study indicates that upfront PTR should be considered only for patients exhibiting symptoms such as tumor bleeding, perforation, or obstruction.
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Affiliation(s)
- Po-Jung Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical UniversityKaohsiung 80708, Taiwan
| | - Chou-Chen Chen
- Department of Surgery, Taichung Veterans General HospitalTaichung 407, Taiwan
| | - Shih-Ching Chang
- Division of Colon and Rectal Surgery, Department of Surgery, Veterans General HospitalTaipei 11217, Taiwan
| | - Yu-Yao Chang
- Department of Colorectal Surgery, Changhua Christian HospitalChanghua 500, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing UniversityTaichung 402, Taiwan
| | - Bo-Wen Lin
- Department of Surgery, National Cheng Kung University HospitalTainan 70101, Taiwan
| | - Hong-Hwa Chen
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial HospitalKaohsiung 833, Taiwan
| | - Yao-Yu Hsieh
- Division of Hematology and Oncology, Shuang-Ho Hospital, Taipei Medical UniversityNew Taipei 23561, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei 11031, Taiwan
| | - Hung-Chih Hsu
- Division of Hematology Oncology, Chang Gung Memorial Hospital at LinkouTaoyuan 33305, Taiwan
- College of Medicine, Chang Gung UniversityTaoyuan 33302, Taiwan
| | - Meng-Che Hsieh
- Division of Hematology Oncology, Department of Internal Medicine, E-Da Hospital, I-Shou UniversityKaohsiung 824, Taiwan
| | - Tao-Wei Ke
- Division of Colorectal Surgery, Department of Surgery, China Medical University HospitalTaichung 404, Taiwan
| | - Feng-Che Kuan
- Department of Hematology and Oncology, Chang Gung Memorial HospitalChiayi 61363, Taiwan
| | - Chih-Chien Wu
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General HospitalKaohsiung 81362, Taiwan
- School of Medicine, National Yang Ming Chiao Tung UniversityTaipei 112, Taiwan
| | - Wei-Chen Lu
- Department of Oncology, National Taiwan University Hospital Yunlin BranchYunlin 640, Taiwan
| | - Yu-Li Su
- Division of Hematology Oncology, Department of Internal Medicine, Chang Gung Memorial HospitalKaohsiung 833, Taiwan
| | - Yi-Hsin Liang
- Department of Oncology, National Taiwan University HospitalTaipei 10002, Taiwan
| | - Joe-Bin Chen
- Department of Surgery, Chung Shan Medical University HospitalTaichung 402, Taiwan
| | - Shuan-Yuan Huang
- Department of Colorectal Surgery, Changhua Christian HospitalChanghua 500, Taiwan
| | - Ching-Wen Huang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical UniversityKaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical UniversityKaohsiung 80708, Taiwan
| | - Jaw-Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical UniversityKaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical UniversityKaohsiung 80708, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical UniversityKaohsiung 80708, Taiwan
- Center for Cancer Research, Kaohsiung Medical UniversityKaohsiung 80708, Taiwan
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Zhou Y, Wu Z, Wang H, Zhang K, Chen H, Zhu S, Sitrakiniaina A, Wu Y, Yang S, Sun X, Li W, Lin X, Jin J. Evaluation of the prognosis in patients with small-cell lung cancer treated by chemotherapy using tumor shrinkage rate-based radiomics. Eur J Med Res 2024; 29:401. [PMID: 39095855 PMCID: PMC11297595 DOI: 10.1186/s40001-024-02001-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Small-cell lung cancer (SCLC) is a leading cause of cancer-related death. However, the prognostic value of the tumor shrinkage rate (TSR) after chemotherapy for SCLC is still unknown. METHODS We performed a retrospective analysis of 235 patients with SCLC. The TSR cutoff was determined based on receiver-operating characteristic curve analysis. The associations of TSR with progression-free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox proportional hazards models. Survival curves were obtained by the Kaplan-Meier method and compared using the log-rank test. Recurrence patterns after first-line treatment were summarized in a pie chart. A nomogram was constructed to validate the predictive role of the TSR in SCLC. RESULTS The TSR cutoff was identified to be - 6.6%. Median PFS and OS were longer in the group with a TSR < -6.6% than in the group with a TSR ≥ - 6.6%. PFS and OS were also longer in patients with extensive SCLC when the TSR was < - 6.6% than when it was > - 6.6%. Brain metastasis-free survival was better in the group with a TSR < - 6.6%. There was a significant positive correlation between TSR and PFS. Furthermore, univariate and multivariate regression analyses showed that the TSR, patient age, and previous radiotherapy were independent prognostic factors for OS while TSR and M stage were independent prognostic factors for PFS. CONCLUSIONS The TSR may prove to be a good indicator of OS and PFS in patients receiving chemotherapy-based first-line treatment for SCLC.
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Affiliation(s)
- Yuchen Zhou
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhonghan Wu
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
- School of the First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Haowen Wang
- Department of Interventional Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Ke Zhang
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Hua Chen
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Siyu Zhu
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Andriamifahimanjaka Sitrakiniaina
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yanting Wu
- Jiaxing Maternal and Child Health Hospital, Jiaxing, China
| | - Shaopeng Yang
- School of the First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Xiaobo Sun
- Department of Laboratory Diagnosis, Changhai Hospital, Navy Military University, Shanghai, China
| | - Wenfeng Li
- Department of Chemoradiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaoming Lin
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Jingjing Jin
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
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He X, Lan H, Jin K, Liu F. Can immunotherapy reinforce chemotherapy efficacy? a new perspective on colorectal cancer treatment. Front Immunol 2023; 14:1237764. [PMID: 37790928 PMCID: PMC10543914 DOI: 10.3389/fimmu.2023.1237764] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/25/2023] [Indexed: 10/05/2023] Open
Abstract
As one of the main threats to human life (the fourth most dangerous and prevalent cancer), colorectal cancer affects many people yearly, decreases patients' quality of life, and causes irreparable financial and social damages. In addition, this type of cancer can metastasize and involve the liver in advanced stages. However, current treatments can't completely eradicate this disease. Chemotherapy and subsequent surgery can be mentioned among the current main treatments for this disease. Chemotherapy has many side effects, and regarding the treatment of this type of tumor, chemotherapy can lead to liver damage, such as steatohepatitis, steatosis, and sinus damage. These damages can eventually lead to liver failure and loss of its functions. Therefore, it seems that other treatments can be used in addition to chemotherapy to increase its efficiency and reduce its side effects. Biological therapies and immunotherapy are one of the leading suggestions for combined treatment. Antibodies (immune checkpoint blockers) and cell therapy (DC and CAR-T cells) are among the immune system-based treatments used to treat tumors. Immunotherapy targets various aspects of the tumor that may lead to 1) the recruitment of immune cells, 2) increasing the immunogenicity of tumor cells, and 3) leading to the elimination of inhibitory mechanisms established by the tumor. Therefore, immunotherapy can be used as a complementary treatment along with chemotherapy. This review will discuss different chemotherapy and immunotherapy methods for colorectal cancer. Then we will talk about the studies that have dealt with combined treatment.
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Affiliation(s)
- Xing He
- Department of Gastroenterology, Jinhua Wenrong Hospital, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Fanlong Liu
- Department of Colorectal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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Nagaoka T, Osumi H, Ueno T, Ooki A, Wakatsuki T, Nakayama I, Ogura M, Takahari D, Chin K, Matsueda K, Yamaguchi K, Shinozaki E. Morphological response and tumor shrinkage as predictive factors in metastatic colorectal cancer treated with first-line capecitabine, oxaliplatin, and bevacizumab. Int J Clin Oncol 2023; 28:1191-1199. [PMID: 37349660 DOI: 10.1007/s10147-023-02370-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 06/08/2023] [Indexed: 06/24/2023]
Abstract
BACKGROUND Morphologic response (MR) is a novel chemotherapeutic efficacy predictor of solid tumors, especially those treated with anti-vascular endothelial growth factor antibodies. Nevertheless, the importance of systemic chemotherapy MR for colorectal liver metastases (CLM) remains unclear. We aimed to evaluate the usefulness of MR as a factor associated with the therapeutic effects of chemotherapy plus bevacizumab for initially unresectable CLM cases. METHODS We retrospectively evaluated the associations between MR and/or Response Evaluation Criteria in Solid Tumors (RECIST), progression-free survival (PFS), and overall survival (OS) in patients who received first-line capecitabine, oxaliplatin, and bevacizumab treatment for initially unresectable CLM using multivariate analysis. Patients who showed a complete or partial response based on the RECIST, or an optimal response based on MR, were defined as "responders." RESULTS Ninety-two patients were examined, including 31 (33%) patients who responded optimally. PFS and OS estimates were comparable in MR responders and non-responders (13.6 vs. 11.6 months, p = 0.47; 26.6 vs. 24.6 months, p = 0.21, respectively). RECIST responders showed better PFS and OS than non-responders (14.8 vs. 8.6 months, p < 0.01; 30.7 vs. 17.8 months, p < 0.01, respectively). The median PFS and OS estimates of MR and RECIST responders were better than those of single responders or non-responders (p < 0.01). Histological type and RECIST response were independently associated with PFS and OS. CONCLUSION MR predicts neither PFS nor OS; nevertheless, it may be useful when combined with the RECIST. The Ethics Committee of The Cancer Institute Hospital of JFCR approved this study in 2017 (No. 2017-GA-1123): retrospectively registered.
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Affiliation(s)
- Tomoyuki Nagaoka
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Hiroki Osumi
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Teruko Ueno
- Diagnostic Imaging Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Akira Ooki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Takeru Wakatsuki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Izuma Nakayama
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Mariko Ogura
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Daisuke Takahari
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Keisho Chin
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Kiyoshi Matsueda
- Diagnostic Imaging Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Eiji Shinozaki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
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Wang XY, Zhang R, Han JH, Chen SQ, Zhao FL, Chen H, Lin J, Fan J, Zhu WW, Lu L, Chen JH. Early Circulating Tumor DNA Dynamics Predict Neoadjuvant Therapy Response and Recurrence in Colorectal Liver Metastases: A Prospective Study. Ann Surg Oncol 2023; 30:5252-5263. [PMID: 37202570 DOI: 10.1245/s10434-023-13604-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/20/2023] [Indexed: 05/20/2023]
Abstract
BACKGROUND For patients with colorectal liver metastases (CRLM) who receive neoadjuvant therapy (NAT), reliable indicators that can early and accurately predict treatment response are lacking. This study was conducted to prospectively investigate the potential of early circulating tumor DNA (ctDNA) dynamics as a precise predictor of NAT response and recurrence in CRLM. METHODS This study prospectively enrolled 34 patients with CRLM who received NAT, with blood samples collected and subjected to deep targeted panel sequencing at two time points: 1 day before the first and the second cycles of NAT. Correlations of ctDNA mean variant allele frequency (mVAF) dynamics and treatment response were assessed. The performance of early ctDNA dynamics in predicting treatment response was assessed and compared with those of carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). RESULTS The baseline ctDNA mVAF was significantly associated with pre-NAT tumor diameter (r = 0.65; P < 0.0001). After one cycle of NAT, the ctDNA mVAF declined remarkably (P < 0.0001). The dynamic change in ctDNA mVAF of 50% or more was significantly correlated with better NAT responses. The discriminatory capacity of ctDNA mVAF changes was superior to that of CEA or CA19-9 in predicting radiologic response (area under the curve [AUC], 0.90 vs 0.71 vs 0.61) and pathologic tumor regression grade (AUC, 0.83 vs 0.64 vs 0.67). The early changes in ctDNA mVAF but not CEA or CA19-9 were an independent indicator of recurrence-free survival (RFS) (hazard ratio, 4.0; P = 0.023). CONCLUSIONS For CRLM patients receiving NAT, an early ctDNA change is a superior predictor of treatment response and recurrence compared with conventional tumor markers.
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Affiliation(s)
- Xiang-Yu Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Rui Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jia-Hao Han
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Shi-Qing Chen
- Department of Medical Affairs, 3D Medicines Inc, Shanghai, China
| | - Fei-Long Zhao
- Department of Medical Affairs, 3D Medicines Inc, Shanghai, China
| | - Hui Chen
- Department of Medical Affairs, 3D Medicines Inc, Shanghai, China
| | - Jing Lin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jie Fan
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China
| | - Wen-Wei Zhu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Lu Lu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jin-Hong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
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Ura T, Hironaka S, Tsubosa Y, Mizusawa J, Kato K, Tsushima T, Fushiki K, Chin K, Tomori A, Okuno T, Matsushita H, Kojima T, Doki Y, Kusaba H, Fujitani K, Seki S, Kitagawa Y. Early tumor shrinkage and depth of response in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil: an exploratory analysis of the JCOG0807. Esophagus 2023; 20:272-280. [PMID: 36427158 DOI: 10.1007/s10388-022-00968-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 10/29/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND We herein investigated the association between early tumor shrinkage (ETS) and depth of response (DpR) and clinical outcomes in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil (bDCF) using data from the JCOG0807, a phase I/II trial of bDCF as first-line chemotherapy for metastatic esophageal cancer. METHODS ETS was defined as a percent decrease in the sum of the target lesions' longest diameter after 8 weeks, whereas DpR was defined as a percentage of the maximal tumor shrinkage during the treatment course. Multivariable analyses were conducted to identify significant prognostic variables in progression-free survival (PFS) and overall survival (OS): one for ETS and covariates, and another for DpR and covariates. RESULTS Among 53 patients, 35 patients with ETS ≥ 20% (66.0%) had longer PFS (7.5 vs. 3.4 months, hazard ratio [HR]: 0.26, 95% confidence interval [95% CI] 0.14-0.49), OS (13.8 vs. 6.1 months, HR 0.20, 95% CI 0.11-0.39), and PPS (6.4 vs. 2.8 months, HR 0.38, 95% CI 0.20-0.72) than those with ETS < 20%. In addition, 37 patients with DpR ≥ 30% (69.8%) had longer PFS (7.5 vs. 2.9 months, HR 0.17, 95% CI 0.08-0.34), OS (13.8 vs. 6.0 months, HR 0.14, 95% CI 0.07-0.27), and PPS (6.8 vs. 2.8 months, HR 0.30, 95% CI 0.15-0.58) than those with DpR < 30%. Multivariable analyses revealed that each ETS and DpR was an independent factor of longer PFS and OS. CONCLUSIONS ETS and DpR might be associated with clinical outcomes in patients with metastatic esophageal cancer treated with bDCF.
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Affiliation(s)
- Takashi Ura
- Department of Medical Oncology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
| | - Shuichi Hironaka
- Department of Medical Oncology, Gastroenterological Oncology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka-Shi, Saitama, 350-1298, Japan.
| | - Yasuhiro Tsubosa
- Division of Esophageal Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Junki Mizusawa
- JCOG Data Center, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Takahiro Tsushima
- Department of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Kunihiro Fushiki
- Department of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Keisho Chin
- Department of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan
| | - Akihisa Tomori
- Department of Gastroenterology, Saku Central Hospital, Saku, Japan
| | - Tatsuya Okuno
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | | | - Takashi Kojima
- Gastrointestinal Oncology Division, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yuichiro Doki
- Gastroenterological Surgery, Osaka University, Suita, Japan
| | - Hitoshi Kusaba
- Department of Medicine and Biosystemic Science, Kyushu University, Fukuoka, Japan
| | - Kazumasa Fujitani
- Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan
| | - Shiko Seki
- Department of Gastroenterological Surgery, Tokyo Medical Center, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
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Depth of response of induction therapy and consecutive maintenance treatment in patients with RAS wild-type metastatic colorectal cancer: An analysis of the PanaMa trial (AIO KRK 0212). Eur J Cancer 2023; 178:37-48. [PMID: 36399909 DOI: 10.1016/j.ejca.2022.09.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND In patients with RAS wild-type metastatic colorectal cancer, depth of response (DpR) has gained importance as a novel end-point in clinical trials. We investigated the overall DpR, as well as the prognostic and predictive impact of DpR to induction therapy (six cycles of 5-fluorouracil, leucovorin [FU/FA], oxaliplatin [FOLFOX] and panitumumab [Pmab]) on consecutive maintenance therapy (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial. METHODS Central radiological assessment was performed according to RECIST 1.1. DpR was defined as percentage change in tumour diameter within defined time intervals (induction therapy, maintenance therapy, total course of therapy). For prognostic and predictive analyses, median DpR (</≥) served as threshold. RESULTS Out of 248 patients receiving maintenance therapy, 211 were evaluable for DpR analyses (FU/FA + Pmab, n = 106; FU/FA alone, n = 105). The overall DpR in all patients was 56.5%. DpR of induction therapy (42.5%) accounted for the largest proportion (75.2%) of the overall DpR. While greater DpR to induction therapy was significantly associated with prolonged PFS (HR 0.70, 95% CI 0.52-0.93, p = 0.013) and OS (HR 0.38, 95% CI 0.28-0.51, p < 0.001), there was no significant correlation of DpR and maintenance treatment arm. CONCLUSIONS In the PanaMa trial, the overall DpR was similar to DpR achieved by other epidermal growth factor receptor-based regimens. DpR to induction therapy accounted for three quarters of the total tumour shrinkage potentially suggesting that FOLFOX plus Pmab can be de-escalated following induction without substantially compromising efficacy. DpR to induction therapy was prognostic but not predictive for efficacy of consecutive maintenance therapy. CLINICAL TRIAL INFORMATION NCT01991873.
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Doleschal B, Petzer A, Rumpold H. Current concepts of anti-EGFR targeting in metastatic colorectal cancer. Front Oncol 2022; 12:1048166. [PMID: 36465407 PMCID: PMC9714621 DOI: 10.3389/fonc.2022.1048166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/26/2022] [Indexed: 11/07/2023] Open
Abstract
Anti-EGFR targeting is one of the key strategies in the treatment of metastatic colorectal cancer (mCRC). For almost two decades oncologists have struggled to implement EGFR antibodies in the mCRC continuum of care. Both sidedness and RAS mutational status rank high among the predictive factors for the clinical efficacy of EGFR inhibitors. A prospective phase III trial has recently confirmed that anti-EGFR targeting confers an overall survival benefit only in left sided RAS-wildtype tumors when given in first line. It is a matter of discussion if more clinical benefit can be reached by considering putative primary resistance mechanisms (e.g., HER2, BRAF, PIK3CA, etc.) at this early stage of treatment. The value of this procedure in daily routine clinical utility has not yet been clearly delineated. Re-exposure to EGFR antibodies becomes increasingly crucial in the disease journey of mCRC. Yet re- induction or re-challenge strategies have been problematic as they relied on mathematical models that described the timely decay of EGFR antibody resistant clones. The advent of liquid biopsy and the implementation of more accurate next-generation sequencing (NGS) based high throughput methods allows for tracing of EGFR resistant clones in real time. These displays the spatiotemporal heterogeneity of metastatic disease compared to the former standard radiographic assessment and re-biopsy. These techniques may move EGFR inhibition in mCRC into the area of precision medicine in order to apply EGFR antibodies with the increase or decrease of EGFR resistant clones. This review critically discusses established concepts of tackling the EGFR pathway in mCRC and provides insight into the growing field of liquid biopsy guided personalized approaches of EGFR inhibition in mCRC.
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Affiliation(s)
- Bernhard Doleschal
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Andreas Petzer
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Holger Rumpold
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Linz, Austria
- Johannes Kepler University Linz, Medical Faculty, Linz, Austria
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Ooki A, Morita S, Tsuji A, Iwamoto S, Hara H, Tanioka H, Satake H, Kataoka M, Kotaka M, Kagawa Y, Nakamura M, Shingai T, Ishikawa M, Miyake Y, Suto T, Hashiguchi Y, Yabuno T, Ando M, Sakamoto J, Yamaguchi K. Impact of early tumor shrinkage on quality of life in patients treated with first-line cetuximab plus chemotherapy for unresectable metastatic colorectal cancer: results of Phase II QUACK trial. BMC Cancer 2022; 22:711. [PMID: 35765021 PMCID: PMC9238042 DOI: 10.1186/s12885-022-09811-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 05/11/2022] [Indexed: 12/09/2022] Open
Abstract
PURPOSE Although early tumor shrinkage (ETS) is a predictor of improved overall survival (OS), the association between ETS and health-related quality of life (HRQOL) remains unclear for patients with metastatic colorectal cancer (mCRC) treated with first-line cetuximab plus chemotherapy. METHODS The data were collected from a prospective trial that assessed HRQOL using the EORTC QLQ-C30. The impact of ETS on HRQOL was estimated using a linear mixed-effects model for repeated measures. RESULTS ETS was achieved in 82 (64.1%) of 128 mCRC patients treated with first-line cetuximab plus chemotherapy, and these patients had a significantly longer OS than those without ETS (HR, 0.38; 95% CI, 0.20-0.72; P = .002). Asymptomatic patients with ETS had a favorable OS, while symptomatic patients without ETS had a worse OS (2-year OS rates, 77.8% vs. 42.5%). Symptomatic patients with ETS had similar outcomes as asymptomatic patients without ETS (2-year OS rates, 64.1% vs. 67.0%). For symptomatic patients, ETS was associated with improved HRQOL scores between baseline and 8 weeks: the mean changes for patients with and without ETS were 5.86 and -4.94 for global health status (GHS)/QOL, 26.73 and 3.79 for physical functioning, and 13.58 and -3.10 for social functioning, respectively. The improved HRQOL was comparable to that of asymptomatic patients without ETS. For asymptomatic patients, ETS showed a decreased deterioration in HRQOL. CONCLUSION Our findings highlight the importance of ETS for HRQOL and prognostic estimates, and assessing ETS may provide clinically useful information for physicians and patients to make more informed decisions.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University, Kyoto, Japan
| | - Akihito Tsuji
- Department of Medical Oncology, Kagawa University, Kita, Japan
| | - Shigeyoshi Iwamoto
- Department of Surgery, Kansai Medical University Kouri Hospital, Neyagawa, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Hiroaki Tanioka
- Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Japan
| | - Hironaga Satake
- Cancer Treatment Center, Kansai Medical University Hospital, Osaka, Japan
| | - Masato Kataoka
- Department of Surgery, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | | | | | - Masato Nakamura
- Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan
| | - Tatsushi Shingai
- Department of Surgery, Osaka Saiseikai Senri Hospital, Suita, Japan
| | - Masashi Ishikawa
- Department of Surgery, Shikoku Central Hospital, Shikokuchuo, Japan
| | - Yasuhiro Miyake
- Department of Surgery, Osaka Minato Central Hospital, Osaka, Japan
| | - Takeshi Suto
- Department of Surgery, Yamagata Prefectural Central Hospital, Yamagata, Japan
| | - Yojiro Hashiguchi
- Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
| | - Taichi Yabuno
- Department of Surgery, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
| | - Masahiko Ando
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | | | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
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Kurreck A, Heinemann V, Fischer von Weikersthal L, Decker T, Kaiser F, Uhlig J, Schenk M, Freiberg-Richter J, Peuser B, Denzlinger C, Graeven U, Heinrich K, Held S, Stahler A, Alig AHS, Jelas I, von Einem JC, Stintzing S, Giessen-Jung C, Modest DP. Response and Disease Dynamics in Untreated Metastatic Colorectal Cancer With Bevacizumab-Based Sequential vs. Combination Chemotherapy—Analysis of the Phase 3 XELAVIRI Trial. Front Oncol 2022; 12:751453. [PMID: 35251955 PMCID: PMC8895369 DOI: 10.3389/fonc.2022.751453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 01/24/2022] [Indexed: 12/22/2022] Open
Abstract
Introduction Early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial. Methods DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex. Results In 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in RAS/BRAF wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS: p < 0.001, HR 0.532; OS: p < 0.001, HR 0.574 vs. PFS: p = 0.107; OS: p = 0.965). Conclusions Initial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.
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Affiliation(s)
- Annika Kurreck
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Tumor Immunology Charité Virchow Klinikum (CVK), Berlin, Germany
| | - Volker Heinemann
- Department of Medicine III, University Hospital, Ludwig-Maximilians-Universität (LMU) Munich, München, Germany
- German Cancer Consortium (DKTK), Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | | | | | | | | | - Michael Schenk
- Department of Hematology and Oncology, Clinic “Barmherzige Brüder Regensburg”, Regensburg, Germany
| | | | - Bettina Peuser
- Oncological Practice am Diakonissenhaus, Leipzig, Germany
| | - Claudio Denzlinger
- Department of Internal Medicine III (Oncology, Hematology, Palliative Care) Marienhospital, Stuttgart, Germany
| | - Ullrich Graeven
- Department of Hematology, Oncology, and Gastroenterology, Kliniken Maria Hilf GmbH, Mönchengladbach, Germany
| | - Kathrin Heinrich
- Department of Medicine III, University Hospital, Ludwig-Maximilians-Universität (LMU) Munich, München, Germany
| | | | - Arndt Stahler
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Tumor Immunology Campus Charité Mitte (CCM), Berlin, Germany
| | - Annabel Helga Sophie Alig
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Tumor Immunology Campus Charité Mitte (CCM), Berlin, Germany
| | - Ivan Jelas
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Tumor Immunology Charité Virchow Klinikum (CVK), Berlin, Germany
| | - Jobst C. von Einem
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Tumor Immunology Campus Charité Mitte (CCM), Berlin, Germany
| | - Sebastian Stintzing
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Tumor Immunology Campus Charité Mitte (CCM), Berlin, Germany
| | - Clemens Giessen-Jung
- Department of Medicine III, University Hospital, Ludwig-Maximilians-Universität (LMU) Munich, München, Germany
| | - Dominik P. Modest
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Tumor Immunology Charité Virchow Klinikum (CVK), Berlin, Germany
- *Correspondence: Dominik P. Modest, ;
orcid.org/0000-0002-6853-0599
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Fujitani K, Shitara K, Takashima A, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Kimura Y, Amagai K, Hosaka H, Komatsu Y, Shimada K, Kawabata R, Ohdan H, Kodera Y, Nakamura M, Nakajima TE, Miyata Y, Moriwaki T, Kusumoto T, Nishikawa K, Ogata K, Shimura M, Morita S, Koizumi W. Effect of early tumor response on the health-related quality of life among patients on second-line chemotherapy for advanced gastric cancer in the ABSOLUTE trial. Gastric Cancer 2021; 24:467-476. [PMID: 33136231 PMCID: PMC7902565 DOI: 10.1007/s10120-020-01131-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 10/07/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND This study evaluated the association between early tumor response at 8 weeks, previously reported as a positive outcome prognosticator, and health-related quality of life (HRQOL) in advanced gastric cancer (AGC) patients enrolled in the ABSOLUTE trial. METHODS HRQOL was assessed using the EuroQol-5 Dimension (EQ-5D) utility index score in patients with complete response (CR) + partial response (PR) and progressive disease (PD) at 8 weeks, and time-to-deterioration (TtD) of the EQ-5D score, with the preset minimally important difference (MID) of 0.05, was compared between these populations. Among the enrolled patients, 143 and 160 patients were assessable in weekly solvent-based paclitaxel (Sb-PTX) arm and weekly nanoparticle albumin-bound paclitaxel (nab-PTX) arm, respectively. RESULTS Changes of the EQ-5D score from baseline to 8 weeks in the nab-PTX arm were 0.0009 and - 0.1229 in CR + PR and PD patients, respectively; the corresponding values for the Sb-PTX arm were - 0.0019 and - 0.1549. For both treatments, changes of the EQ-5D score from baseline at 8 weeks were significantly larger in patients with PD than in those with CR + PR. The median TtD was 3.9 and 2.2 months in patients with CR + PR and PD, respectively, for nab-PTX [hazard ratio (HR) = 0.595, 95% confidence interval (CI) 0.358-0.989]. For Sb-PTX, the corresponding values were 4.7 and 2.0 months (HR = 0.494, 95% CI 0.291-0.841). CONCLUSIONS Early tumor shrinkage was associated with maintained HRQOL in AGC patients on the second-line chemotherapy with taxanes.
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Affiliation(s)
- Kazumasa Fujitani
- Department of Surgery, Osaka General Medical Center, 3-1-56, Bandaihigashi, Sumiyoshi-ku, Osaka, 558-0056, Japan.
| | - Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Atsuo Takashima
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Keisuke Koeda
- Department of Medical Safety Science, Iwate Medical University, Morioka, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, Ina-machi, Japan
| | - Norisuke Nakayama
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Shuichi Hironaka
- Clinical Trial Promotion Department, Chiba Cancer Center, Chiba, Japan
- Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Oita, Japan
| | - Kazuhiro Nishikawa
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Yutaka Kimura
- Department of Surgery, Sakai City Medical Center, Sakai, Japan
| | - Kenji Amagai
- Department of Gastroenterology, Ibaraki Prefectural Central Hospital, Kasama, Japan
| | - Hisashi Hosaka
- Division of Gastroenterology, Gunma Prefectural Cancer Center, Ohta, Japan
| | - Yoshito Komatsu
- Division of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, Japan
| | - Ken Shimada
- Division of Medical Oncology, Department of Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama, Japan
| | | | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masato Nakamura
- Aizawa Comprehensive Cancer Center, Aizawa Hospital, Nagano, Japan
| | - Takako Eguchi Nakajima
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
- Kyoto Innovation Center for Next Generation Clinical Trials and iPS Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Yoshinori Miyata
- Department of Medical Oncology, Saku Central Hospital Advanced Care Center, Saku, Japan
| | - Toshikazu Moriwaki
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Tetsuya Kusumoto
- Department of Gastroenterological Surgery and Clinical Research Institute Cancer Research Division, National Kyushu Medical Center, Fukuoka, Japan
| | - Kazuo Nishikawa
- Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Oita, Japan
| | - Kazuhiro Ogata
- Medical Affairs Department, Taiho Pharmaceutical Co., Ltd, Tokyo, Japan
| | - Masashi Shimura
- Data Science Department, Taiho Pharmaceutical Co., Ltd, Tokyo, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
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12
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Holch JW, Held S, Stintzing S, Fischer von Weikersthal L, Decker T, Kiani A, Kaiser F, Heintges T, Kahl C, Kullmann F, Scheithauer W, Moehler M, von Einem JC, Michl M, Heinemann V. Relation of cetuximab-induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients: results of the randomized phase 3 trial FIRE-3 (AIO KRK0306). Ann Oncol 2021; 31:72-78. [PMID: 31912799 DOI: 10.1016/j.annonc.2019.10.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/01/2019] [Accepted: 10/02/2019] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Cetuximab-induced skin toxicity (Cet-ST) is positively associated with outcome in metastatic colorectal cancer (mCRC). Besides its predictive relevance for targeted therapy, we investigated its prognostic impact with early tumor shrinkage (ETS) ≥20%, another on-treatment surrogate for clinical outcome in FIRE-3. PATIENTS AND METHODS FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumors (i.e. wild-type in KRAS and NRAS exons 2-4). Retrospective data on Cet-ST that occurred during cycles 1-3 of treatment were correlated with efficacy endpoints, including ETS. To control for guarantee-time bias, only patients who had completed three or more treatment cycles were considered. RESULTS Of 199 patients treated with FOLFIRI/Cet, 181 (91.0%) completed three or more treatment cycles. A significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was only evident in patients developing Cet-ST grade 2-3 [41.0 versus 26.6 months; hazard ratio (HR) = 0.73; 95% confidence interval (CI): 0.61-0.87; P < 0.001] compared with Cet-ST grade 0-1 (HR = 0.90; 95% CI: 0.67-1.20; P = 0.48). Regarding prognosis, Cet-ST grade 2-3 (n = 75; 41.4%), compared with Cet-ST grade 0-1 (n = 106; 58.6%), was associated with prolonged overall survival (OS; HR = 0.62; 95% CI: 0.42-0.91; P = 0.01). In multivariate analysis, both Cet-ST (HR = 0.66; 95% CI: 0.50-0.87; P = 0.003) and ETS (HR = 0.55; 95% CI: 0.41-0.74; P < 0.0001) were independently prognostic for OS. Absence of both Cet-ST grade ≥2 and ETS identified a subgroup of patients with very poor prognosis (median OS 15.1 months). CONCLUSIONS In FIRE-3, the addition of cetuximab to FOLFIRI was associated with superior OS compared with FOLFIRI/Bev only in patients developing Cet-ST grade ≥2. Regarding prognostic relevance, both Cet-ST and ETS were independent and early predictors of survival. The present analysis supports that a combined evaluation of on-treatment parameters such as Cet-ST and ETS may help to guide treatment of mCRC.
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Affiliation(s)
- J W Holch
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany; Comprehensive Cancer Center Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany.
| | - S Held
- ClinAssess GmbH, Leverkusen, Germany
| | - S Stintzing
- Medical Department, Division of Hematology, Oncology and Tumor Immunology (CCM), Charité Universitaetsmedizin Berlin, Berlin, Germany
| | | | - T Decker
- Onkologie Ravensburg, Ravensburg, Germany
| | - A Kiani
- Department of Medicine IV, Klinikum Bayreuth GmbH, Bayreuth, Germany
| | - F Kaiser
- Hämato-onkologische Tagesklinik, Landshut, Germany
| | - T Heintges
- Department of Medicine II, Lukaskrankenhaus, Neuss, Germany
| | - C Kahl
- Department of Hematology, Oncology and Palliative Care, Klinikum Magdeburg gGmbH, Magdeburg, Germany
| | - F Kullmann
- Department of Internal Medicine I, Klinikum Weiden, Weiden, Germany
| | - W Scheithauer
- Department of Internal Medicine I & CCC, Medical University Vienna, Vienna, Austria
| | - M Moehler
- University Medical Center Mainz, I. Department of Internal Medicine, Mainz, Germany
| | - J C von Einem
- Medical Department, Division of Hematology, Oncology and Tumor Immunology (CCM), Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - M Michl
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany; Comprehensive Cancer Center Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - V Heinemann
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany; Comprehensive Cancer Center Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany
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13
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Izawa N, Shitara K, Yonesaka K, Yamanaka T, Yoshino T, Sunakawa Y, Masuishi T, Denda T, Yamazaki K, Moriwaki T, Okuda H, Kondoh C, Nishina T, Makiyama A, Baba H, Yamaguchi H, Nakamura M, Hyodo I, Muro K, Nakajima TE. Early Tumor Shrinkage and Depth of Response in the Second-Line Treatment for KRAS exon2 Wild-Type Metastatic Colorectal Cancer: An Exploratory Analysis of the Randomized Phase 2 Trial Comparing Panitumumab and Bevacizumab in Combination with FOLFIRI (WJOG6210G). Target Oncol 2020; 15:623-633. [PMID: 32960408 DOI: 10.1007/s11523-020-00750-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Predictive markers for the clinical outcomes of second-line treatment in patients with metastatic colorectal cancer (mCRC) remain unclear. OBJECTIVE This retrospective biomarker study was conducted to explore predictive markers for patients with KRAS exon 2 wild-type mCRC who were treated with FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev) in the WJOG6210G trial. PATIENTS AND METHODS The associations of early tumor shrinkage (ETS), tumor location, and VEGF-D with progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox proportional hazards model. Spearman's correlation coefficient was used to analyze the association of depth of response (DpR) with PFS and OS. Serum VEGF-D levels were measured in samples collected before treatment using magnetic bead panel Milliplex xMAP kits. RESULTS In total, 101 patients (Pani, n = 49; Bev, n = 52) were enrolled in this study. Patients with ETS had longer PFS (Pani: hazard ratio (HR) 0.40, P = 0.009; Bev: HR 0.078, P = 0.0002) and OS (Pani: HR 0.49, P = 0.044; Bev: HR 0.35, P = 0.048) than patients without ETS. The DpR was moderately correlated with PFS and OS in Pani (rs = 0.75, P < 0.001; rs = 0.60, P < 0.001) and Bev groups (rs = 0.68, P < 0.001; rs = 0.44, P = 0.002). No significant differences were observed in PFS and OS between the two treatment groups even if in left-sided tumors. No significant interaction between VEGF-D levels and treatment was observed in PFS and OS. CONCLUSIONS ETS and DpR serve as surrogate markers of PFS and OS in the second-line treatment with FOLFIRI plus targeted agent for mCRC.
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Affiliation(s)
- Naoki Izawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kimio Yonesaka
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Toshiki Masuishi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Tadamichi Denda
- Department of Gastroenterology, Chiba Cancer Center Hospital, Chiba, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shimonagakubo, Japan
| | - Toshikazu Moriwaki
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Hiroyuki Okuda
- Department of Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan
| | - Chihiro Kondoh
- Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Akitaka Makiyama
- Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kita-Kyushu, Japan
- Cancer Center, Gifu University Hospital, Gifu, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hironori Yamaguchi
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Masato Nakamura
- Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan
| | - Ichinosuke Hyodo
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Takako Eguchi Nakajima
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
- Kyoto Innovation Center for Next Generation Clinical Trials and iPS Cell Therapy (Ki-CONNECT), Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
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14
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Kurreck A, Geissler M, Martens UM, Riera-Knorrenschild J, Greeve J, Florschütz A, Wessendorf S, Ettrich T, Kanzler S, Nörenberg D, Seidensticker M, Held S, Buechner-Steudel P, Atzpodien J, Heinemann V, Stintzing S, Seufferlein T, Tannapfel A, Reinacher-Schick AC, Modest DP. Dynamics in treatment response and disease progression of metastatic colorectal cancer (mCRC) patients with focus on BRAF status and primary tumor location: analysis of untreated RAS-wild-type mCRC patients receiving FOLFOXIRI either with or without panitumumab in the VOLFI trial (AIO KRK0109). J Cancer Res Clin Oncol 2020; 146:2681-2691. [PMID: 32449003 PMCID: PMC7467910 DOI: 10.1007/s00432-020-03257-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 05/12/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints. METHODS We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively. RESULTS BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (- 57.6% vs. - 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1-4.4) vs. 3.9 (95% CI 2.5-5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9-8.0) versus 2.6 (95% CI 1.2-4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11-0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0-41.3) vs. 5.4 (95% CI 5.0-5.9) months; HR 0.27 (95% CI 0.13-0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site. CONCLUSIONS BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.
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Affiliation(s)
- A Kurreck
- Department of Hematology, Oncology, and Tumor Immunology (CVK/CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | | | - U M Martens
- Klinik für Innere Medizin III, SLK-Kliniken Heilbronn, Heilbronn, Germany
| | | | - J Greeve
- St. Vincenz-Krankenhaus Paderborn, Paderborn, Germany
| | | | | | - T Ettrich
- Universitätsklinikum Ulm, Ulm, Germany
| | - S Kanzler
- Leopoldina Krankenhaus, Schweinfurt, Germany
| | - D Nörenberg
- Medical Faculty Mannheim, Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
| | - M Seidensticker
- Klinik Und Poliklinik für Radiologie, LMU Klinikum, München, Germany
| | - S Held
- ClinAssess, Leverkusen, Germany
| | | | - J Atzpodien
- Franziskus-Hospital Harderberg, Georgsmarienhütte, Germany
| | - V Heinemann
- Department of Medicine III and Comprehensive Cancer Center, University Hospital Munich (LMU), Munich, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany
| | - S Stintzing
- Department of Hematology, Oncology, and Tumor Immunology (CVK/CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | | | - A Tannapfel
- Institute of Pathology, Ruhr-University Bochum, Bochum, Germany
| | - A C Reinacher-Schick
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany
| | - D P Modest
- Department of Hematology, Oncology, and Tumor Immunology (CVK/CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
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Aykan NF, Özatlı T. Objective response rate assessment in oncology: Current situation and future expectations. World J Clin Oncol 2020; 11:53-73. [PMID: 32133275 PMCID: PMC7046919 DOI: 10.5306/wjco.v11.i2.53] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 11/05/2019] [Accepted: 11/28/2019] [Indexed: 02/06/2023] Open
Abstract
The tumor objective response rate (ORR) is an important parameter to demonstrate the efficacy of a treatment in oncology. The ORR is valuable for clinical decision making in routine practice and a significant end-point for reporting the results of clinical trials. World Health Organization and Response Evaluation Criteria in Solid Tumors (RECIST) are anatomic response criteria developed mainly for cytotoxic chemotherapy. These criteria are based on the visual assessment of tumor size in morphological images provided by computed tomography (CT) or magnetic resonance imaging. Anatomic response criteria may not be optimal for biologic agents, some disease sites, and some regional therapies. Consequently, modifications of RECIST, Choi criteria and Morphologic response criteria were developed based on the concept of the evaluation of viable tumors. Despite its limitations, RECIST v1.1 is validated in prospective studies, is widely accepted by regulatory agencies and has recently shown good performance for targeted cancer agents. Finally, some alternatives of RECIST were developed as immune-specific response criteria for checkpoint inhibitors. Immune RECIST criteria are based essentially on defining true progressive disease after a confirmatory imaging. Some graphical methods may be useful to show longitudinal change in the tumor burden over time. Tumor tissue is a tridimensional heterogenous mass, and tumor shrinkage is not always symmetrical; thus, metabolic response assessments using positron emission tomography (PET) or PET/CT may reflect the viability of cancer cells or functional changes evolving after anticancer treatments. The metabolic response can show the benefit of a treatment earlier than anatomic shrinkage, possibly preventing delays in drug approval. Computer-assisted automated volumetric assessments, quantitative multimodality imaging in radiology, new tracers in nuclear medicine and finally artificial intelligence have great potential in future evaluations.
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Affiliation(s)
- Nuri Faruk Aykan
- Department of Medical Oncology, Istinye University Medical School, Bahcesehir Liv Hospital, Istanbul 34510, Turkey
| | - Tahsin Özatlı
- Department of Medical Oncology, Istinye University Medical School, Bahcesehir Liv Hospital, Istanbul 34510, Turkey
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16
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Relationship Between Tumor Response and Tumor-Related Symptoms in RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses From 3 Panitumumab Trials. Clin Colorectal Cancer 2019; 18:245-256.e5. [DOI: 10.1016/j.clcc.2019.07.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/18/2019] [Accepted: 07/22/2019] [Indexed: 12/24/2022]
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17
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Colloca GA, Venturino A, Guarneri D. Analysis of response-related endpoints in trials of first-line medical treatment of metastatic colorectal cancer. Int J Clin Oncol 2019; 24:1406-1411. [PMID: 31289956 DOI: 10.1007/s10147-019-01504-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 06/30/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Tumor radiologic response after systemic chemotherapy has been used as endpoint of trials of patients with metastatic colorectal cancer (mCRC), which can report the best overall response rate (ORR) and the disease control rate (DCR) by RECIST criteria as well as the early tumor shrinkage (ETS). The present study perform a trial-level analysis to verify whether such response-related endpoints are predictive of overall survival (OS). METHODS After a systematic search, randomized clinical trials (RCTs) were selected each time they evaluated the three response endpoints and progression-free survival (PFS). Two arms per trial were selected, and the correlation between the difference in each endpoint and the difference in OS was calculated. The analysis then evaluated the effects of treatment on ∆ORR, or ∆DCR, ∆ETS, ∆PFS, and on ∆OS, using separate linear regressions for each of them, and the proportion of variability explained (R2trial) on OS for each of the four endpoints was calculated. RESULTS The systematic review of the literature led to the selection of 12 RCTs, 7 phase-3 and 5 phase-2. ETS reported a different performance in the entire sample compared to phase-3 trials (R2trial = 0.172 vs. 0.842), differently from DCR (R2trial = 0.541 vs. 0.816) and ORR (R2trial = 0.349 vs. 0.740). Surprisingly, PFS predicted OS with a weak correlation, which was not significant in the subgroup of phase-3 studies (R2trial = 0.455 vs. 0.466). CONCLUSION The results of the present trial-level analysis report a good performance of two response-related endpoints, DCR and ETS, and suggest that they could be differently used depending on the setting of disease and the type of medical treatment.
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Affiliation(s)
- Giuseppe A Colloca
- Department of Oncology, Ospedale Civile di Sanremo, Via G. Borea n. 56, 18038, Sanremo, Imperia, Italy.
| | - Antonella Venturino
- Department of Oncology, Ospedale Civile di Sanremo, Via G. Borea n. 56, 18038, Sanremo, Imperia, Italy
| | - Domenico Guarneri
- Department of Oncology, Ospedale Civile di Sanremo, Via G. Borea n. 56, 18038, Sanremo, Imperia, Italy
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Chow FCL, Chok KSH. Colorectal liver metastases: An update on multidisciplinary approach. World J Hepatol 2019; 11:150-172. [PMID: 30820266 PMCID: PMC6393711 DOI: 10.4254/wjh.v11.i2.150] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/24/2018] [Accepted: 12/04/2018] [Indexed: 02/06/2023] Open
Abstract
Liver metastasis is the commonest form of distant metastasis in colorectal cancer. Selection criteria for surgery and liver-directed therapies have recently been extended. However, resectability remains poorly defined. Tumour biology is increasingly recognized as an important prognostic factor; hence molecular profiling has a growing role in risk stratification and management planning. Surgical resection is the only treatment modality for curative intent. The most appropriate surgical approach is yet to be established. The primary cancer and the hepatic metastasis can be removed simultaneously or in a two-step approach; these two strategies have comparable long-term outcomes. For patients with a limited future liver remnant, portal vein embolization, combined ablation and resection, and associating liver partition and portal vein ligation for staged hepatectomy have been advocated, and each has their pros and cons. The role of neoadjuvant and adjuvant chemotherapy is still debated. Targeted biological agents and loco-regional therapies (thermal ablation, intra-arterial chemo- or radio-embolization, and stereotactic radiotherapy) further improve the already favourable results. The recent debate about offering liver transplantation to highly selected patients needs validation from large clinical trials. Evidence-based protocols are missing, and therefore optimal management of hepatic metastasis should be personalized and determined by a multi-disciplinary team.
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Affiliation(s)
| | - Kenneth Siu-Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, the University of Hong Kong, Hong Kong, China.
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Chen D, Gu K, Wang H. Optimizing sequential treatment with anti-EGFR and VEGF mAb in metastatic colorectal cancer: current results and controversies. Cancer Manag Res 2019; 11:1705-1716. [PMID: 30863179 PMCID: PMC6388996 DOI: 10.2147/cmar.s196170] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Anti-EGFR mAb (cetuximab or panitumumab) and anti-VEGF mAb (bevacizumab) are the two main targeted agents available for RAS wild-type (WT) metastatic colorectal cancer (mCRC) treatment. Nonetheless, three head-to-head clinical trials evaluating anti-EGFR mAb vs -VEGF mAb in first-line treatment failed to conclude a uniform result. Recently, a few small clinical studies revealed that prior use of bevacizumab may impair the effect of cetuximab or panitumumab. Preclinical studies have also suggested that pretreatment with bevacizumab may lead to simultaneous resistance to anti-EGFR mAb. Therefore, we performed this review to summarize the available data regarding the optimal sequential treatment of anti-EGFR and -VEGF mAb for RAS or KRAS WT mCRC and discuss the potential mechanisms that may explain this phenomenon. Primary tumor location and early tumor shrinkage have emerged as new potential prognostic and predictive factors in mCRC. We also collected information to explore whether these factors affect the optimal sequencing of targeted therapy in mCRC. However, definite conclusions cannot be made, and we can only speculate on optimal treatment recommendations based on the contradictory results.
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Affiliation(s)
- Datian Chen
- Department of Oncology, Haimen People's Hospital, Haimen, People's Republic of China
| | - Kaikai Gu
- Haimen Hospital of Traditional Chinese Medicine, Haimen, People's Republic of China
| | - Huiyu Wang
- Wuxi People's Hospital Affiliatedto Nanjing Medical University, Wuxi, People's Republic of China,
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20
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Early tumor shrinkage after first-line medical treatment of metastatic colorectal cancer: a meta-analysis. Int J Clin Oncol 2019; 24:231-240. [PMID: 30719690 DOI: 10.1007/s10147-019-01405-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 01/23/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND Early tumor shrinkage (ETS) is a response-related endpoint of clinical trials of chemotherapy (CHT) of patients with metastatic colorectal cancer (mCRC). It identifies a dimensional reduction of tumor size by at least 20-30% after 6-8 weeks of CHT. METHODS A literature search of randomized trials of systemic treatment including CHT with or without antiangiogenics or anti-EGFR inhibitors in patients with mCRC has been conducted, and studies reporting the results of the relationship of ETS with overall survival (OS) and progression-free survival (PFS) were selected. RESULTS Twelve trials, including 3117 patients, have been included; all data were retrospective and only 72% of the enrolled patients have been evaluated for ETS. Two meta-analyses, each including 20 study cohorts from the selected 12 trials, reported a strong relationship of ETS with OS (HR 0.62; CIs 0.55-0.69) and of ETS with PFS (HR 0.66; CIs 0.60-0.73). However, both meta-analyses displayed a high level of heterogeneity. Among nine possible moderators, three variables (median age, surgery of metastases, and publication year) were able to explain at least a part of this heterogeneity. CONCLUSION ETS is a simple and interesting intermediate endpoint for clinical practice and future trials of medical treatments of patients with mCRC, but a large prospective analysis and validation are mandatory.
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21
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Zhou Y, Zhang J, Dan Pu, Bi F, Chen Y, Liu J, Li Q, Gou H, Wu B, Qiu M. Tumor calcification as a prognostic factor in cetuximab plus chemotherapy-treated patients with metastatic colorectal cancer. Anticancer Drugs 2019; 30:195-200. [PMID: 30570508 PMCID: PMC6365256 DOI: 10.1097/cad.0000000000000726] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 11/10/2018] [Indexed: 02/07/2023]
Abstract
This study aimed to explore the correlation between survival and tumor calcification in patients with metastatic colorectal cancer who received cetuximab combined with chemotherapy. The study was a single-center retrospective analysis that enrolled 111 patients who had received therapy between April 2011 and October 2016. Tumor calcification and treatment efficacy were evaluated independently by radiologists on the basis of computed tomography scans. Clinical characteristics and follow-up data were collected from electronic medical records. Correlations between tumor calcification and clinical characteristics, tumor response rate, and patient survival were analyzed. Among the 111 enrolled patients, 27 had tumor calcification [27/111 (24.3%)]. The median progression-free survival was significantly longer for patients with tumor calcification than for those without calcification (9.3 vs. 6.2 months, P=0.022). Patients with tumor calcification also had a higher objective response rate (55.6 vs. 31%, P=0.021) and better overall survival (21.9 vs. 16.5 months, P=0.084). The correlation between calcification features and prognosis showed that patients with an increasing number of calcifications after treatment had a significantly longer median overall survival (22.9 vs. 9.1 months, P=0.033). Simultaneously, new liver metastases and multiple calcifications also showed a trend toward better overall survival. There were also no significant correlations between clinical characteristics (sex, age, gene mutation, primary tumor location, pathological type, blood test result) and survival (Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/ACD/A280). Tumor calcification is associated with a better treatment outcome and is a potential prognostic marker.
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Affiliation(s)
- Yuwen Zhou
- Department of Medical Oncology, Cancer Center
| | | | - Dan Pu
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Feng Bi
- Department of Medical Oncology, Cancer Center
| | - Ye Chen
- Department of Medical Oncology, Cancer Center
| | - Jiyan Liu
- Department of Medical Oncology, Cancer Center
| | - Qiu Li
- Department of Medical Oncology, Cancer Center
| | | | | | - Meng Qiu
- Department of Medical Oncology, Cancer Center
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22
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Tumor-size responses to first-line is a predictor of overall survival in metastatic colorectal cancer. Eur Radiol 2019; 29:3871-3880. [PMID: 30706121 DOI: 10.1007/s00330-018-5967-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 12/03/2018] [Accepted: 12/12/2018] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Early tumor shrinkage (ETS) has been reported to be associated with survival of metastatic colorectal cancer (mCRC) patients. Our aim was to analyze long-term tumor-size evolution, according to early mCRC best responses during the first-line therapy, to evaluate first best response-survival links. METHODS Sixty-five patients with unresectable mCRCs, treated between 2010 and 2015, were included retrospectively in this descriptive monocenter study and grouped according to their RECIST 1.1 first-line best responses: progressive disease (PDfl), stable disease with tumor-size evolution between 0 and + 19% (SDfl+) or 0 and - 29% (SDfl-), and partial responders (PRs), who were classed PR with ETS (ETSfl) or without (PRfl). Tumor-size evolution and best tumor responses to each chemotherapy line were analyzed. RESULTS Tumor loads of ETSfl or PRfl mCRCs tended to remain inferior to their initial values: 60% of patients died with target lesion sums below baseline. For first-line SDfl+ or PDfl mCRCs, rapid tumor load increases continued during successive lines: > 80% died with target lesion sums above baseline. ETSfl mCRCs responded better to subsequent lines (37.5% second-line PR), whereas PDfl mCRCs remained refractory to other therapies (0% second- and third-line PR). Overall survival rates were significantly (p = 0.03) longer for the ETSfl group (29.9 [95% CI: 12.6-47.1] months) and shorter for the PDfl group (17.1 [95% CI: 1.5-37.5] months). CONCLUSION Tumors responding to first-line chemotherapy also responded better to subsequent lines, whereas PDfl mCRCs remained refractory, which may explain the better survival associated with ETSfl. KEY POINTS • Early shrinking tumors under first-line chemotherapy responded better to subsequent lines, maintaining low tumor loads, potentially explaining the link between early tumor shrinkage and overall survival of metastatic colorectal cancer (mCRC) patients. • mCRCs progressing under first-line chemotherapy remained refractory to other therapies and their tumor loads increased rapidly. • Even outside a clinical trial, an early first CT scan reevaluation with RECIST criteria 8 weeks after starting first-line therapy is crucial to determine long-term mCRC evolution.
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Nishina T, Azuma M, Nishikawa K, Gotoh M, Bando H, Sugimoto N, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Mitome T, Kageyama H, Hyodo I. Early tumor shrinkage and depth of response in patients with advanced gastric cancer: a retrospective analysis of a randomized phase III study of first-line S-1 plus oxaliplatin vs. S-1 plus cisplatin. Gastric Cancer 2019; 22:138-146. [PMID: 29948386 DOI: 10.1007/s10120-018-0845-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 06/01/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND We investigated early tumor shrinkage (ETS) and depth of response (DpR) using data from the G-SOX study comparing S-1 plus oxaliplatin with S-1 plus cisplatin as the first-line treatment for advanced gastric cancer (AGC). METHODS ETS was determined as % decrease in the sum of the longest diameters of the target lesions at the first evaluation of week 6 compared to baseline. DpR was the maximum % shrinkage during the study treatment. The impact of ETS (cutoff value 20%) and DpR (continuous value) on progression-free survival (PFS) and overall survival (OS) were assessed by the log-rank test and Cox regression analysis including prognostic factors obtained in the G-SOX study; ECOG performance status, baseline sum of tumor diameters, disease status (recurrent/unresectable), and histology (diffuse/intestinal). RESULTS Among 685 patients enrolled in the G-SOX study, 632 patients who had the first tumor evaluation were analyzed. Patients with ETS ≥ 20% had longer PFS (median 4.5 vs. 2.8 months, p < 0.0001) and OS (median 14.8 vs. 10.5 months, p < 0.0001) than those with ETS < 20%. Adjusted hazard ratios of ETS < 20 vs. ≥ 20% were 0.606 (95% confidence interval (CI) 0.506-0.725) for PFS and 0.589 (95% CI 0.492-0.704) for OS. DpR was also significantly associated with PFS and OS (both p < 0.0001). These results were similar between the SOX and CS groups. CONCLUSIONS In AGC patients receiving the first-line therapy, ETS and DpR might be predictors for PFS and OS.
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Affiliation(s)
- Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemotomachi, Matsuyama, 791-0280, Japan.
| | - Mizutomo Azuma
- Department of Gastroenterology, Kitasato University East Hospital, 2-1-1 Asamizodai, Minami-ku, Sagamihara, 252-0380, Japan
| | - Kazuhiro Nishikawa
- Department of Surgery, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan
| | - Masahiro Gotoh
- Cancer Chemotherapy Center, Osaka Medical College Hospital, 2-7 Daigakumachi, Takatsuki, 569-8686, Japan
| | - Hideaki Bando
- Division of Gastrointestinal Oncology and Digestive Endoscopy, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, 277-0882, Japan
| | - Naotoshi Sugimoto
- Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511, Japan
| | - Kenji Amagai
- Department of Gastroenterology, Ibaraki Prefectural Central Hospital, 6528 Koibuchi, Kasama, 309-1703, Japan
| | - Keisho Chin
- Department of Gastroenterology, Cancer Institute Hospital of JFCR, 3-8-31 Ariake, Tokyo, 135-8550, Japan
| | - Yasumasa Niwa
- Department of Endoscopy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
| | - Akihito Tsuji
- Department of Medical Oncology, Kochi Health Sciences Center, 2125-1 Ike, Kochi, 781-8555, Japan
| | - Hiroshi Imamura
- Department of Surgery, Sakai City Hospital, 1-1-1 Minamiyasui-cho, Sakai, 590-0064, Japan
| | - Masahiro Tsuda
- Department of Gastroenterological Oncology, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi, 673-8558, Japan
| | - Hirofumi Yasui
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Nagaizumi-cho, Shimonagakubo, Sunto-gun, 411-8777, Japan
| | - Hirofumi Fujii
- Department of Clinical Oncology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, 329-0498, Japan
| | - Kensei Yamaguchi
- Division of Gastroenterology, Saitama Cancer Center, 780 Inamachi Oaza Komuro, Kita-adachi-gun, 362-0806, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusamukaihata-cho, Fushimi-ku, Kyoto, 612-0861, Japan
| | - Shuichi Hironaka
- Clinical Trial Promotion Department, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan
| | - Ken Shimada
- Department of Internal Medicine, Showa University Northern Yokohama Hospital, Chigasakichuo, Tsuzuki-ku, Yokohama, 224-0032, Japan
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, 663-8131, Japan
| | - Terukazu Mitome
- Pharmaceutical Research and Development Department, Yakult Honsha Co., Ltd., 16-21 Ginza 7-chome, Chuo-ku, Tokyo, 104-0061, Japan
| | - Hiroki Kageyama
- Pharmaceutical Research and Development Department, Yakult Honsha Co., Ltd., 16-21 Ginza 7-chome, Chuo-ku, Tokyo, 104-0061, Japan
| | - Ichinosuke Hyodo
- Division of Gastroenterology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan
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Additional Biomarkers beyond RAS That Impact the Efficacy of Cetuximab plus Chemotherapy in mCRC: A Retrospective Biomarker Analysis. JOURNAL OF ONCOLOGY 2018; 2018:5072987. [PMID: 30305811 PMCID: PMC6165607 DOI: 10.1155/2018/5072987] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Revised: 06/17/2018] [Accepted: 06/27/2018] [Indexed: 12/22/2022]
Abstract
Purpose We aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). Methods The study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next-generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort. Results Thirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed. Conclusions In the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations.
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Reck M, Mellemgaard A, Novello S, Postmus PE, Gaschler-Markefski B, Kaiser R, Buchner H. Change in non-small-cell lung cancer tumor size in patients treated with nintedanib plus docetaxel: analyses from the Phase III LUME-Lung 1 study. Onco Targets Ther 2018; 11:4573-4582. [PMID: 30122949 PMCID: PMC6084077 DOI: 10.2147/ott.s170722] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Nintedanib in combination with docetaxel is approved in the European Union and other countries for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) of adenocarcinoma histology after first-line chemotherapy, based on the overall survival findings of Phase III LUME-Lung 1 study. Change in target lesion size over time as a treatment effect was assessed in patients from this study. Methods Tumor size was evaluated using predefined tumor measurements. Mixed-effects models were used to quantify individual relationships between time from randomization and tumor burden, measured as the sum of longest diameter (SLD) of target lesions and assessed by an independent review (Response Evaluation Criteria In Solid Tumors [RECIST] v1.0). Exploratory analyses were conducted on the overall adenocarcinoma population, adenocarcinoma patients with time from start of first-line therapy <9 months (TSFLT <9), adenocarcinoma patients who had progressive disease as best response to first-line therapy (PD-FLT), and in squamous cell carcinoma patients. Results Estimated mean baseline SLD was 82.5 mm in the adenocarcinoma (n=658), 88.3 mm in the TSFLT <9 (n=405), 98.1 mm in the PD-FLT (n=117), and 94.3 mm in the squamous cell carcinoma (n=555) populations. Treatment with nintedanib/docetaxel showed a significant reduction in tumor size over time (P<0.0001) in patients with adenocarcinoma compared with placebo/docetaxel, and in patients with squamous cell carcinoma (P=0.0049). Treatment difference at 6 months was 9.7 mm in the overall adenocarcinoma population, 16.8 mm in the TSFLT <9 population, 19.7 mm in the PD-FLT population, and 6.8 mm in the squamous cell carcinoma population. SLD at 2 months post-randomization was identified as a surrogate endpoint for overall survival, in addition to progression-free survival, for all except the PD-FLT population. Conclusion Treatment with nintedanib/docetaxel significantly decreased tumor burden and decelerated tumor size over time compared with placebo/docetaxel in the overall adenocar-cinoma population, including in patients with the poorest prognosis due to aggressive tumor dynamics.
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Affiliation(s)
- Martin Reck
- Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany,
| | - Anders Mellemgaard
- Department of Internal Medicine and Oncology, Bornholms Hospital, Ronne, Denmark
| | - Silvia Novello
- Department of Oncology, University of Turin, S. Luigi Hospital, Torino, Italy
| | | | | | - Rolf Kaiser
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.,Institute of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
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Mazard T, Boonsirikamchai P, Overman MJ, Asran MA, Choi H, Herron D, Eng C, Maru DM, Ychou M, Vauthey JN, Loyer EM, Kopetz S. Comparison of early radiological predictors of outcome in patients with colorectal cancer with unresectable hepatic metastases treated with bevacizumab. Gut 2018; 67:1095-1102. [PMID: 29084828 PMCID: PMC10109500 DOI: 10.1136/gutjnl-2017-313786] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 09/27/2017] [Accepted: 09/28/2017] [Indexed: 01/17/2023]
Abstract
OBJECTIVE The purpose was to validate the prognostic value of an early optimal morphological response on CT in patients treated with bevacizumab-containing chemotherapy for unresectable colorectal cancer liver metastases (CLM). It also evaluated the prognostic value of size-based criteria and the association of optimal morphological response with the receipt of bevacizumab. DESIGN 141 patients treated first using bevacizumab and 142 patients from a randomised study evaluating the addition of bevacizumab to oxaliplatin-based chemotherapy were retrospectively analysed. Radiologists evaluated pretreatment and restaging CT scans using morphological response criteria. Responses were also assessed with size-based criteria: Response Evaluation Criteria in Solid Tumors (RECIST), early tumour shrinkage (ETS) and deepness of response (DpR). The ability of each criterion to predict progression-free survival (PFS), overall survival (OS) and postprogression survival (PPS) was determined using a univariate Cox proportional hazards model. RESULTS In both populations, median PFS was significantly longer for patients achieving an optimal morphological response (10.4 vs 6.8 months, p=0.03; and 8.3 vs 4.9 months, p<00001, respectively). Neither RECIST nor ETS responses were associated with a prolonged PFS. Median OS was longer for those with an optimal morphological response but only at second restaging in the first population (n=141, 20.8 vs 12.3 months, p=0.002). DpR but not optimal morphological response was associated with PPS. In the randomised study, an optimal morphological response was 6.2 times more likely among patients receiving bevacizumab (p<0.0001). CONCLUSION In patients with unresectable CLM, early morphological response may be a better predictor of PFS than size-based response. The addition of bevacizumab improves morphological response rate.
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Affiliation(s)
- Thibault Mazard
- Department of Digestive Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Piyaporn Boonsirikamchai
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Michael J Overman
- Department of Digestive Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mohamed A Asran
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Haesun Choi
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Delise Herron
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Cathy Eng
- Department of Digestive Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Dipen M Maru
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Marc Ychou
- Department of Oncology, ICM-Vald'Aurelle Cancer Center, Montpellier, France
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Evelyne M Loyer
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Scott Kopetz
- Department of Digestive Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Lee CK, Kim SS, Park S, Kim C, Heo SJ, Lim JS, Kim H, Kim HS, Rha SY, Chung HC, Park S, Jung M. Depth of response is a significant predictor for long-term outcome in advanced gastric cancer patients treated with trastuzumab. Oncotarget 2018; 8:31169-31179. [PMID: 28415714 PMCID: PMC5458198 DOI: 10.18632/oncotarget.16099] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/01/2017] [Indexed: 12/22/2022] Open
Abstract
Purpose We aimed to determine and compare the predictive values of depth of response (DpR) and early tumor shrinkage (ETS) on long-term outcomes in gastric cancer patients treated with trastuzumab. Results From a total of 368 computed tomography examinations, DpR and ETS were evaluated. DpR was a significant tumor-size metric in predicting PFS and OS, and showed better discriminatory ability (higher Cτ indices, 0.6957 for PFS; 0.7191 for OS) than ETS. DpR ≥ 45% (vs. < 45%) was the optimal cutoff value, as it was best able to identify patients with longer PFS (median 9.0 vs. 6.3 months, hazard ratio [HR] = 0.608; 95% confidence interval [CI]: 0.335 to 1.104; P = 0.102) and OS (median 23.5 vs. 13.1 months, HR = 0.441; 95% CI: 0.203 to 0.955; P = 0.038). Materials and Methods Sixty-one gastric cancer patients who received first-line trastuzumab-based chemotherapy were assessed for DpR and ETS. We employed Kaplan-Meier estimates, log-rank tests, Cox proportional hazards regression models, time-dependent receiver operating characteristics, and Youden's J index to evaluate and determine cutoff values of DpR and ETS as predictors of progression-free survival (PFS) and overall survival (OS). Conclusions DpR and ETS were significant predictors of long-term outcomes in gastric cancer patients treated with first-line trastuzumab. Validation in prospective trials with larger patient populations is needed.
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Affiliation(s)
- Choong-Kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University, College of Medicine, Seoul, Korea
| | - Seung-Seob Kim
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - Saemi Park
- Department of Biostatistics, Graduate School of Public Health, Yonsei University, Seoul, Korea
| | - Chan Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University, College of Medicine, Seoul, Korea
| | - Su Jin Heo
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University, College of Medicine, Seoul, Korea
| | - Joon Seok Lim
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyo Song Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University, College of Medicine, Seoul, Korea
| | - Sun Young Rha
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University, College of Medicine, Seoul, Korea
| | - Hyun Cheol Chung
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University, College of Medicine, Seoul, Korea
| | - Sohee Park
- Department of Biostatistics, Graduate School of Public Health, Yonsei University, Seoul, Korea
| | - Minkyu Jung
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University, College of Medicine, Seoul, Korea
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Feng Q, Wei Y, Ren L, Zheng P, Yu Y, Ye Q, Ding J, Chen J, Chang W, Zhong Y, Zhu D, Lin Q, Yang L, Qin X, Xu J. Efficacy of continued cetuximab for unresectable metastatic colorectal cancer after disease progression during first-line cetuximab-based chemotherapy: a retrospective cohort study. Oncotarget 2017; 7:11380-96. [PMID: 26863631 PMCID: PMC4905480 DOI: 10.18632/oncotarget.7193] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 01/23/2016] [Indexed: 12/22/2022] Open
Abstract
This study assessed second-line continued use of cetuximab for treatment of unresectable metastatic colorectal cancer (mCRC) after disease progression during first-line cetuximab-based therapy. Consecutive patients with wild-type KRAS exon 2 and unresectable mCRC were retrospectively enrolled after disease progression during first-line cetuximab-based chemotherapy. Second-line continued cetuximab plus changed chemotherapy (cetuximab continuation group, n = 102) was compared with changed chemotherapy only (chemotherapy only group, n = 96) with respect to treatment efficacy and safety endpoints. NRAS and other KRAS genotypes were also detected as a post hoc analysis. The cetuximab continuation group showed better progression-free survival (median, 6.3 vs. 4.5 months, P = 0.004), overall survival (median, 17.3 vs. 14.0 months, P < 0.001) and disease control rate (70.6% vs. 53.1%, P = 0.011), and a potentially better overall response rate (18.6% vs. 9.4%, P = 0.062) than the chemotherapy only group. These benefits were seen mainly in patients with all RAS wild-type and exhibiting first-line early tumor shrinkage (ETS). For patients with other RAS mutations or who did not achieve first-line ETS, there was no difference between the two groups. These findings suggest that for patients with all RAS wild-type and unresectable mCRC who had disease progression during first-line cetuximab-based treatment, second-line continued cetuximab is effective. Moreover, ETS during first-line cetuximab-based treatment may be predictive of the efficacy of second-line continued cetuximab.
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Affiliation(s)
- Qingyang Feng
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ye Wei
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li Ren
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Peng Zheng
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qinghai Ye
- Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jianyong Ding
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jingwen Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenju Chang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunshi Zhong
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dexiang Zhu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qi Lin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liangliang Yang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xinyu Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jianmin Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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Sakamaki K, Kito Y, Yamazaki K, Izawa N, Tsuda T, Morita S, Boku N. Exploration of time points and cut-off values for early tumour shrinkage to predict survival outcomes of patients with metastatic colorectal cancer treated with first-line chemotherapy using a biexponential model for change in tumour size. ESMO Open 2017; 2:e000275. [PMID: 29177097 PMCID: PMC5687555 DOI: 10.1136/esmoopen-2017-000275] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Revised: 10/23/2017] [Accepted: 10/24/2017] [Indexed: 12/22/2022] Open
Abstract
Background Several studies reported that early tumour shrinkage (ETS) was associated with overall survival in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy. However, appropriate time point and cut-off value for ETS remain unclear because these varied in previous studies. Patients and methods We investigated patients with mCRC who received FOLFOX or FOLFIRI with/without molecular-targeted agents as first-line treatment between 2005 and 2014. Using a biexponential model for change in tumour size, a relative change in the sum of the longest diameters of target lesions from baseline was estimated at a certain time point in each individual patient. Associations of survival outcomes with ETS at various time points based on various cut-off values were evaluated by Cox regression analysis with a landmark approach. Results Among the 67 patients reviewed, the objective response rate was 73.1% (95% CI 62.5% to 83.7%), the median progression-free survival was 10.9 months (95% CI 8.7 to 13.0 months) and the median overall survival was 25.6 months (95% CI 20.1 to 27.3 months). The model for change in tumour size agreed with the actual measured sizes well. Multivariate Cox regression analysis, including performance status, number of metastatic sites and use of targeted agents, showed that ETS at 8 weeks based on a cut-off value of 20% was most significantly associated with overall survival (HR: 0.404, 95% CI 0.231 to 0.707, P=0.0015). Conclusion It is suggested that a time point of 8 weeks and a cut-off value of 20% may be optimal criteria for defining ETS.
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Affiliation(s)
- Kentaro Sakamaki
- Department of Biostatistics and Bioinformatics, The University of Tokyo, Tokyo, Japan
| | - Yosuke Kito
- Division of Gastrointestinal Oncology, Shizuoka Kenritsu Shizuoka Gan Center, Sunto-gun, Shizuoka, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Kenritsu Shizuoka Gan Center, Sunto-gun, Shizuoka, Japan
| | - Naoki Izawa
- Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Takashi Tsuda
- Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Narikazu Boku
- Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
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Exploratory analyses assessing the impact of early tumour shrinkage and depth of response on survival outcomes in patients with RAS wild-type metastatic colorectal cancer receiving treatment in three randomised panitumumab trials. J Cancer Res Clin Oncol 2017; 144:321-335. [PMID: 29080924 PMCID: PMC5794806 DOI: 10.1007/s00432-017-2534-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 10/13/2017] [Indexed: 12/28/2022]
Abstract
Purpose To report exploratory analyses of early tumour shrinkage (ETS) and depth of response (DpR) in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), receiving the first-line treatment in three randomised panitumumab trials.
Methods Data from the PRIME (NCT00364013), PEAK (NCT00819780) and PLANET (NCT00885885) studies were included. Median DpR, the proportion of patients achieving ETS ≥ 20% or ≥ 30% at week 8, and the impact of ETS and DpR (including by category) on outcome were analysed. Factors associated with ETS and DpR and the optimal ETS/DpR cut-off values for predicting improved overall survival (OS) were assessed. Results Overall, 505, 170 and 53 patients had RAS WT mCRC in PRIME, PEAK and PLANET, respectively. Patients receiving panitumumab had higher ETS rates (≥ 30%: PRIME 59% vs. 38%; PEAK 64% vs. 45%) and greater DpR (PRIME: 54% vs. 46%; PEAK: 65% vs. 46%) than those receiving treatment without panitumumab. In multiple regression analyses, panitumumab treatment, liver-only metastases and WT BRAF status were consistently associated with improved ETS and DpR outcomes. Irrespective of treatment, ETS and DpR were associated with improved progression-free survival, overall survival and resection rates; most resections occurred in patients in the two highest DpR categories. In PRIME and PEAK, respectively, the optimal cut-offs for predicting improved OS were 32 and 34% for ETS, and 59 and 70% for DpR. Conclusions These exploratory analyses suggest that panitumumab is associated ETS and DpR benefits in patients with RAS WT mCRC and that achieving these endpoints during first-line treatment is linked with favourable outcomes. Electronic supplementary material The online version of this article (doi:10.1007/s00432-017-2534-z) contains supplementary material, which is available to authorized users.
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Carrato A, Abad A, Massuti B, Grávalos C, Escudero P, Longo-Muñoz F, Manzano JL, Gómez A, Safont MJ, Gallego J, García-Paredes B, Pericay C, Dueñas R, Rivera F, Losa F, Valladares-Ayerbes M, González E, Aranda E. First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: A randomised, phase II trial (PLANET-TTD). Eur J Cancer 2017. [PMID: 28633089 DOI: 10.1016/j.ejca.2017.04.024] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND In first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations. METHODS Multicentre, open-label study in untreated patients ≥ 18 years with (WT)-KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI. The primary end-point was objective response rate (ORR). Secondary end-points included liver metastases resection rate (R0 + R1), progression-free survival (PFS), overall survival (OS), adverse events and perioperative safety. Exploratory end-points were: response by RAS status, early tumour shrinkage (ETS) and depth of response (DpR) in WT-RAS patients. RESULTS Data on 77 patients were analysed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI; WT-RAS: 27/26, respectively). ORR was 74% with Pmab-FOLFOX4 and 67% with Pmab-FOLFIRI (WT-RAS: 78%/73%). Out of the above, 45% and 59% underwent surgical resection, respectively (WT-RAS: 37%/69%). The R0-R1 resection rate was 34%/46% (WT-RAS:26%/54%). Median PFS was 13/14 months (hazard ratio [HR] Pmab-FOLFIRI versus Pmab-FOLFOX4: 0.9; 95% confidence interval: [0.6-1.5]; WT-RAS:13/15; HR: 0.7 [0.4-1.3]). Median OS was 37/41 months (HR:1.0 [0.6-1.8]; WT-RAS: 39/49; HR:0.9 [0.4-1.9]). In WT-RAS patients with confirmed response, median DpR was 71%/66%, and 65%/77% of patients showed ETS ≥ 30%/ ≥ 20% at week 8, without significant differences between arms; these patients had longer median PFS and OS and higher resectability rates. Surgery was associated with longer survival. Perioperative and overall safety were similar, except for higher grade 3/4 neutropenia (40%/10%; p = 0.003) and neuropathy (13%/0%; p = 0.025) in the Pmab-FOLFOX4 arm. CONCLUSIONS In patients with WT-KRAS mCRC and LLD, both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS, allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens. (clinicaltrials.gov:NCT00885885).
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Affiliation(s)
- Alfredo Carrato
- Ramon y Cajal University Hospital, Ramon y Cajal Institute for Health Research - IRYCIS, Alcala University, CIBERONC, Carretera de Colmenar Viejo, km 9.100, ES-28034 Madrid, Spain.
| | - Albert Abad
- Germans Trias i Pujol Hospital-ICO, Carretera de Canyet s/n, ES-08916 Badalona, Spain
| | - Bartomeu Massuti
- Alicante General Hospital, Pintor Baeza, 11, ES-03010 Alicante, Spain
| | - Cristina Grávalos
- Doce de Octubre Hospital, Avenida de Córdoba, s/n, ES-28041 Madrid, Spain
| | - Pilar Escudero
- Clínico Lozano Blesa Hospital, Avenida San Juan Bosco, 15, ES-50009 Zaragoza, Spain
| | - Federico Longo-Muñoz
- Ramon y Cajal University Hospital, Ramon y Cajal Institute for Health Research - IRYCIS, Alcala University, CIBERONC, Carretera de Colmenar Viejo, km 9.100, ES-28034 Madrid, Spain
| | - José-Luis Manzano
- Germans Trias i Pujol Hospital-ICO, Carretera de Canyet s/n, ES-08916 Badalona, Spain
| | - Auxiliadora Gómez
- Maimonides Institute of Biomedical Research, IMIBIC, Spain, Reina Sofía Hospital, University of Córdoba, Spanish Cancer Network, (RTICC), Instituto de Salud Carlos III, Avenida Menéndez Pidal, s/n, ES-14004, Córdoba, Spain
| | - María José Safont
- Valencia General Hospital, Avenida Tres Cruces, 2, ES-46014 Valencia, Spain
| | - Javier Gallego
- Elche General University Hospital, Camí de l'Almazara, 11, ES-03203 Alicante, Spain
| | - Beatriz García-Paredes
- San Carlos Hospital, Calle del Professor Martín Lagos, S/N, ES-28040 Madrid, Center affiliated to the Red Temática de Investigación Cooperativa, RD06/0020/0021, Spain, Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid, Spain
| | - Carles Pericay
- Sabadell Hospital, Corporación Sanitaria Parc Taulí, Parc del Taulí, 1, ES-08208 Sabadell, Spain
| | - Rosario Dueñas
- Jaén Hospital Complex, Av. del Ejército Español, 10, ES-23007 Jaén, Spain
| | - Fernando Rivera
- Marqués de Valdecilla Hospital, Av. de Valdecilla, s/n, ES-39008 Santander, Spain
| | - Ferrán Losa
- L´Hospitalet General Hospital, Av. Josep Molins, 29, ES-08906 L´Hospitalet de Llobregat, Spain
| | | | - Encarnación González
- Virgen de las Nieves Hospital, Av. de las Fuerzas Armadas, 2, ES-18014 Granada, Spain
| | - Enrique Aranda
- Maimonides Institute of Biomedical Research, IMIBIC, Spain, Reina Sofía Hospital, University of Córdoba, Spanish Cancer Network, (RTICC), Instituto de Salud Carlos III, Avenida Menéndez Pidal, s/n, ES-14004, Córdoba, Spain
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Modest DP, Stintzing S, Fischer von Weikersthal L, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Scheithauer W, Kirchner T, Jung A, Stauch M, von Einem JC, Moehler M, Held S, Heinemann V. Relation of early tumor shrinkage (ETS) observed in first-line treatment to efficacy parameters of subsequent treatment in FIRE-3 (AIOKRK0306). Int J Cancer 2017; 140:1918-1925. [PMID: 28032641 DOI: 10.1002/ijc.30592] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 11/23/2016] [Accepted: 12/09/2016] [Indexed: 11/08/2022]
Abstract
We explored the association of early tumor shrinkage (ETS) and non-ETS with efficacy of first-line and consecutive second-line treatment in patients with KRAS wild-type metastatic colorectal cancer treated in FIRE-3. Assessment of tumor shrinkage was based on the sum of longest diameters of target lesions, evaluated after 6 weeks of treatment. Shrinkage was classified as ETS (shrinkage by ≥ 20%), mETS (shrinkage by 0 to <20%), mPD (minor progression >0 to <20%) and PD (progression ≥20%). Overall survival (OS) was 33.2 (95% CI 28.0-38.4) months in ETS patients, while non-ETS was associated with less favorable outcome (mETS 24.0 (95% CI 21.2-26.9) months, mPD 19.0 (95% CI 13.0-25.0) months, PD 12.8 (95% CI 11.1-14.5) months). Differences in PFS of first-line therapy were less pronounced. ETS subgroups defined in first-line therapy also correlated with efficacy of second-line therapy. Progression-free survival in second-line (PFS2nd) was 6.5 months (5.8-7.2) for ETS, and was 5.6 (95% CI 4.7-6.5) months for mETS, 4.9 (95% CI 3.7-6.1) months for mPD and 3.3 (95% CI 2.3-4.3) months for PD. PFS of first-line and PFS2nd showed a linear correlation (Bravais-Pearson coefficient: 0.16, p = 0.006). While ETS is associated with the most favorable outcome, non-ETS represents a heterogeneous subgroup with distinct characteristics of less favorable initial tumor response to treatment. This is the first analysis to demonstrate that early tumor response observed during first-line FOLFIRI-based therapy may also relate to efficacy of second-line treatment. Early response parameters may serve as stratification factors in trials recruiting pretreated patients.
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Affiliation(s)
- Dominik P Modest
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany.,German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Sebastian Stintzing
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany.,German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | | | | | - Alexander Kiani
- Klinikum Bayreuth, Medizinische Klinik IV, Bayreuth, Germany
| | | | - Salah-Eddin Al-Batran
- Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt/Main, Germany
| | - Tobias Heintges
- Department of Medicine II, Städtisches Klinikum Neuss, Neuss, Germany
| | | | - Christoph Kahl
- Haematology and Oncology, Staedtisches Klinikum Magdeburg, Magdeburg, Germany
| | | | - Frank Kullmann
- Department of Medicine I, Klinikum Weiden, Weiden in der Oberpfalz, Germany
| | - Werner Scheithauer
- Department of Internal Medicine I & Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
| | - Thomas Kirchner
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Institute of Pathology University of Munich, Munich, Germany
| | - Andreas Jung
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Institute of Pathology University of Munich, Munich, Germany
| | | | - Jobst Christian von Einem
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany
| | - Markus Moehler
- Medical Department 1, Johannes-Gutenberg Universität Mainz, Mainz; University Cancer Center Frankfurt/Mainz, Frankfurt/Mainz, Germany
| | | | - Volker Heinemann
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany.,German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
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Nakayama G, Fujii T, Murotani K, Uehara K, Hattori N, Hayashi M, Tanaka C, Kobayashi D, Kanda M, Yamada S, Sugimoto H, Koike M, Fujiwara M, Ando Y, Kodera Y. Modified two-dimensional response as surrogate marker of overall survival in patients with metastatic colorectal cancer. Cancer Sci 2017; 107:1492-1498. [PMID: 27479846 PMCID: PMC5084659 DOI: 10.1111/cas.13023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 07/27/2016] [Accepted: 07/28/2016] [Indexed: 12/22/2022] Open
Abstract
The identification of surrogate markers for long‐term outcomes in patients with metastatic colorectal cancer (mCRC) may help in designing treatment regimens. The aim of this study was to assess whether two‐dimensional response (2‐DR) can serve as a new surrogate marker for overall survival (OS) in patients with mCRC. The study group consisted of 99 patients with mCRC from two independent cohorts who were treated with oxaliplatin‐based chemotherapy plus bevacizumab. Two‐dimensional response was defined as an area enclosed by coordinate points, including early tumor shrinkage at 8 weeks, depth of response at nadir, and 20% increase over nadir at progression. Each variable was weighted by its contribution rate to OS. The model was developed and internally validated in the learning cohort, and the performance of this model was externally verified in the validation cohort. Spearman correlation coefficients for 2‐DR and OS in the learning and validation cohorts were 0.593 and 0.661, respectively. The C‐indexes in predicting OS were 0.724 (95% confidence interval, 0.623–0.815) in the learning cohort and 0.762 (95% confidence interval, 0.651–0.873) in the validation cohort. Overall survival was significantly longer in patients with high 2‐DR values than in patients with low 2‐DR values in both the learning (37.0 vs. 24.1 months, P < 0.001) and validation (41.2 vs. 20.4 months, P < 0.001) cohorts. In contrast, differences in early tumor shrinkage and depth of response were not statistically significant. Multivariate analyses showed that 2‐DR was an independent prognostic factor for OS.
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Affiliation(s)
- Goro Nakayama
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenta Murotani
- Division of Biostatistics, Clinical Research Center, Aichi Medical University Hospital, Nagakute, Japan
| | - Keisuke Uehara
- Department of Surgical Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norifumi Hattori
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiko Koike
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuichi Ando
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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34
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Tsuji A, Sunakawa Y, Ichikawa W, Nakamura M, Kochi M, Denda T, Yamaguchi T, Shimada K, Takagane A, Tani S, Kotaka M, Kuramochi H, Furushima K, Koike J, Yonemura Y, Takeuchi M, Fujii M, Nakajima T. Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05). Target Oncol 2016; 11:799-806. [PMID: 27306648 DOI: 10.1007/s11523-016-0445-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Retrospective studies have found that early tumor shrinkage (ETS) and depth of response (DpR) are associated with favorable outcomes in patients with metastatic colorectal cancer (mCRC); however, few prospective studies have evaluated ETS and DpR. PATIENTS AND METHODS We performed a phase II study of FOLFOX plus cetuximab as first-line treatment in Japanese patients with KRAS wild-type mCRC. The primary endpoint was response rate (RR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), chronological tumor shrinkage (evaluated every 8 weeks), and safety. The association of ETS and DpR with survival time was analyzed using Spearman's rank correlation coefficient. RESULTS In 54 participants, the RR, median PFS, and OS were 66.7 % (95 % CI, 53.4-77.8 %), 11.1 months, and 33.9 months, respectively. There was no unexpected toxicity. Forty (80 %) of 50 assessable patients had ETS, which was associated with prolonged PFS and OS (11.3 vs. 3.7 months, HR 0.26, p = 0.0003; 42.8 vs. 9.0 months, HR 0.40, p = 0.0279, respectively). Median DpR was 56.3 %. The DpR correlated with OS (r s = 0.314, p = 0.027) as well as post-progression survival (PPS) (r s = 0.366, p = 0.017). Interestingly, DpR was moderately associated with OS and PPS (r s = 0.587, r s = 0.570, respectively) in patients harboring tumors with larger target lesions, but was not associated with OS or PPS in patients with smaller target lesions. FOLFOX plus cetuximab was active as a first-line treatment for Japanese mCRC patients, with no unexpected toxicities. CONCLUSIONS Our prospective evaluation of chronological tumor shrinkage showed that ETS and DpR correlate with outcomes in patients with KRAS wild-type mCRC who receive cetuximab-based chemotherapy (UMIN000004197).
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Affiliation(s)
- Akihito Tsuji
- Department of Clinical Oncology, Kagawa University Faculty of Medicine Cancer Center, Kagawa University Hospital, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Yu Sunakawa
- Division of Medical Oncology, Department of Internal Medicine, Showa University Northern Yokohama Hospital, 35-1, Chigasaki-chuo, Tsuzuki-ku, Yokohama, Kanagawa, 224-8503, Japan
| | - Wataru Ichikawa
- Division of Medical Oncology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa, 227-8501, Japan.
| | - Masato Nakamura
- Aizawa Comprehensive Cancer Center, Aizawa Hospital, 2-5-1, Honjyo, Matsumoto, Nagano, 390-8510, Japan
| | - Mitsugu Kochi
- Department of Digestive Surgery, Nihon University School of Medicine, 30-1, Oyaguchikami-machi, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, 666-2, Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan
| | - Tatsuro Yamaguchi
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan
| | - Ken Shimada
- Division of Medical Oncology, Department of Internal Medicine, Showa University Koto Toyosu Hospital, 5-1-38 Toyosu, Koto-ku, Tokyo, 135-8577, Japan
| | - Akinori Takagane
- Department of Surgery, Hakodate Goryoukaku Hospital, 38-3, Goryokaku-machi, Hakodate, Hokkaido, 040-8611, Japan
| | - Satoshi Tani
- Department of Internal Medicine, Konan Hospital, 1-5-16, Kamokogahara, Higashinada-ku, Kobe, Hyogo, 658-0064, Japan
| | - Masahito Kotaka
- Gastrointestinal Cancer Center, Sano Hospital, 2-5-1, Shimizugaoka, Tarumi-ku, Kobe, Hyogo, 655-0031, Japan
| | - Hidekazu Kuramochi
- Department of gastroenterological Surgery, Tokyo Women's Medical University Yachiyo Medical Center, 477-96, Owadashinden, Yachiyo, Chiba, 276-8524, Japan
| | - Kaoru Furushima
- Department of Surgery, NTT Medical Center, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo, 141-8625, Japan
| | - Junichi Koike
- Department of Digestive Surgery, Toho University School of Medicine, 6-11-1, Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Yutaka Yonemura
- Department of Surgery, Kishiwada Tokushukai Hospital, 4-27-1, Kamoricho, Kishiwada, Osaka, 596-0042, Japan
| | - Masahiro Takeuchi
- Department of Clinical Medicine (Biostatistics), Kitasato University School of Pharmacy, 5-9-1, Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Masashi Fujii
- Department of Digestive Surgery, Nihon University School of Medicine, 30-1, Oyaguchikami-machi, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Toshifusa Nakajima
- Japan Clinical Cancer Research Organization, 7F Ginza Wing Bldg. 1-14-5, Ginza, Chuo-ku, Tokyo, 104-0061, Japan
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Hu J, Zhang Z, Zheng R, Cheng L, Yang M, Li L, Liu B, Qian X. On-treatment markers as predictors to guide anti-EGFR MoAb treatment in metastatic colorectal cancer: a systematic review with meta-analysis. Cancer Chemother Pharmacol 2016; 79:275-285. [PMID: 27878357 DOI: 10.1007/s00280-016-3196-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 11/11/2016] [Indexed: 01/29/2023]
Abstract
PURPOSE Skin toxicity (ST) and early tumor shrinkage (ETS) are early phenomenon during the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) treatment. We conducted a meta-analysis and included relevant studies that reported the impact of ST and ETS on survival- and life quality-based outcome of metastatic colorectal cancer (mCRC) patients treated with anti-EGFR MoAb. METHODS Relevant studies were identified from PubMed and Embase reporting the correlation of ST and ETS with the clinical outcome of mCRC patients treated with anti-EGFR MoAb. We also collected evidences on the impact of ST and ETS on absolute benefit acquired from additional anti-EGFR treatment and quality of life (ST only). Pooled hazard ratio and rate difference were all estimated by using random-effects model. RESULTS Pooled data revealed that the occurrence of ST and ETS ≥20% (v < 20%) during anti-EGFR MoAb treatment were both associated with better OS, PFS and ORR. This association could not be disturbed by KRAS status. Mean changes in safety follow-up life health state from baseline appeared unaffected by ST. Only mCRC patients with wild-type KRAS tumor who suffered grade 2+ ST could benefit from additional anti-EGFR treatment to chemotherapy or best supportive care (BSC) alone. ETS was also a predictor for absolute survival benefit acquired from additional anti-EGFR treatment for patients with wild-type KRAS tumors, and the more early shrinkage the tumor was, the much benefit was observed. CONCLUSION ST and ETS are predictive of absolute benefit acquired from anti-EGFR treatment in mCRC patients with wild-type KRAS tumors. These two on-treatment markers can be used for clinical decision-making if no adequate biological markers from tissues are provided.
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Affiliation(s)
- Jing Hu
- Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing, China.,Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Zhen Zhang
- Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing, China
| | - Rui Zheng
- College of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lei Cheng
- Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Mi Yang
- Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Li Li
- Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing, China
| | - Baorui Liu
- Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Xiaoping Qian
- Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing, China. .,Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China.
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36
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Bouchahda M, Boige V, Smith D, Karaboué A, Ducreux M, Hebbar M, Lepère C, Focan C, Guimbaud R, Innominato P, Awad S, Carvalho C, Tumolo S, Truant S, De Baere T, Castaing D, Rougier P, Morère JF, Taieb J, Adam R, Lévi F. Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer. Eur J Cancer 2016; 68:163-172. [PMID: 27768923 DOI: 10.1016/j.ejca.2016.09.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 09/07/2016] [Accepted: 09/13/2016] [Indexed: 01/20/2023]
Abstract
BACKGROUND Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m2) and triplet hepatic artery infusion (HAI) within European trial OPTILIV. METHODS Irinotecan (180 mg/m2), 5-fluorouracil (2800 mg/m2) and oxaliplatin (85 mg/m2) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models. RESULTS Response was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33-76 years, with a median of 12 liver metastases (LMs) (2-50), involving five segments (1-8). Ten patients had a late response, and 31 patients had no response. Grade 3-4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation-odds ratio (OR): 6.0 (1.2-29.8; p = 0.029)-and LM diameter ≤57 mm-OR: 5.3 (1.1-25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection-OR: 11.8 (1.4-100.2; p = 0.024) and overall survival-hazard ratio: 0.39 (0.17-0.88; p = 0.023) in multivariate analyses. CONCLUSIONS Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making. Protocol numbers: EUDRACT 2007-004632-24 NCT00852228.
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Affiliation(s)
- Mohamed Bouchahda
- AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France; INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France; Ramsay-GDS Mousseau Clinics, Evry, France
| | | | | | - Abdoulaye Karaboué
- INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France; AK-SCIENCES, Research and Therapeutic Innovation, Vitry-Sur-Seine, France
| | | | | | | | | | - Rosine Guimbaud
- Digestive Medical Oncology Unit, Toulouse University Hospital, Toulouse, France
| | - Pasquale Innominato
- AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France; INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France; Cancer Chronotherapy Unit, Warwick Medical School, Coventry, United Kingdom
| | - Sameh Awad
- AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France
| | - Carlos Carvalho
- Medical Oncology Unit, Fernando Fonseca Hospital, Amadora, Portugal
| | | | | | | | - Denis Castaing
- AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France
| | | | - Jean-François Morère
- AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France
| | - Julien Taieb
- Georges Pompidou European Hospital, Paris, France
| | - René Adam
- AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France; INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France
| | - Francis Lévi
- AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France; INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France; Cancer Chronotherapy Unit, Warwick Medical School, Coventry, United Kingdom.
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37
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Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Held S, Giessen-Jung C, Moehler M, Jagenburg A, Kirchner T, Jung A, Heinemann V. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol 2016; 17:1426-1434. [PMID: 27575024 DOI: 10.1016/s1470-2045(16)30269-8] [Citation(s) in RCA: 312] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 06/01/2016] [Accepted: 06/16/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes (KRAS and NRAS exons 2-4). We report here efficacy results for the FIRE-3 final RAS (KRAS/NRAS, exons 2-4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival. METHODS FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov, number NCT00433927. FINDINGS In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33·1 months [95% CI 24·5-39·4] vs 25·0 months [23·0-28·1]; hazard ratio 0·70 [0·54-0·90]; p=0·0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72·0% [95% CI 64·3-78·8] vs 97 of 173, 56·1% [48·3-63·6]; p=0·0029), frequency of early tumour shrinkage (107 of 157, 68·2% [60·3-75·4] vs 85 of 173, 49·1% [41·5-56·8]; p=0·0005), and median depth of response (-48·9% [-54·3 to -42·0] vs -32·3% [-38·2 to -29·2]; p<0·0001) were significantly better in extended RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups. INTERPRETATION This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup. FUNDING Merck KGaA and Pfizer.
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Affiliation(s)
- Sebastian Stintzing
- Department of Hematology and Oncology, University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
| | - Dominik P Modest
- Department of Hematology and Oncology, University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Lisa Rossius
- Department of Hematology and Oncology, University of Munich, Munich, Germany
| | - Markus M Lerch
- Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald, Greifswald, Germany
| | | | - Thomas Decker
- Studienzentrum Onkologie Ravensburg, Ravensburg, Germany
| | | | | | | | | | | | - Christoph Kahl
- Städtisches Klinikum Magdeburg, Hämatologie/Onkologie, Magdeburg, Germany
| | - Gernot Seipelt
- Onkologische Schwerpunktpraxis und Tagesklinik, Bad Soden, Germany
| | | | - Martina Stauch
- Praxis für Hämatologie und internistische Onkologie, Kronach, Germany
| | - Werner Scheithauer
- Univ.-Klinik für Innere Medizin I, Klin. Abteilung für Onkologie, Wien, Austria
| | | | | | - Markus Moehler
- Universität Mainz, 1. Medizinische Klinik und Poliklinik, Mainz, Germany
| | | | - Thomas Kirchner
- Institute of Pathology, University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Andreas Jung
- Institute of Pathology, University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Volker Heinemann
- Department of Hematology and Oncology, University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
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Aprile G, Fontanella C, Bonotto M, Rihawi K, Lutrino SE, Ferrari L, Casagrande M, Ongaro E, Berretta M, Avallone A, Rosati G, Giuliani F, Fasola G. Timing and extent of response in colorectal cancer: critical review of current data and implication for future trials. Oncotarget 2016; 6:28716-30. [PMID: 26308250 PMCID: PMC4745687 DOI: 10.18632/oncotarget.4747] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 07/10/2015] [Indexed: 12/20/2022] Open
Abstract
The identification of new surrogate endpoints for advanced colorectal cancer is becoming crucial and, along with drug development, it represents a research field increasingly studied. Although overall survival (OS) remains the strongest trial endpoint available, it requires larger sample size and longer periods of time for an event to happen. Surrogate endpoints such as progression free survival (PFS) or response rate (RR) may overcome these issues but, as such, they need to be prospectively validated before replacing the real endpoints; moreover, they often bear many other limitations. In this narrative review we initially discuss the role of time-to-event endpoints, objective response and response rate as surrogates of OS in the advanced colorectal cancer setting, discussing also how such measures are influenced by the tumor assessment criteria currently employed. We then report recent data published about early tumor shrinkage and deepness of response, which have recently emerged as novel potential endpoint surrogates, discussing their strengths and weaknesses and providing a critical comment. Despite being very compelling, the role of such novel response measures is yet to be confirmed and their surrogacy with OS still needs to be further investigated within larger and well-designed trials.
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Affiliation(s)
- Giuseppe Aprile
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | - Caterina Fontanella
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | - Marta Bonotto
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | - Karim Rihawi
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | | | - Laura Ferrari
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | | | - Elena Ongaro
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | | | - Antonio Avallone
- Gastrointestinal Medical Oncology Unit, National Cancer Institute, Napoli, Italy
| | - Gerardo Rosati
- Medical Oncology Unit, San Carlo Hospital, Potenza, Italy
| | | | - Gianpiero Fasola
- Department of Medical Oncology, University and General Hospital, Udine, Italy
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Kobayashi M, Endo S, Hamano Y, Imanishi M, Akutsu D, Sugaya A, Ochi D, Moriwaki T, Hyodo I. Successful Treatment with Modified FOLFOX6 and Panitumumab in a Cecal Cancer Patient Undergoing Hemodialysis. Intern Med 2016; 55:127-30. [PMID: 26781010 DOI: 10.2169/internalmedicine.55.5113] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Combination chemotherapy of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) plus panitumumab, a fully human monoclonal antibody against epidermal growth factor receptor (EGFR), is one of the standard treatments for metastatic colorectal cancer (mCRC) without KRAS mutation. A few reports suggested no need of dose adjustment of cetuximab, a similar chimeric anti-EGFR antibody, in patients with renal impairment. However, panitumumab combined with cytotoxic drugs for hemodialysis patients has not been reported. We herein report a case of a hemodialysis mCRC patient successfully treated with mFOLFOX6 and panitumumab combination therapy.
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Affiliation(s)
- Mariko Kobayashi
- Division of Gastroenterology, University of Tsukuba Hospital, Japan
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Adam R, de Gramont A, Figueras J, Kokudo N, Kunstlinger F, Loyer E, Poston G, Rougier P, Rubbia-Brandt L, Sobrero A, Teh C, Tejpar S, Van Cutsem E, Vauthey JN, Påhlman L. Managing synchronous liver metastases from colorectal cancer: a multidisciplinary international consensus. Cancer Treat Rev 2015; 41:729-741. [PMID: 26417845 DOI: 10.1016/j.ctrv.2015.06.006] [Citation(s) in RCA: 391] [Impact Index Per Article: 39.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 06/23/2015] [Indexed: 02/07/2023]
Abstract
An international panel of multidisciplinary experts convened to develop recommendations for managing patients with colorectal cancer (CRC) and synchronous liver metastases (CRCLM). A modified Delphi method was used. CRCLM is defined as liver metastases detected at or before diagnosis of the primary CRC. Early and late metachronous metastases are defined as those detected ⩽12months and >12months after surgery, respectively. To provide information on potential curability, use of high-quality contrast-enhanced computed tomography (CT) before chemotherapy is recommended. Magnetic resonance imaging is increasingly being used preoperatively to aid detection of subcentimetric metastases, and alongside CT in difficult situations. To evaluate operability, radiology should provide information on: nodule size and number, segmental localization and relationship with major vessels, response after neoadjuvant chemotherapy, non-tumoral liver condition and anticipated remnant liver volume. Pathological evaluation should assess response to preoperative chemotherapy for both the primary tumour and metastases, and provide information on the tumour, margin size and micrometastases. Although the treatment strategy depends on the clinical scenario, the consensus was for chemotherapy before surgery in most cases. When the primary CRC is asymptomatic, liver surgery may be performed first (reverse approach). When CRCLM are unresectable, the goal of preoperative chemotherapy is to downsize tumours to allow resection. Hepatic resection should not be denied to patients with stable disease after optimal chemotherapy, provided an adequate liver remnant with inflow and outflow preservation remains. All patients with synchronous CRCLM should be evaluated by a hepatobiliary multidisciplinary team.
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Affiliation(s)
- René Adam
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Villejuif, France.
| | | | - Joan Figueras
- Hepato-biliary and Pancreatic Surgery Unit, Department of Surgery, Dr Josep Trueta Hospital, Institut d'Investigació Biomèdica (IDIBGi), Girona, Spain.
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, University of Tokyo, Tokyo, Japan.
| | - Francis Kunstlinger
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Villejuif, France.
| | - Evelyne Loyer
- Department of Diagnostic Radiology, Division of Diagnostic Imaging, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
| | - Graeme Poston
- Surgery Department, Aintree University Hospital, School of Translational Studies, University of Liverpool, Liverpool, UK.
| | - Philippe Rougier
- Digestive Oncology Department, Hôpital Européen Georges Pompidou, University Paris V-René Descartes and AP-HP Paris, France.
| | - Laura Rubbia-Brandt
- Pathology Department, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland.
| | | | - Catherine Teh
- Liver Centre and Department of Surgery, National Kidney & Transplant Institute, Quezon City, Philippines.
| | - Sabine Tejpar
- Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
| | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
| | - Lars Påhlman
- Department of Surgical Science, Uppsala University Hospital, Uppsala, Sweden.
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Kim ST, Jang KT, Lee SJ, Jang HL, Lee J, Park SH, Park YS, Lim HY, Kang WK, Park JO. Tumour shrinkage at 6 weeks predicts favorable clinical outcomes in a phase III study of gemcitabine and oxaliplatin with or without erlotinib for advanced biliary tract cancer. BMC Cancer 2015; 15:530. [PMID: 26189560 PMCID: PMC4507321 DOI: 10.1186/s12885-015-1552-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 07/14/2015] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The aim of this study was to determine whether early tumor shrinkage (ETS) at 6 weeks after treatment correlates with progression-free survival (PFS) and overall survival (OS) in advanced biliary tract cancer (BTC) patients receiving gemcitabine plus oxaliplatin (GEMOX), with or without erlotinib. METHODS This was a multicenter, open label, randomized, phase III trial of 103 BTC patients (ClinicalTrials.gov Identifier; NCT01149122, and Rigistration date; January, 7, 2010), comparing GEMOX with GEMOX plus erlotinib. Tumor shrinkage was expressed as a relative decrease compared to baseline and was dichotomized according to a previously reported cutoff value of 10 %. RESULTS Fifty-four patients (52.4 %) received GEMOX and 49 patients (47.6 %) received GEMOX plus erlotinib. The latter achieved a better overall response rate (RR) (40.8 % vs. 18.6 %, p = 0.02) and showed ETS more frequently (63.2 % vs. 40.7 %, p = 0.03). ETS was significantly correlated with the overall RR (correlation coefficient, 0.53; p < 0.01). The median PFS and OS did not differ according to erlotinib administration. However, the median PFS (7.3 vs. 2.1 months, p < 0.01) and OS (10.7 vs. 5.8 months, p < 0.01) were significantly longer amongst patients with ETS at 6 weeks after treatment, irrespective of erlotinib administration. In patients with wild-type KRAS who were treated with GEMOX plus erlotinib, ETS was a significant prognostic factor for PFS (p < 0.01). CONCLUSIONS ETS might predict PFS and OS in BTC patients treated with GEMOX with or without erlotinib. Additionally, ETS may be an indication for adding erlotinib to chemotherapy for BTC patients wild-type KRAS. These findings need to be prospectively validated.
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Affiliation(s)
- Seung Tae Kim
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, 135-710, South Korea.
| | - Kee-Taek Jang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - Su Jin Lee
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, 135-710, South Korea.
| | - Hye-Lim Jang
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, 135-710, South Korea.
| | - Jeeyun Lee
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, 135-710, South Korea.
| | - Se Hoon Park
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, 135-710, South Korea.
| | - Young Suk Park
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, 135-710, South Korea.
| | - Ho Yeong Lim
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, 135-710, South Korea.
| | - Won Ki Kang
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, 135-710, South Korea.
| | - Joon Oh Park
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, 135-710, South Korea.
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Heinemann V, Stintzing S, Modest DP, Giessen-Jung C, Michl M, Mansmann UR. Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC). Eur J Cancer 2015; 51:1927-36. [PMID: 26188850 DOI: 10.1016/j.ejca.2015.06.116] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 06/08/2015] [Accepted: 06/20/2015] [Indexed: 01/02/2023]
Abstract
BACKGROUND Response evaluation criteria in solid tumours (RECIST) are used to define degrees of response to anti-tumour agents. In retrospective analyses, early tumour shrinkage (ETS) has been investigated as an alternative early-on-treatment predictor of treatment efficacy with regard to progression-free and overall survival. While cut-off based analysis of ETS facilitates the categorisation of patients into responders and non-responders after a defined period of treatment, depth of response (DpR) serves as a continuous measure, which defines the nadir of tumour response. METHODS A systematic literature search for 'early tumour shrinkage' or 'tumour size decrease' in 'metastatic colorectal cancer' reported from January 2000 to July 2014 was performed. The present review summarises available data concerning ETS and DpR and evaluates their potential as predictive markers for the clinical management of patients with metastatic colorectal cancer (mCRC). RESULTS A total of 10 clinical trials investigated the role of ETS as a marker of clinical outcome in patients with mCRC. In addition, DpR was investigated using the efficacy data from three of these trials. Available data show that ETS differentiates patients with high sensitivity to treatment and more favourable prognosis from a heterogeneous group of patients classified as non-ETS patients. ETS is an early indicator of the potentially achievable response. In contrast, DpR estimates the nadir of tumour response as a continuous measure, which may affect the subsequent disease history, thus translating into superior survival. CONCLUSIONS The concepts of ETS and DpR offer potential as clinical end-points to aid the clinical decision making process and thus further optimise mCRC patient management in the era of tailored therapy approaches.
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Affiliation(s)
- Volker Heinemann
- Department of Medical Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University Munich, Germany, Marchioninistr. 15, 81377 Munich, Germany; Comprehensive Cancer Center, Klinikum Grosshadern, University of Munich, Germany, Marchioninistr. 15, 81377 Munich, Germany
| | - Sebastian Stintzing
- Department of Medical Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University Munich, Germany, Marchioninistr. 15, 81377 Munich, Germany.
| | - Dominik P Modest
- Department of Medical Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University Munich, Germany, Marchioninistr. 15, 81377 Munich, Germany.
| | - Clemens Giessen-Jung
- Department of Medical Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University Munich, Germany, Marchioninistr. 15, 81377 Munich, Germany.
| | - Marlies Michl
- Department of Medical Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University Munich, Germany, Marchioninistr. 15, 81377 Munich, Germany.
| | - Ulrich R Mansmann
- Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-University Munich, Germany, Marchioninistr. 15, 81377 Munich, Germany.
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Impact of early tumour shrinkage and resection on outcomes in patients with wild-type RAS metastatic colorectal cancer. Eur J Cancer 2015; 51:1231-42. [PMID: 25956209 DOI: 10.1016/j.ejca.2015.03.026] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 03/17/2015] [Accepted: 03/31/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Tumour shrinkage (TS) increases the possibility of resection in metastatic colorectal cancer (mCRC) and may improve tumour-related symptoms. Here we report prespecified secondary response-related end-points and exploratory TS/resection outcomes for patients with RAS wild-type (WT) tumours (no mutations in KRAS/NRAS exons 2/3/4) from the PRIME study (NCT00364013). METHODS PRIME was a randomised phase 3 study comparing first-line panitumumab+FOLFOX4 versus FOLFOX4 in mCRC patients. Tumour response analyses were conducted to compare response rates and their impact on survival outcomes. RESULTS Overall, 505 patients had RAS WT mCRC. More patients receiving panitumumab+FOLFOX4 versus FOLFOX4 had ⩾30% (59% versus 38%; P<0.001) or ⩾20% (72% versus 57%; P<0.001) TS at week 8 (early TS); consistent TS benefits were observed over the first ∼40weeks of treatment. Objective response rate (P=0.003), duration of response (P=0.0027), depth of response (P=0.0149), progression-free survival (PFS; P=0.0015) and overall survival (OS; P=0.0057) were improved in the panitumumab+FOLFOX4 group. Both early TS and resection were associated with improved PFS and OS. 2-year OS rates for patients who did (n=64) versus did not (n=441) undergo resection were 88% versus 40%; 2-year OS rates for patients who did (n=45) versus did not (n=460) undergo complete resection were 96% versus 41%. CONCLUSIONS More patients receiving panitumumab+FOLFOX4 versus FOLFOX4 had ⩾30% or ⩾20% TS at week 8; PFS and OS were also improved with panitumumab+FOLFOX4. The clinical value of achieving early TS in mCRC warrants further investigation.
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Ye LC, Wei Y, Zhu DX, Chen T, Xu J. Impact of early tumor shrinkage on clinical outcome in wild-type-KRAS colorectal liver metastases treated with cetuximab. J Gastroenterol Hepatol 2015; 30:674-679. [PMID: 25387601 DOI: 10.1111/jgh.12847] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/04/2014] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIM To evaluate the impact of early tumor shrinkage (ETS) on long-term outcome in patients with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) unresectable colorectal liver metastases (CLM) receiving cetuximab plus chemotherapy. METHODS A total of 138 patients in a randomized controlled trial (70 in armA received cetuximab plus chemotherapy, 68 in armB received chemotherapy alone), as previously reported (Ye et al., 2013) were included into this analysis. The cut-off date updated for overall survival (OS) was June 2014. ETS was defined as a ≥ 20% reduction of the longest diameters of the target lesions compared with baseline at the first evaluation (8 weeks). Outcome measures were progression-free survival (PFS) and OS. RESULTS There were 132 patients available for evaluation, and ETS occurred more frequently in armA than that in armB (P = 0.003). ETS was associated with longer OS (armA: 35.7 vs. 19.5 months, P < 0.001; armB 28.7 vs. 18.7 months, P = 0.01) and PFS (armA: 13.4 vs. 4.2 months, P < 0.001; armB 7.0 vs. 4.2 months, P = 0.001) compared with patients with no-ETS. Among patients with ETS, there was a significant difference between armA and armB in PFS (P = 0.03), but not in OS (P = 0.19). All 23 patients who underwent liver surgery achieved ETS. In armA, for patients without liver surgery, patients observed ETS also gained an increased survival benefit over those no-ETS in OS (P = 0.02) and PFS (P < 0.001). ETS was an independent predictor of improved OS (hazard ratio 0.56, P = 0.007). CONCLUSION ETS may serve as a predictor of favorable outcome in patients with wild-type KRAS CLM receiving cetuximab plus chemotherapy.
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Affiliation(s)
- Le-chi Ye
- Department of Oncological Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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Petrelli F, Pietrantonio F, Cremolini C, Di Bartolomeo M, Coinu A, Lonati V, de Braud F, Barni S. Early tumour shrinkage as a prognostic factor and surrogate end-point in colorectal cancer: a systematic review and pooled-analysis. Eur J Cancer 2015; 51:800-7. [PMID: 25794604 DOI: 10.1016/j.ejca.2015.02.011] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 02/11/2015] [Accepted: 02/19/2015] [Indexed: 12/16/2022]
Abstract
PURPOSE Early tumour shrinkage (ETS), defined as a reduction of at least 20% in tumour size at first reassessment, has been recently investigated retrospectively in first-line trials of metastatic colorectal cancer (CRC), and appears to be associated with better outcomes. We have performed a systematic review and meta-analysis of published trials to evaluate the prognostic value of ETS in CRC in terms of overall survival (OS) and progression-free survival (PFS). MATERIAL AND METHODS An electronic search of the PubMed, SCOPUS, EMBASE, the Web of Science, and the Cochrane Central Register of Controlled Trial databases identified trials that compared outcomes of patients with or without ETS during first-line chemotherapy for metastatic CRC. The OS, reported as a hazard ratio (HR) with a 95% confidence interval (CI), was the primary outcome measure; the correlation coefficient (R) between ETS with median OS was also estimated. RESULTS Twenty-one trials from 10 publications were analysed. Overall, patients with ETS were associated with a better OS (HR, 0.58; 95% CI, 0.53 to 0.64; P<0.00001) and PFS (HR, 0.57; 95% CI, 0.47-0.69; P<0.00001) compared with patients who were early non-responders. However, ETS was poorly correlated with OS in terms of surrogacy (R=0.37; 95% CI - 0.31-0.78; P=0.28). CONCLUSIONS ETS is a good prognostic factor but an inappropriate surrogate for predicting outcome in CRC patients. These findings support ETS as prognostic tool in ascertaining earlier non-responders; however, its role as a surrogate end-point deserves further evaluation.
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Affiliation(s)
- Fausto Petrelli
- Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy.
| | - Filippo Pietrantonio
- Department of Medical Oncology, Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy.
| | - Chiara Cremolini
- UO Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana and Università di Pisa, via Roma 67, 56126 Pisa, Italy.
| | - Maria Di Bartolomeo
- Department of Medical Oncology, Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy.
| | - Andrea Coinu
- Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy.
| | - Veronica Lonati
- Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy.
| | - Filippo de Braud
- Department of Medical Oncology, Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy.
| | - Sandro Barni
- Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy.
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Ohhara Y, Suenaga M, Matsusaka S, Shinozaki E, Mizunuma N, Yamaguchi T. Comparison between three oxaliplatin-based regimens with bevacizumab in patients with metastatic colorectal cancer. Onco Targets Ther 2015; 8:529-37. [PMID: 25767397 PMCID: PMC4354450 DOI: 10.2147/ott.s77190] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND A previous pivotal Phase III study (NO16966) demonstrated the benefit of the addition of bevacizumab (BV) to oxaliplatin-based regimens in metastatic colorectal cancer (MCRC). Our study evaluated the safety and efficacy of three oxaliplatin-based chemotherapy regimens (FOLFOX4 [intravenous twice-bolus and twice-infusional 5-fluorouracil/folinic acid plus oxaliplatin], mFOLFOX6 [intravenous once-bolus and once-infusional 5-fluorouracil/folinic acid plus oxaliplatin], and XELOX [capecitabine plus oxaliplatin]) plus BV in the first-line treatment of MCRC patients. METHODS Patients with MCRC who started treatment between June 2007 and September 2010 were evaluated in this retrospective cohort study. We also evaluated early objective tumor response (EOTR) within 12 weeks, which was defined as a relative change of ≥30% in the sum of the longest diameters of target lesions when compared with baseline. The primary study endpoints were progression-free survival (PFS) and response rate. RESULTS A total of 185 patients received the following chemotherapy: FOLFOX4 + BV (FF4 arm, n=85), mFOLFOX6 + BV (FF6 arm, n=40), and XELOX + BV (XELOX arm, n=60). The overall response rates were 61.2%, 72.5%, and 75.0% (95% confidence interval: 50.6%-71.8%, 58.0%-87.0%, and 63.7%-86.3%). Median PFS was 18.0, 15.5, and 13.7 months, respectively (log-rank: P=0.254; data cut-off: May 2013). Patients with EOTR (n=117) had significantly better PFS than those without-EOTR (n=68) (17.5 versus 12.7 months, P=0.004). CONCLUSION This study suggests that these three BV plus oxaliplatin-based treatments might have comparable benefit in terms of tumor response and PFS. Moreover, EOTR may be a predictive factor for PFS in patients with MCRC.
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Affiliation(s)
- Yoshihito Ohhara
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan ; Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Mitsukuni Suenaga
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoshi Matsusaka
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Eiji Shinozaki
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Nobuyuki Mizunuma
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Toshiharu Yamaguchi
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
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Yoshita H, Hosokawa A, Ueda A, Ando T, Kajiura S, Kato H, Kawabe H, Tomizawa G, Horikawa N, Yabuhita K, Note M, Sugiyama T. Predictive value of optimal morphologic response to first-line chemotherapy in patients with colorectal liver metastases. Digestion 2014; 89:43-8. [PMID: 24458112 DOI: 10.1159/000356218] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND It has been reported that morphologic response to preoperative chemotherapy is an independent prognostic factor in patients who undergo hepatic resection of colorectal liver metastases (CLM). The aim of this study was to evaluate the predictive value of morphologic response to first-line chemotherapy in patients with CLM. METHODS We assessed 41 patients with CLM who received fluorouracil-based chemotherapy with or without bevacizumab as the first-line chemotherapy between April 2006 and June 2012. Three blinded radiologists evaluated computed tomography images and classified them as optimal, incomplete or no response according to the morphologic criteria. Response to systemic chemotherapy was also evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Predictive factors associated with progression-free survival (PFS) were identified in multivariate analysis. RESULTS Twenty-three patients (56%) received chemotherapy with bevacizumab, while 18 patients (44%) received chemotherapy without bevacizumab. Optimal morphologic response was observed in 11 patients (48%) treated with bevacizumab and in 5 patients (28%) treated without bevacizumab (p = 0.19). Eight patients (20%) underwent hepatic resection after chemotherapy. The median follow-up period was 31.3 months. The median PFS was 13.3 months for patients with optical morphologic response and 8.7 months in those with incomplete/no morphologic response (p = 0.0026). On multivariate analysis, performance status and morphologic response were significant independent predictors of PFS. CONCLUSION Optimal morphologic response was significantly associated with PFS in patients with CLM who were treated with fluorouracil-based chemotherapy as the first-line chemotherapy.
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Affiliation(s)
- Hiroki Yoshita
- Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Toyama, Japan
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Guo XJ, Cao ND, Gu Y, Zhu YJ, Zheng J. Therapeutic evaluation criteria for advanced colorectal cancer: Recent progress. Shijie Huaren Xiaohua Zazhi 2014; 22:4281-4287. [DOI: 10.11569/wcjd.v22.i28.4281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Evaluation criteria like overall survival (OS), progression-free survival (PFS), the response evaluation criteria in solid tumors, quality of life and adverse reactions have been widely used in clinical studies of advanced colorectal cancer. However, these criteria have different significance, and with the development of molecular targeted drugs and new therapies, the drawbacks of these criteria have been revealed. Therefore, searching for new evaluation criteria which can reflect the curative effect in the earlier stage is becoming inevitable.
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Anti-EGFR MoAb treatment in colorectal cancer: limitations, controversies, and contradictories. Cancer Chemother Pharmacol 2014; 74:1-13. [PMID: 24916545 DOI: 10.1007/s00280-014-2489-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 05/13/2014] [Indexed: 10/25/2022]
Abstract
Anti-epidermal growth-factor receptor (EGFR) monoclonal antibody (MoAb) treatment for chemotherapy refractory or metastatic colorectal cancer has obtained great achievement. However, not every colorectal patient responds to such molecular-targeted agent well. Biomarkers associated with anti-EGFR resistance are not limited to KRAS mutation up to now. It was recently reported that cross-talking molecular effectors interacted with EGFR-related pathway were also negative predictor for anti-EGFR treatment. However, the limited data, controversial results, and contradictories between in vitro and clinical studies restrict the clinical application of these new biomarkers. Although the current theory of tumor microenvironment supported the application of multi-target treatment, the results from the clinical studies were less than expected. Moreover, WHO or RECIST guideline for response assessment in anti-EGFR MoAb treatment was also queried by recent AIO KRK-0306 trial. This review focuses on these controversies, contradictories, and limitations, in order to uncover the unmet needs in current status of anti-EGFR MoAb treatment in colorectal cancer.
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Feng QY, Wei Y, Chen JW, Chang WJ, Ye LC, Zhu DX, Xu JM. Anti-EGFR and anti-VEGF agents: Important targeted therapies of colorectal liver metastases. World J Gastroenterol 2014; 20:4263-4275. [PMID: 24764664 PMCID: PMC3989962 DOI: 10.3748/wjg.v20.i15.4263] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 02/07/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal liver metastasis (CLM) is common worldwide. Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials, and are now becoming standards for patients with CLM. The development and application of anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies represents significant advances in the treatment of this disease. However, new findings continue to emerge casting doubt on the efficacy of this approach. The Kirsten rat sarcoma viral oncogene (KRAS) has been proven to be a crucial predictor of the success of anti-EGFR treatment in CLM. Whereas a recent study summarized several randomized controlled trials, and showed that patients with the KRAS G13D mutation significantly benefited from the addition of cetuximab in terms of progress-free survival (PFS, 4.0 mo vs 1.9 mo, HR = 0.51, P = 0.004) and overall survival (OS, 7.6 mo vs 5.7 mo, HR = 0.50, P = 0.005). Some other studies also reported that the KRAS G13D mutation might not be absolutely predictive of non-responsiveness to anti-EGFR therapy. At the same time, “new” RAS mutations, including mutations in neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) and exons 3 and 4 of KRAS, have been suggested to be predictors of a poor treatment response. This finding was first reported by the update of the PRIME trial. The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations, panitumumab-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)4 treatment led to inferior PFS (HR = 1.28, 95%CI: 0.79-2.07) and OS (HR = 1.29, 95%CI: 0.79-2.10), which was consistent with the findings in patients with KRAS mutations in exon 2. Then, the update of the PEAK trial and the FIRE-III trial also supported this finding, which would reduce candidates for anti-EGFR therapy but enhance the efficacy. In first-line targeted combination therapy, the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-VII trial. Also, bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966 trial. By the update and further analysis of the COIN trial and the NORDIC-VII trial, cetuximab plus FOLFOX was reported to be reliable again. But bevacizumab plus oxaliplatin-based chemotherapy was still controversial. In addition, some trials have reported that bevacizumab is not suitable for conversion therapy. The results of the FIRE-III trial showed that cetuximab led to a significant advantage over bevacizumab in response rate (72% vs 63%, P = 0.017) for evaluable population. With the balanced allocation of second-line treatment, the FIRE-III trial was expected to provide evidence for selecting following regimens after first-line progression. There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM, although the combined regimen is often administered based on experience. Combination therapy with more than one targeted agent has been proven to provide no benefit, and even was reported to be harmful as first-line treatment by four large clinical trials. However, recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment. The mechanism of antagonism between different targeted agents deserves further study, and may also provide greater understanding of the development of resistance to targeted agents.
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