Polistina F, Natale GD, Bonciarelli G, Ambrosino G, Frego M. Neoadjuvant strategies for pancreatic cancer. World J Gastroenterol 2014; 20(28): 9374-9383 [PMID: 25071332 DOI: 10.3748/wjg.v20.i28.9374]
Corresponding Author of This Article
Francesco Polistina, MD, Department of General Surgery, Monselice Hospital, Ospedale di Monselice, Via G. Marconi 19, 35043 Monselice, Italy. francescopolistina@hotmail.it
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Oncology
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Francesco Polistina, Giuseppe Di Natale, Mauro Frego, Department of General Surgery, Monselice Hospital, 35043 Monselice, Italy
Giuseppe Di Natale, Rome University “La Sapienza” School of Surgery, Piazzale Aldo Moro, 500185 Roma, Italy
Giorgio Bonciarelli, Department of Clinical Oncology, Monselice Hospital, 135043 Monselice, Italy
Giovanni Ambrosino, Department of Surgery, Malzoni Hospital, 483100 Avellino, Italy
ORCID number: $[AuthorORCIDs]
Author contributions: Polistina F, Bonciarelli G, Frego M and Ambrosino G selected, discussed and criticized the papers for the issue; Di Natale G retrieved the articles and took part to the discussion and drawing of the manuscript; Polistina F draw the manuscript and took part to the revision process together with Frego M, Bonciarelli G and Ambrosino G.
Correspondence to: Francesco Polistina, MD, Department of General Surgery, Monselice Hospital, Ospedale di Monselice, Via G. Marconi 19, 35043 Monselice, Italy. francescopolistina@hotmail.it
Telephone: +39-429-788272 Fax: +39-429-788080
Received: October 29, 2013 Revised: January 3, 2014 Accepted: February 17, 2014 Published online: July 28, 2014 Processing time: 270 Days and 7.6 Hours
Abstract
Pancreatic cancer (PC) is the fourth cause of cancer death in Western countries, the only chance for long term survival is an R0 surgical resection that is feasible in about 10%-20% of all cases. Five years cumulative survival is less than 5% and rises to 25% for radically resected patients. About 40% has locally advanced in PC either borderline resectable (BRPC) or unresectable locally advanced (LAPC). Since LAPC and BRPC have been recognized as a particular form of PC neoadjuvant therapy (NT) has increasingly became a valid treatment option. The aim of NT is to reach local control of disease but, also, it is recognized to convert about 40% of LAPC patients to R0 resectability, thus providing a significant improvement of prognosis for responding patients. Once R0 resection is achieved, survival is comparable to that of early stage PCs treated by upfront surgery. Thus it is crucial to look for a proper patient selection. Neoadjuvant strategies are multiples and include neoadjuvant chemotherapy (nCT), and the association of nCT with radiotherapy (nCRT) given as either a combination of a radio sensitizing drug as gemcitabine or capecitabine or and concomitant irradiation or as upfront nCT followed by nRT associated to a radio sensitizing drug. This latter seem to be most promising as it may select patients who do not go on disease progression during initial treatment and seem to have a better prognosis. The clinical relevance of nCRT may be enhanced by the application of higher active protocols as FOLFIRINOX.
Core tip: The present paper is a review on the upcoming issue of neoadjuvant strategies for pancreatic cancer patients. Protocols, timing and results of the largest series from different strategies are here presented and discussed. To authors knowledge this is the first published paper that considers even latest papers on neoadjuvant treatment for even potentially resectable pancreatic cancer.
Citation: Polistina F, Natale GD, Bonciarelli G, Ambrosino G, Frego M. Neoadjuvant strategies for pancreatic cancer. World J Gastroenterol 2014; 20(28): 9374-9383
Pancreatic cancer (PC) is the fourth-leading cause of death due to cancer in Western countries and accounts for nine cases per 100000 inhabitants per year in Europe[1]. The only chance for long-term survival is an R0 surgical resection that is feasible in about 10%-20% of all cases. Cumulative survival after 5 years is less than 5% and rises to 25% for radically resected patients; in this latter group, local recurrences occur in about 50% of cases and distant metachronous metastases appear in more than 70% of patients[2,3].
Only about 20% of patients are diagnosed with surgically resectable pancreatic cancer; 40% of patients have the metastatic disease and the remaining 40% have locally advanced pancreatic cancer in either the Borderline Resectable Pancreatic Cancer (BRPC) or the Locally Advanced Pancreatic Cancer (LAPC) form[4].
DEFINITION OF LAPC AND BRPC
Due to the complexity of the anatomy in the pancreatic region, even small cancers may be found at an advanced stage where the vascular invasion is so far as to be deemed unresectable (UR). Thanks to technological progresses in the field of preoperative imaging in the last decade, a new pathological entity has arisen. BRPC is seen in a subgroup of patients in the LAPC group whose conditions are considered to be resectable with a need for vascular resection and reconstruction, but who remain at a higher risk for local recurrence. A definitive definition of BRPC is still lacking and currently there are two different classification systems: the MD Anderson Cancer Center[5] (MDACC) system and the American Hepatopancreatobiliary Association (AHPBA)/Society of Surgical Oncology (SSO)/Society for Surgery of the Alimentary Tract (SSAT) system[6], which has been endorsed by the National Comprehensive Cancer Network (NCCN) guidelines. These two classification systems substantially overlap each other with one particular difference: the abutment of the celiac trunk is classified to be “borderline resectable” in the MDACC classification while it is considered to be unresectable in the AHPBA/SSO/SSAT/NCCN classification; this discrepancy is probably due the increased confidence in pancreatic surgery associated with vascular resections of some surgical groups as compared with other surgeries[7]. The criteria for the definition of UR, LAPC and BRPC are summarized in Table 1. Moreover, the MDACC added cancer feature data from tumors and the patient’s biology as considerations to create three groups of patients: (1) patients with radiologically well defined cancers; (2) patients with inconclusive but suspicious metastatic disease radiologic findings; and (3) patients with a borderline status for major abdominal surgery. This last classification may have some importance in assigning patients to a somewhat personalized treatment but, on the other hand, it further enhances the discrepancies between classification systems.
Table 1 Definition of borderline resectable and locally advanced according to the MD Anderson Cancer Center and the American Hepatopancreatobiliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract/National Comprehensive Cancer Network classification systems of stage III pancreatic cancer.
Triphasic, thin-cut, contrast-enhanced CT scans show an 87% success rate in diagnosing vascular invasion from pancreatic cancer[8-11]. The main limitations of this technique include its poor effectiveness of diagnosing small amounts of hepatic and/or peritoneal spread[12,13]. As a consequence, approximately 20% of patients that were thought to be resectable on CT scans show the metastatic disease when a laparotomy is conducted[14,15].
Magnetic Resonance Imaging (MRI) is of limited interest in such a setting; this technique is effective only in cases of patients with ascites and a previously known intolerance to iodinated contrast media. Moreover MRI may be helpful in better characterizing small (< 1 cm) hepatic lesions shown by CT scans and small intrapancreatic lesions that have not yet altered the pancreatic profile[16,17].
Endoscopic ultrasounds are increasing important with an accuracy as high as 85%, with a 75% specificity and a 100% sensitivity of diagnosing pancreatic cancer resectability[18-20].
Staging laparoscopy, coupled with laparoscopic ultrasounds of the liver and pancreatic region, has shown to produce a better definition of either nodal invasion or the local invasiveness of the disease. This technique has been shown to be superior to CT scans in terms of accuracy in detecting the presence of hepatic metastases[13,21-24].
The most widely accepted criteria for selecting patients that should undergo staging laparoscopy for pancreatic cancer currently are pancreatic head tumors > 3 cm in maximum diameter, cancers located in the body and tail of the gland, and cancers with unclear margins on imaging and Carbohydrate Antigen 19.9 > 100 U/mL in patients with normal serum bilirubin levels[25].
BASIS FOR NEOADJUVANT THERAPY
Patients with LAPC and either BRPC or UR pancreatic cancer have about a 50% chance for curative resection, as compared with stage I and II pancreatic cancers[5,26-28]. This is mainly due to the high frequency of invasion of the retroperitoneal margin and/or the nervous plexus of the SMA, whose resection adds further morbidity to the intrinsic morbidity related to pancreatic resections with vascular reconstructions[29-32]. The most significant factor predicting long-term survival in pancreatic cancer patients is an R0 resection, a widely accepted procedure. An R1 resection is associated, independent of the original stage of disease, with a prognosis similar to patients with the inoperable disease[33-42].
Early retrospective analyses showed that the chance to obtain an R0 resection for both UR-LAPC and BRPC patients was about one half compared with that for T1 and T2 patients[43-45].
At the same time, some randomized multicentric studies with adjuvant therapies for resectable pancreatic cancer showed a survival advantage for treated patients for both overall survival and disease-free survival[33,46,47], while studies performed with adjuvant radiotherapy and Intraoperative Radiotherapy showed a good efficacy in a local control of disease.
Recent meta-analyses done on early published studies on neoadjuvant treatments of BRPC and LAPC[48] showed an increased rate of R0 resections with unchanged mortality and morbidity as compared with those treated by upfront surgery. Moreover, these meta-analyses show some evidence of additional advantages over neoadjuvant strategies: (1) patients treated by upfront surgery often show a delay in the beginning of adjuvant treatment due to surgical complications, even minor ones. This fact leads to an evident survival handicap. Neoadjuvant therapy may avoid this handicap[25]. In three different studies, patients who underwent neoadjuvant therapies completed the cycles in 90%-100% of cases, compared with 62% of patients who completed adjuvant chemotherapy in the CONLO-001 study[25]; (2) neoadjuvant therapies may help in avoiding unnecessary major abdominal surgery for patients who go on disease progression during treatment; (3) giving chemotherapic agents to a patient with pancreatic tissue not yet altered by the trauma of surgery seems to have a better effect due to better vascularization and subsequent drug delivery to neoplastic tissues[34]; (4) for BRPC and LAPC patients, neoadjuvant therapy lead to a downstaging of the disease, increasing the rate of R0 resections[5,38-44]; (5) some studies report a decreased incidence of anastomotic fistulas after neoadjuvant therapies, probably due to the pancreatic and peripancreatic fibrosis inducted by treatment[45,49-51]; and (6) two recent comparative analyses on the costs of various treatments for pancreatic cancer showed an economic advantage in neoadjuvant treatment regimens[45,52].
NEOADJUVANT CHEMOTHERAPY FOR LAPC AND BRPC
Gemcitabine-based chemotherapy
Older randomized trials exploring the effects of neoadjuvant chemotherapy alone on pancreatic cancer included both BRPC/LAPC patients and metastatic pancreatic cancer patients (Table 2). Gemcitabine-based studies evaluated both metastatic and LAPC patients and showed a 20%-30% response rate without any difference between metastatic and locally advanced. In two studies, Gemcitabine was given with Oxaliplatin vs Gemcitabine alone[45,46]. In one study, Gemcitabine was given with Irinotecan vs Gemcitabine alone[47]. In another study, Gemcitabine was given with Bevacizumab vs Gemcitabine alone[49]. All of these studies showed that results were significantly superior in favor of the combination therapy vs Gemcitabine alone but no study had resection as an endpoint. In a meta-analysis by Andriulli and others exploring the effects of Gemcitabine-based neoadjuvant therapy for pancreatic cancer, the reported of 1 and 2 year survival rates are 54.2% and 27% for patients with LAPC, respectively, with a complete/partial response ratio of 27% (95%CI: 18-38)[50]. A recent report by Lee et al[51] studied 43 patients affected by both LAPC (25) and BRPC (18), as defined by the NCCN criteria. The patients were treated with a combination of Gemcitabine and Capecitabine and the authors reported a 18.6% radiological response rate and a stable disease rate of 69.8%. In the LAPC group, 24% underwent surgical resection with 83.3% having R0 resections. In the BRPC group, 61% underwent resection with 81.8% having R0 resections. Sahora and collaborators, in a prospective study on 13 LAPC patients and 12 BRPC patients treated by neoadjuvant Gemcitabine and docetaxel chemotherapy, reported an overall resection rate of 32% with 87.5% having R0 resections and a median survival time of 16 mo for resected patients (95%CI: 8-24 mo) vs 12 mo for unresected patients[51]. An overview of these studies is given in Table 3.
Table 2 Studies on chemotherapy for advanced pancreatic cancer.
Based on the work of Conroy et al[33] reporting on the results of a phase III study on the efficacy of FOLFIRINOX chemotherapy on both LAPC and metastatic pancreatic cancer, this study compared FOLFIRINOX with Gemcitabine alone and showed the significant superiority of FOLFIRINOX in Overall Survival (OS), Progression Free Survival (PFR) and Overall Response Rate. Notably, as for the Gemcitabine-based studies, LAPC showed the same response rate as metastatic pancreatic cancer. Retrospective and registry analyses data on neoadjuvant FOLFIRINOX are currently available and show mostly consistent results for both metastatic pancreatic cancer and LAPC[33,53-55]. A recent retrospective study published by Hosein et al[39] on 18 patients with LAPC (4 BRPC and 14 UR, as defined using the AHPBA/SSO/SSAT criteria for resectability definition) report a 38.8% post-treatment radiologic resectability with a 62.5% rate of R0 resections and a 1 year progression free survival (PFS) rate as high as 83%; the 1 year overall survival rate was 100%. They did not find any statistically significant difference in survival rates between the R0 and R1 resected patients. Moreover, several dosage adjustments of chemotherapic were required during treatment, although this procedure did not seem to interfere with the overall results[39]. A more recent study from Marthey on a preliminary prospective database with FOLFIRINOX in 53 LAPC patients showed an 83% disease control rate with a 30% response rate and a final 32% resectability rate although some of the responding patients underwent external beam radiotherapy as a continuation of the treatment schedule[56]. The preliminary result of this study is that FOLFIRINOX is effective at controlling pancreatic cancer with an overall response rate higher than 30%. This finding forecasts more focused phase III clinical trials on this subject.
Neoadjuvant chemoradiotherapy
Evidence to support the use of neoadjuvant chemoradiotherapy (CRT) for LAPC is limited but rapidly increasing. The theoretical hypothesis that CRT is based on is that while chemotherapy provides control for a micro-disseminated disease and also acts as a radiation sensitizer, radiotherapy (RT) may have a huge impact on the local control of the disease. Since the mid-1980s, studies have been published on the treatment of LAPC by 5-FU-based CRT protocols that were shown to prolong survival when compared with radiation alone[57].
The next step was the use of Gemcitabine as a chemotherapic drug instead of 5-FU, with some evidence of a higher efficacy on both local response and overall survival[57]. In a recent meta-analysis from Gillen et al[40] 111 trials including as many as 4394 pancreatic cancer patients were evaluated[47]. The authors found an overall response rate of 42% for LAPC and overall disease control for 77% of LAPC patients. Laparotomies was performed in 47% of initially UR patients and, among these patients, 33% were resected; 79% had R0 resections. The overall reported median survival duration was 10.2 mo while for the 33% of resected patients, the median survival duration was 20.5 mo. Similar results were found by other systematic reviews[39,48,58-60]. A recent multi-institutional phase II study on GEMOX-based CRT by Kim et al[61] clearly reports on the efficacy of their CRT protocol. This is the first prospective trial where resectability is a clear endpoint, including resectable pancreatic cancer, BRPC, and UR with a clear definition according to NCCN criteria. The study enrolled 68 patients (23 resectable, 39 BRPC and 6 UR). Sixty-six patients completed the protocol and were evaluated for surgery and 48 underwent laparotomies with 84% having R0 resections. In particular, 13 out of 19 eligible patients from the BRPC group had a post-CRT R0 resection. The median OS was 18.2 mo (95%CI: 13-26.9 mo) with the best performance for the initially resectable patients (26.5 mo). The resected patients from the BRPC pre-treatment group had a median OS of 18.4 mo.
The evidence that about 30% of LAPC patients develop systemic metastases during the early cycles of treatment[40] indicates the need for some early systemic control of the disease. To this end, some researchers treated LAPC patients with upfront chemotherapy followed by CRT. The presumed advantage of such a treatment schedule is that the early therapeutic approach may use not only RT-sensitizing drugs such as 5-FU and Gemcitabine or Capecitabine but rather drugs that are more effective against cancer. On the other hand, this approach may select patient who did not progress, thus avoiding the additional toxicity of unnecessary Radiotherapy (RT). Two retrospective and two prospective studies on this issue showed promising results. Huguet et al[62] used an upfront administration of Gemcitabine followed by Gemcitabine-based CRT for 71% of patients who did not progress. The authors recorded a 15 mo median OS with a 10.8 mo median PFS that was significantly better than the median OS and PFS of patients treated by Gemcitabine-based CT only in the same study. These data completely consist with those reported by Krishnan[63], who retrospectively analyzed the effect on 323 LAPC patients who had received primary CRT (247 patients) or induction Gemcitabine-based CT followed by Gemcitabine-based CRT (76 patients). They found that there was a strongly statistically significant improvement in both OS and PFS in the CT-CRT group when compared with patients in the CT-alone group (P < 0.001 in both cases).
Last year, data from one phase II and one phase III prospective trials on CT followed by CRT became available. Mukherjee et al[64] treated 114 patients (the SCALOP study) with induction Gemcitabine/Capecitabine-based chemotherapy. The 74 patients who were not progressing were randomized to undergo a course of external beam RT given with Capecitabine (36 patients) or Gemcitabine (36 patients) administered concomitantly. In the setting of a strong survival advantage for CRT patients vs CT alone, the authors reported a better performance in both OF and DFS for the Capecitabine group, which showed a median OS of 15.2 mo and a DFS of 12 mo vs 13.4 mo (OS) and 10.4 mo (DFS) for the Gemcitabine-based CRT patients (P < 0.001).
Leone et al[65] published results of upfront GEMOX CT followed by Gemcitabine-based CRT; this study is the only one to include surgery as an option while also reporting on the resectability rate. The authors enrolled 39 patients with both BRPC (15 patients) and LAPC (24 patients) as defined by the NCCN criteria and applied an induction GEMOX-based CT and then a restaging; non-progressing patients then underwent a 50.5 Gy fractioned RT with concomitant Gemcitabine infusion on a twice-weekly base standard dose. The study reports that 94.9% of patients maintained at least a stable disease with no complete responses and 10.2% were partial responses; 15 patients were deemed resectable at the end of the treatment (38.4%) and, of these, 14 were operated on (one patient refused) with nine R0 resections (64.2%). The overall median PFS was 10.2 mo with 40% DFS at 1 year and 12% DFS at 2 years. The DFS was significantly longer for resected patients (P < 0.000001). The overall median OS was 16.7 mo while it was 27.8 mo for BRPC and 13.3 mo for LAPC (Table 4). These data substantially confirm that BRPC and LAPC patients converted to resectability may have a significant survival advantage and even a chance for a cure by an appropriate multimodal treatment.
Table 4 Studies on neoadjuvant chemoradiotherapy for locally advanced pancreatic cancer.
NEOADJUVANT TREATMENT FOR RESECTABLE PANCREATIC CANCER
The impressive initial results obtained by neoadjuvant treatment for LAPC lead one to consider applying neoadjuvant strategies even to resectable pancreatic cancer. In a prospective phase II trial giving GEMOX CT to 28 patients, Heinrich et al[66] showed that neoadjuvant treatment did not affect resectability rates with a good tolerance profile since the same author began, in 2011, a randomized multicentric phase III study tht gave adjuvant Gemcitabine vs neoadjuvant GEMOX to resectable pancreatic cancer patients (NEOPAC study). This study is still continuing[67]. Tujima et al[68] reported on 34 patients with resectable pancreatic cancer randomized to receive standard upfront resection (21 patients) or two cycles of neoadjuvant therapy with Gemcitabine and oral S-1. They found no difference in resectability rates between the two groups and a statistically significant difference in the 1 and 2 years survival rates for treated patients that decreased over time to become consistent with that of the untreated patient survival rates at 3 years. More recent papers including neoadjuvant CRT are available. The study from Sho et al[69] compared 61 resectable (22 patients) or borderline resectable (39 patients) pancreatic cancer patients treated by a Gemcitabine-based 50 Gy fractionated course of RCT with 71 pancreatic cancer patients treated by upfront resection. The study presents some potential biases from the lack of pre-neoadjuvant Chemoradiotherapy (nCRT) histological confirmation of the diagnosis for some patients and the administration of adjuvant CT to some others. Otherwise, they report no difference in the resection rates between the groups and a statistically significant reduction in post-operative pancreatic fistulas (P = 0.045) and length of hospital stay (P = 0.0173) for nCRT patients vs upfront surgery. Moreover, there was a statistically significant reduction on nodal metastases in nCRT patients (P = 0.0001) and an R0 resection rate that was statistically higher in nCRT patients vs upfront surgery patients (92% vs 56%; P < 0.0001); no data on OS and DFS are reported.
In the most recently published study of Van Buren et al[70] in a phase II trial, the effects of induction fixed dose rate Gemcitabine followed by 30 Gy RT as neoadjuvant treatment of potentially resectable pancreatic cancer were examined. They enrolled 59 patients, of which 29 had BRPC. They report a 72.8% resection rate with a toxicity similar to other reported series and an R0 resection rate of 88% of resected patients (95%CI: 75-96) and a median OS of 16.8 mo (19.7 mo for resected patients).
Neoadjuvant therapy for resectable pancreatic cancer is an upcoming issue to be explored since it appears to have no significant toxicity nor shows a reduction in surgical resections. Conversely, from preliminary results, neoadjuvant therapy appears to reduce post-operative complications and hospital stay durations and also increase the rate of R0 resections. Further large randomized studies are necessary to confirm its usefulness and to assess the best treatment planning and schedule. An overview of studies is given in Table 5.
Table 5 Studies on neoadjuvant chemotherapy for potentially resectable pancreatic cancer.
Pancreatic cancer remains a highly lethal disease in spite of all surgical, oncological, and technological progress of the last 30 years. Over this period, the prognosis of virtually all solid cancers has significantly increased; the prognosis for pancreatic cancer has remained almost the same. Pancreatic cancer patients had an overall 3% 5 year survival rate in the 1970s compared with the 5%-6% survival rate they have nowadays. In the last decade, LAPC has been recognized as an autonomous pathological entity; surgeons and oncologists have begun to try to standardize specific therapeutic strategies according to the evidence that only the achievement of surgical resection with negative margins may give a chance for a cure. The evidence that R0 resection rates are higher after neoadjuvant therapies highlights the need for research in this specific field. Based on a literature review on the issue, it appears that there are several critical points that still remain unresolved. First of all, there is a need for an univocal classification system that clearly distinguishes between borderline resectable and UR pancreatic cancer; the currently available systems do not allow for this distinction and tumors deemed “resectable” by the MDACC are deemed “unresectable” by the NCCN classification. This situation is somewhat misleading in objectively interpreting data from various groups of researchers.
Most of the studies are retrospective and done on series collected before the rise of LAPC as an independent entity, therefore the classification was done “ex-post” and this may be a further bias. Very few studies report on resectability rates or even have resection as a study endpoint; the data are mostly extracted from a larger series of patients including mostly metastatic pancreatic cancer. These studies are of great significance as they show the potentialities of treatment but are non-specific and therefore potentially highly biased.
Nonetheless, an encouraging level of evidence suggests that patients undergoing neoadjuvant therapies for LAPC have a better prognosis than patients treated by upfront surgery or adjuvant therapy alone. At the same time, it appears that even patients with LAPC may have a chance for cure if down-staged to have an R0 resection, thereby achieving survival curves identical to those of primarily resectable patients. Such evidence currently suggests that even initially resectable pancreatic cancer can benefit from a neoadjuvant treatment, but this hypothesis is yet to be confirmed.
We are convinced that there is an enormous need for high-quality, randomized prospective studies that include a better selection of patients and searches for better strategies for each patient.
LOOKING FORWARD
As a future perspective, there are new advances in the field of chemotherapy agents and newer RT technologies such as Intensity Modulated Radiotherapy or Stereotactic Body Radiotherapy.
There are recently closed and ongoing trials on metastatic pancreatic cancer testing the efficacy of combined Gemcitabine and the Epidermal Growth Factor Receptor antibodies Cetuximab and Erlotinib[71,72]. However, at the present time, the results are not encouraging. Preliminary results on the use of Gemcitabine and the Vascular Endothelial Growth Factor inhibitor Axitinib did not improve outcomes in a published series[73] and the anti-HER2 drug Trastuzumab associated with Capecitabine did not seem to improve patient outcomes[74].
Recently, interest has been rising about a tumoral cytoplasmic protein involved in intracellular transport and RNA inclusion of Gemcitabine metabolites: the Intratumoral Human Equilibrative Nucleoside Transporter-1, whose presence seems to be related to responses to Gemcitabine therapy[75], but which still lacks a standard definition of a proper tissutal concentration of the molecule.
Stereotactic Body Radiotherapy has been tested in some non-randomized studies. Polistina et al[76] treated 24 patients with intraoperatively proven UR LAPC with a 3 wk Gemcitabine CT followed by 30 Gy SBRT in three consecutive fractions and concomitant Gemcitabine at a standard dose. They report a 33% radiologic conversion to resectability and 8% R0 resections (with three patients refusing reoperation) and minimal treatment toxicity (no grade 3 or 4 events) with a 20 mo median survival time for resected patients and one histological complete tumor response. Similar toxicity and response rate results have been published by other groups[77].
SBRT CRT is a promising tool as it hypothetically adds the benefits of systemic CT to the local control of disease as obtained with more focused delivery of radiation to the tumor bed. There is less risk to nearby organs and a subsequent decreased toxicity. However, there is a strong need for prospective, randomized trials to confirm these preliminary results.
Footnotes
P- Reviewer: Cappellani A, Lee MA S- Editor: Qi Y L- Editor: A E- Editor: Zhang DN
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