Esophageal cancer is a complex clinical picture. Interdisciplinary consultation and care of the patient are therefore useful. What is the place of radiotherapy or radiochemotherapy in multimodality treatment?
Depending on localization, stage and secondary diseases, there are different therapeutic concepts for esophageal cancer. The studies that define the therapy standards to this day were conducted with technology that is outdated from today’s perspective. What is certain is that both radiotherapy and surgery have made enormous technical advances in recent years, so that both forms of treatment can now be used more gently and with fewer complications. Regardless of the type of local treatment, distant metastasis remains the limiting factor for survival. Especially in the elderly or morbid patient, as well as in locally advanced disease situations, it is not always easy to determine the optimal therapeutic concept. In this article, we would like to summarize the role of radiotherapy or radiochemotherapy in the multimodality treatment of esophageal cancer.
Neoadjuvant radiochemotherapy
Radiochemotherapy has been established for the treatment of esophageal cancer since the 1990s [1]. It was not until 2012 that randomized results were available with the CROSS trial [2], which demonstrated the clear advantage of combined radiochemotherapy over surgery in locally advanced esophageal cancer. The CROSS trial randomly compared radiochemotherapy with 41.4 Gy in 23 fractions, concurrent carboplatin AUC2 and paclitaxel 50 mg/sqm weekly, followed by surgery versus surgery alone, in patients at stages T1 N1 or T2-3 N0/N1. Locally advanced tumors (T3-4) were present in 78% of patients.
The significant increase in R0 resections and pathological complete remissions, the reduction in the number of positive lymph nodes in the surgical specimen as well as a clinically relevant improved median survival as well as 5-year survival (47% vs. 34%, p=0.003) made this concept the new therapeutic standard. Prior to the CROSS study, there was a common belief among clinicians that adenocarcinomas were not as radiosensitive. It should be noted that 75% of patients in this study had adenocarcinomas. The CROSS regimen has not yet been compared against definitive radiochemotherapy using modern radiation techniques. Therefore, the extent to which definitive radiochemotherapy might be an equivalent alternative to trimodal therapy remains to be determined.
Definitive radiochemotherapy
The standard of care for unresectable esophageal cancer is definitive combined radiochemotherapy. This mainly includes unresectable thoracic esophageal carcinomas and unresectable carcinomas of the gastroesophageal junction (GEJ) type Siewert I and II. Cervical esophageal carcinomas are usually not operated on, but treated for laryngeal preservation with definitive radiochemotherapy analogous to advanced hypopharyngeal carcinoma, with radiation doses of 66-70 Gy. Siewert III type GEJ carcinoma is the domain of surgery and systems therapy and is not treated with curative radiation. The different target volumes depending on the primary tumor location and the therapeutic goal are shown in Figure 1.
In the RTOG 8501 trial, patients with unresectable esophageal cancer were randomized to either 64 Gy alone or 50 Gy in combination with 1000 mg/m2 FU and 75 mg/m2 cisplatin × 4 (weeks 1, 4, 8, and 11) [3]. The 5-year survival was 0% after radiotherapy alone vs. 27% after combined treatment (p<0.0001). Radiochemotherapy has since become the curative treatment alternative to surgery, and radiotherapy alone is considered palliative treatment only. However, the locoregional recurrence rate in this study was still 45% within two years even after combined treatment. To further improve the outcome of radiochemotherapy, a dose-escalation study (RTOG94-05) was performed comparing 50.4 Gy with 64.80 Gy, both in combination with 5FU/cisplatin-based chemotherapy [4]. Median survival was significantly shorter in the high-dose arm with, however, a high rate of G5 toxicity. The majority of the treatment-related deaths occurred before the 50.4 Gy dose threshold was reached, making the results of the study difficult to interpret. The reason for the high toxicity is thought to be the use of outdated 2D and 3D irradiation techniques and the associated higher cardiac and pulmonary exposure. With modern IMRT, the heart and lungs can now be spared relevantly better and radiation doses of up to 60 Gy or higher can be applied with moderate toxicity [5].
Regarding the comparison between surgery and radiochemotherapy alone, it must be said that to date there is no evidence from randomized trials for the advantage of trimodal treatment over radiochemotherapy alone. Pöttgen et al. suggested in a 2012 meta-analysis of six randomized trials that surgery after radiochemotherapy improves local control but has no effect on overall survival. In view of these data, patients with relevant comorbidities or an individually increased risk of surgery must be critically questioned as to what extent surgery should be performed and whether definitive radiochemotherapy would not be the adequate means of choice in these cases instead [6].
Palliative radiotherapy concepts
It is not uncommon for polymorbid or elderly patients to be diagnosed with esophageal cancer. These patients are often not amenable to combination or even trimodal therapy, as this would be too toxic. Due to the frequent pre-existing local problems and possible impending complications with further progression of the primary tumor (e.g., fistulization, stenosis, regurgitation with aspiration), local control is often beneficial for palliation and improvement of quality of life. In addition, for many patients, receiving peroral nutrition is essential for a good quality of life and thus avoiding permanent tube feeding – especially in light of the limited lifespan.
There are few prospective studies and few retrospective cohort descriptions on this topic. In a randomized trial of 111 patients, short-term radiotherapy alone (35 Gy in 15 fractions or 30 Gy in 10 fractions) was shown to produce only slightly less improvement in dysphagia (35% vs. 45% p=0.13) with, however, significantly less toxicity (16% vs. 36% p=0.0017) than palliative radiochemotherapy [7].
Overall, a palliative effect can be achieved within a reasonable therapy time with a so-called “mild” hypofractionation. This should be considered in the multimodal palliative therapy concept, taking into account the overall prognosis.
Current clinical scientific issues
The PRODIGE-32-ESOSTRATE1-FFCD1401 trial (Fig. 2) is currently comparing subsequent surgery with close monitoring and surgery only for local relapse in patients who have complete clinical remission after pretreatment with chemoradiotherapy. In this Phase II/III intergroup study, a total of 593 patients will be enrolled and, in the event of a complete response, approximately 260 patients will be randomized. The study PI is Laurent Bedenne from CHU Dijon.
The combination of radiochemotherapy and immunotherapy is also of scientific interest in esophageal cancer. In a recently published phase II trial, 45% of 90 patients with esophageal cancer recurrence had PDL1-positive tumors on immunohistochemistry. The response of these patients to monotherapy with the anti-PDL1 inhibitor pembrolizumab was 30%. Using genetic analyses, an IFNy score was calculated, with a higher score correlating with longer progression-free survival. Nearly half of the patients with a good response to pembrolizumab had received prior radiotherapy. It is possible that radiotherapy also has an immunomodulatory effect in esophageal cancer, similar to that in bronchial carcinoma [8].
The EORTC will soon open the randomized phase II CRUCIAL trial (EORTC-1714-ROG-GITCG, NCT03437200). Patients with unresectable esophageal cancer are treated with definitive radiochemotherapy in combination with the anti-PD1 antibody nivolumab with or without the anti-CTLA-4 antibody ipilimumab. The study’s PI is Eric Deutsch of the Radiation Oncology Unit at the Institut Villejuif in Paris. All patients receive 50 Gy in 2 Gy single doses in combination with six cycles of FOLFOX. Antibodies are administered during radiochemotherapy and for one year thereafter. The primary endpoint of the study is PFS at twelve months according to RECIST 1.1. A total of 130 patients will be included.
Two other trials combine radiochemotherapy with nivolumab ± ipilimumab or with durvalumab in the preoperative setting (NCT03044613, NCT02962063). In addition to clinical endpoints, the expression of immune markers will be examined in the resected tumors.
Another randomized North American phase II trial is currently comparing proton- versus photon-based radiochemotherapy at 54 Gy/1.8 Gy (NCT0151258). Primary endpoints are PFS and radiogenic toxicity.
Take-Home Messages
- Interdisciplinary patient counseling and care, including consideration of individual patient preferences and comorbidities, are essential in this complex clinical picture.
- For fit patients with operable advanced tumors, trimodal therapy consisting of neoadjuvant radiochemotherapy followed by surgery is the treatment of choice.
- In comorbid patients with increased risk of surgery or patients with unresectable tumors, definitive combined radiochemotherapy is a curative treatment option.
- In the palliative setting, short-term palliative radiotherapy can be a valuable option in symptom control.
- Current clinical trials are investigating the omission of surgery after radiochemotherapy for clinically complete response and the combination of radiochemotherapy and immunotherapy in both the neoadjuvant and definitive settings.
Literature:
- Herskovic A, et al: Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992 Jun 11; 326(24): 1593-1598.
- van Hagen P, et al: Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012 May 31; 366(22): 2074-2084.
- al-Sarraf M, et al: Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 1997; 15(1): 277-284.
- Minsky BD, et al: INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002; 20(5): 1167-1174.
- Roeder F, et al: Intensity modulated radiotherapy (IMRT) with concurrent chemotherapy as definitive treatment of locally advanced esophageal cancer. Radiat Oncol 2014; 9: 191.
- Pöttgen C, Stuschke M: Radiotherapy versus surgery within multimodality protocols for esophageal cancer–a meta-analysis of the randomized trials. Cancer Treat Rev 2012 Oct; 38(6): 599-604.
- Penniment MG, et al: Palliative chemoradiotherapy versus radiotherapy alone for dysphagia in advanced oesophageal cancer: a multicentre randomised controlled trial (TROG 03.01). Lancet Gastroenterol Hepatol 2018 Feb; 3(2): 114-124.
- Doi T, et al: Safety and Antitumor Activity of the Anti-Programmed Death-1 Antibody Pembrolizumab in Patients With Advanced Esophageal Carcinoma. J Clin Oncol 2018; 36(1): 61-67.
InFo ONCOLOGY & HEMATOLOGY 2018; 6(3): 18-21.
