Advances in radiotherapy in the treatment of esophageal cancer

Abstract

Recent advancements in radiotherapy for esophageal cancer have significantly improved treatment outcomes and patient quality of life. Traditional radiotherapy techniques have been enhanced by the integration of advanced imaging and precision targeting technologies, such as intensity-modulated radiotherapy and proton therapy, which allow for more accurate tumor targeting while minimizing damage to surrounding healthy tissues. Additionally, combining radiotherapy with immunotherapy has shown promising results, leveraging the body’s immune response to enhance the effectiveness of cancer treatment. Studies have also highlighted the benefits of neoadjuvant chemoradiation followed by surgical resection, which has been associated with improved overall survival rates compared to radiotherapy alone. These innovations are paving the way for more effective and personalized treatment strategies, offering new hope for patients with esophageal cancer.

Key Words: Esophageal cancer; Radiotherapy; Advances; Immunotherapy; Multi-modality treatment; Chemoradiotherapy

Core Tip: In the era of targeted therapy, radiotherapy practices have been modified based on the evidence available. This article summarizes the current practices of curative radiotherapy as a part of the multi-modality treatment of esophageal carcinoma.

TO THE EDITOR

We have had the opportunity to review the work by Christodoulidis et al[1] on the advancements and challenges in esophageal cancers. The article describes the current role of immunotherapy, particularly immune checkpoint inhibitors, therapeutic vaccines, immunomodulators, monoclonal antibodies, and adoptive cellular immunotherapy. The article, additionally, sheds light on the role, the targets, and commonly used drugs in the categories of anti-combining programmed cell death 1 (anti-PD-1) antibodies, anti-PD-L-1 antibodies, anti cytotoxic T- lymphocyte-associated protein 4 (anti-CTLA-4) antibody, and cancer-associated fibroblasts. The article concludes by stating the future directions regarding these therapies, human epidermal growth factor receptor 2 (HER2)-positive gastroesophageal junction (GEJ) malignancies, and by citing landmark malignancies about these therapies. We commend the authors for their concise description of recent advances in immunotherapy.

Esophageal and GEJ cancers have been treated using multi-modality therapy since time immemorial. Advances in the therapy of esophageal cancers have not only taken place in targeted therapy but also in radiotherapy and surgery. We look to shed light on some of the advances in the field of esophageal cancer radiotherapy in the curative setting.

Current guidelines for local and locally advanced esophageal cancers [cT2, N0 with high-risk lesions: Lymphovascular invasion ≥ 3 cm, poorly differentiated, and in lesions > cT2, and any N+ lesions] are based on the results of the CROSS trial[2,3]. Neoadjuvant chemoradiotherapy (CTRT) followed by surgery is the treatment of choice. Long-term results of the CROSS trial reported a median overall survival (OS) of 48.6 months in the neoadjuvant CTRT plus surgery group and 24.0 months in the surgery alone group. Median OS for patients with squamous carcinomas of the esophagus was 81·6 months in the neoadjuvant CTRT plus surgery group and 21.1 months in the surgery alone group. Patients with adenocarcinomas had a median OS of 43.2 months in the neoadjuvant CTRT plus surgery group and 27.1 months in the surgery alone group. Radiation is given to a dose of 41.4–50.4 Gy in the pre-operative setting with concurrent paclitaxel and carboplatin or 5-fluorouracil and oxaliplatin. In inoperable cases, and cases in the cervical esophagus, definitive CTRT using RT to a dose of 50–50.4 Gy with the paclitaxel and carboplatin or 5-fluorouracil and oxaliplatin, or cisplatin is the treatment modality of choice[3,4]. Dose escalation is not practiced routinely, and this is based on the results of the INT 0123 (Radiation Therapy Oncology Group 94-05) trial and the ARTDECO study[5,6]. Neoadjuvant Trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study results were reported in 2023 and showed the benefit of multi-modality therapy over perioperative chemotherapy[7]. At the second futility analysis, the 3-year estimated survival probability was 56% (95%CI: 47-64) in the CROSS arm and 57% (95%CI: 48-65) in the FLOT (5-FU/ leucovorin/oxaliplatin/docetaxel) arm. Implementation of the CROSS protocol has had major drawbacks due to the lack of equipped radiotherapy facilities or trained surgeons. A study from Homi Bhabha Cancer Hospital in Sangrur, Punjab reported the outcomes of neoadjuvant treatment and compliance to surgery, and it showed a complete pathological response in 59.4% of the patients who underwent neoadjuvant CTRT[8]. The key reasons for not undergoing surgery were patient refusal (8, 34.8%) and the presence of inoperable (5, 21.7%) or metastatic disease (3, 13%) on imaging after chemoradiation. The median OS in patients who received chemoradiation followed by surgery vs no surgery was 17 months vs 17 months and the results were not statistically significant. Pre-operative CTRT in esophageal adenocarcinomas, however, has come under scrutiny after the abstract of the ESOPEC trial was presented[9]. The trial showed a survival advantage in the FLOT arm as compared to the CROSS arm [median OS: 66 (95%CI: 36-not estimable) months in the FLOT arm vs 37 (95%CI: 28-43) months in the CROSS arm; 3-year OS rates: 57.4% (95%CI: 50.1%-64.0%) for FLOT vs 50.7% (95%CI: 43.5%-57.5%) for CROSS]. Further research to validate these results is required and underway. Future modifications look to go in the direction of FLOT as the standard of care and CROSS an option for ineligible patients. Xiang et al[10] compared induction chemotherapy followed by CTRT with or without consolidation chemotherapy to CTRT followed by consolidation chemotherapy in squamous cell carcinoma of the esophagus. Induction-based regimens did not have any survival advantage when compared to concurrent CTRT in terms of survival [median progression-free survival (PFS) in the CCRT-C, I-CCRT, and I-CCRT-C groups: 32.5, 16.1, and 27.1 months, respectively (P = 0.464); median OS of the CCRT-C, I-CCRT, and I-CCRT-C groups: 45.9, 35.5, and 54.0 months, respectively (P = 0.788)].

Another modification has been response-adapted multi-modality therapy in esophageal cancer, based on the results of the CALGB 80803 (Alliance) Trial[11]. The use of a positron emission tomography (PET) scan after induction chemotherapy to identify responders and nonresponders and switching them to an alternative chemotherapy regimen during CTRT increases pathological complete response (pCR) rates, and responders to oxaliplatin, leucovorin, and fluorouracil (FOLFOX) had better 5-year survival rates when continued on FOLFOX-based CTRT. This trial provided additional insight into the MUNICON II trial, where the value of PET in response assessment was established[12].

Technological advances including intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and proton beam therapy have shown excellent results with minimal toxicities[13-18]. While the mechanism of action of IMRT and VMAT are the same, namely by causing DNA damage, VMAT is more conformal as compared to IMRT. The conformity index (CI) of VMAT plans is around 0.8 while the CI of IMRT plans is around 0.65-0.7[19,20]. VMAT additionally has similar to better sparing of critical normal tissues and a lower normal tissue complication probability (NTCP). Lung V30 was lower in VMAT than in IMRT, and V30, V40, and V50 of the heart in VMAT were lower than in IMRT in the study by Yin et al[19] Increasing the number of fields, however, made the IMRT plan closer to a VMAT plan dosimetrically. Proton beam therapy has the advantage of a Bragg peak where maximum dose deposition occurs at the end of the particle track[21]. This leads to minimal exit dose, and minimal dose to tissues along the entry point of the beam. Additionally, the interactions of protons used in the treatment energy range with tissue cause minimal scatter, and therefore the scatter component of radiation is very low. It can be delivered as passively scattered proton therapy, and intensity-modulated proton therapy[21]. A significantly better OS (42% vs 32%) and PFS (35% vs 20%) with proton beam therapy[22]. They also reported a lower rate of pulmonary, hematological, and local toxicity compared to photon beam therapies[23,24]. The major drawback of proton beam therapy remains its high cost and lack of access in most institutions across the globe[25]. In most institutions, IMRT is the treatment modality of choice to provide good coverage to the target volumes while sparing the surrounding critical structures.

In the era of targeted therapy, the combination of immunotherapy and radiotherapy has shown promising results. The CheckMate 577 trial found a disease-free survival (DFS) benefit when nivolumab was used in the adjuvant setting after neoadjuvant CTRT and surgery [median DFS with nivolumab: 22.4 months (95%CI: 16.6-34.0) vs with placebo: 11.0 months (95%CI: 8.3-14.3)][26]. A systematic review and meta-analysis by Liu et al[27] showed that neoadjuvant immune-CTRT had a trend towards better pCR and major pathological response rates when compared to neoadjuvant immune-chemotherapy (38% vs 78% and 67% vs 57% respectively) however the results were not statistically significant. Both the neoadjuvant combinations seemed to be viable options for patients with esophageal cancers. These results were seconded by the reviews done by Yang et al[28] and Sardaro et al[29]. Mechanisms of action of immunotherapy in combination with radiotherapy include an increase in tumor-infiltrating CD8+ T cells and a decrease in T cell exhaustion[30,31], production of immunogenic cell death by radiation that is the target of immunotherapy[32], and remodeling of the immune microenvironment and upregulating PD-L1 expression[33] which is the target of drugs like nivolumab. The most common adverse events of combination therapy included anemia, leukopenia, and thrombocytopenia[34-37]. Other toxicities included hepatic enzyme disturbances and an increase in local esophageal toxicities[34,37].

In selected cases, active surveillance after neoadjuvant CTRT has been chosen as the action of choice. This was based on the results of the pre-SANO and the SANO trial[38,39]. The results of these trials have been met with skepticism due to various debatable factors in the study design (10% false-negative rates were accepted in the pre-SANO trial, histological stratification of the data is unknown, methods of active surveillance defined have raised doubts as well). The pre-SINO trial had set a sensitivity of 80.5% in the protocol for active surveillance and found sensitivity, specificity, negative predictive value, and positive predictive value of detecting any residual tumor of 82%, 93%, 69%, and 97%, respectively[40]. The low value of sensitivity that was accepted in this trial has also been debated due to the aggressive biology of esophageal cancers. Additionally, most patients do not achieve complete response after neoadjuvant treatment which makes observation a questionable form of action in the current landscape of esophageal cancer treatment. As of today, active surveillance is not advised by any guideline, however with better neoadjuvant therapies and better surveillance protocols, this could be included as a part of the standard of care in the near future.

The drawbacks of multi-modality therapy in esophageal cancer stem from its intensive and complex nature, often leading to significant treatment-related toxicity and complications[41]. The combination also increases the risk of perioperative complications, particularly in high-risk groups like elderly patients or those with comorbidities, who may struggle to tolerate the full intensity of treatment. It often requires a coordinated approach which can be challenging in resource-limited settings. The complexity of care can also place psychological and logistical burdens on patients and their attenders, requiring multiple sessions of visits, prolonged admissions, and regular monitoring. Lastly, variability in response rates has a larger range than most other malignancies, with squamous carcinomas of the esophagus generally responding better to CTRT than adenocarcinomas, which can complicate decisions on optimal treatment sequencing and selection[41].

CONCLUSION

The protocols of radiotherapy have evolved with the changing dynamics of esophageal cancer management, however, multi-modality treatment remains the fundamental practice in its treatment. Targeted therapy being included at the forefront of multi-modality therapy is the key avenue of future research. Targets that are being tested include PD-L1, HER2, microsatellite instability, and nicotinamide N-methyltransferase[42-44]. Theoretical areas in the field of cancer therapy such as RNA and DNA targets can also be areas of focus in the coming days[45,46]. Future trials to find new treatment protocols and verify the existing ones will reinforce management practices.