Summary
To select the treatment policy for cStage II and III esophageal carcinoma, the tolerability to surgical intervention should first be confirmed through evaluation of the patient’s general condition after accurate diagnosis of the clinical stage by means of upper gastrointestinal endoscopy, CT, and PET. When no problem is identified with respect to the tolerability for surgical operation, preoperative chemotherapy should be administered, followed by radical resection, as the first-line therapy. Radical resection without preoperative treatment or with preoperative chemoradiotherapy may also be selected. In cases of surgery without any preoperative treatments, administration of adjuvant chemotherapy should be considered in accordance with the histopathologic diagnosis confirmed from resected specimens (especially for lymph node metastasis-positive cases). Definitive chemoradiotherapy (≥ 50 Gy) should be considered in patients who are unable to tolerate surgery, or refuse surgery, in whom chemoradiotherapy is feasible. Patients in whom complete response is achieved should be followed up, and in case of a remnant or recurrent lesion, the practicability of surgical resection as salvage therapy should be explored. In patients unable to tolerate surgery in whom chemoradiotherapy is not indicated either, radiation therapy (e.g., in patients with depressed renal function, elderly subjects), chemotherapy (e.g., in patients with a history of radiation), palliative symptomatic treatment, or palliative chemotherapy should be considered.
CQ8: Which is recommended, therapy primarily consisting of surgery or definitive chemoradiotherapy, in patients with cStage II or III esophageal cancer?
Recommendation statement
There is weak evidence to recommend therapy primarily consisting of surgery for patients with cStage II or III esophageal cancer (Rate of consensus: 70% [14/20], strength of evidence: C).
Explanatory note
For the treatment of cStage II or III esophageal cancer, preoperative chemotherapy + surgery is recommended in view of the results of the JCOG9907 Study [31]. Meanwhile, definitive chemoradiotherapy is also one of the treatment alternatives that offer the potential for radical cure.
A search of the literature in relation with this CQ yielded 486 PubMed articles, 306 Cochrane articles, and 167 ICHUSHI articles, which were subjected to primary and secondary screenings. Finally, 3 papers dealing with randomized comparative studies and 11 papers related to observational studies were retrieved and subjected to a qualitative systematic review.
There are 3 reports of randomized comparative studies directly comparing the results of surgery and definitive chemoradiotherapy [32,33,34]. Because all these reports are from overseas, however, they differed greatly in the therapy regimens and treatment policies adopted as compared to those in Japan.
In regard to the results of definitive chemoradiotherapy in Japan, the 5-year survival rate was 36.8% in the JCOG9906 Study, which was a single-group phase II clinical study [35].
With regard to observational studies, 10 papers of studies comparing surgery and definitive chemoradiotherapy in patients with cStage II or III esophageal cancer, including 6 papers from Japan, were retrieved [36,37,38,39,40,41,42,43,44]. None of the studies was a randomized comparative study; therefore, many of the studies differed in terms of the background factors of the patients and in the therapeutic regimens adopted from those currently adopted in Japan. As for comparison of the survival time, 3 of the 10 papers indicated that surgery yielded a significant prolongation of the overall survival time. Only 1 paper indicated prolongation of the overall survival time in patients administered radical chemoradiotherapy.
Thus, it was rather difficult to draw a conclusion to respond to this CQ on the ground of the evidence from the systematic review.
With regard to toxicity, the late toxicities reported in patients receiving definitive chemoradiotherapy in the JCOG9906 Study were esophagitis (Grades 3–4; 13%), pericardial effusion (Grades 3–4; 16%), pleural effusion (Grades 3–4; 9%), and radiation pneumonitis (Grades 3–4; 4%); death of 4 cases was also reported. Out of the 10 observational studies, 6 papers from Japan reported operation-related deaths at an incidence rate of 0–4% among patients treated by surgery. In the JCOG9907 Study, there were 2 cases of operation-related death among 330 cases. It should be noted that there is a potential risk of serious adverse events among patients receiving definitive chemoradiotherapy as well as among those treated by surgery.
The basis for considering that surgery may yield greater improvement of the overall survival rate as compared to definitive chemoradiotherapy is thus rather tenuous, and both treatment modalities entail a significant risk of toxicity. However, there is weak evidence to recommend preoperative chemotherapy plus surgery for the treatment of cStage II or III esophageal cancer, because the 5-year survival rate obtained with this treatment in the JCOG9907 Study was 55%, as compared to 37% in the JCOG9906 Study [45], and because many single-institution observational studies conducted in Japan have revealed more gratifying results in surgically treated groups.
Furthermore, the JCOG0909 Study aimed at assessing the usefulness of preoperative definitive chemoradiotherapy followed by positive surgical intervention as salvage operation in patients with cStage II or III esophageal cancer is now in progress. In patients administered definitive chemoradiotherapy, the benefits and risks of subsequent salvage operation for remnant or recurrent lesions should also be considered. According to a report by Tachimori et al. the incidence of postoperative complications was higher in patients who underwent salvage esophagectomy after definitive chemoradiotherapy at a total dose of 60 Gy, along with an increased in-hospital postoperative mortality of 8%, as compared to 2% associated with surgery, in general [46]. In the JCOG0909 Study, a three-dimensional treatment plan and multiple-field irradiation were introduced and the fractional and total radiation doses were modified to 1.8 and 50.4 Gy, respectively, in an attempt to reduce the risk of adverse events and the risk associated with salvage operation that was seen in the JCOG9906 Study. Accumulation of patients has already been completed and the observation period is now progressing in the study; the results of the study are anticipated for clarification of the usefulness of multimodal treatment, such as definitive chemoradiotherapy plus surgery.
Therapy primarily consisting of surgery and definitive chemoradiotherapy are both covered by the national health insurance, and taking into consideration the benefit–risk balance, strength of evidence and patient preferences, we concluded to state that there is weak evidence to recommend therapy primarily consisting of surgery for patients with cStage II or III esophageal cancer.
CQ9: Which of the following three is recommended, preoperative chemotherapy, postoperative chemotherapy, or preoperative chemoradiotherapy, in cStage II or III esophageal cancer patients scheduled to receive therapy primarily consisting of surgery?
Recommendation statement
In patients with cStage II or III esophageal cancer who are scheduled to receive therapy primarily consisting of surgery:
-
(1)
There is strong evidence to recommend preoperative chemotherapy over postoperative chemotherapy (Rate of consensus: 89.5% [17/19], strength of evidence: B).
-
(2)
There is weak evidence to recommend preoperative chemotherapy over preoperative chemoradiotherapy (Rate of consensus: 100% [18/18], strength of evidence: C).
Explanatory note
A search of the literature in relation with this CQ yielded 419 PubMed articles, 321 Cochrane articles, 98 ICHUSHI articles, which were subjected to primary and secondary screenings with an additional 4 articles, followed by qualitative and quantitative systematic reviews of the selected articles.
In regard to comparison between preoperative chemotherapy and postoperative chemotherapy, the most appropriate timing of adjuvant chemotherapy with cisplatin and 5-FU was assessed in the JCOG9907 Study, whose results showed a significantly better overall survival time in the preoperative chemotherapy group as compared to the postoperative chemotherapy group. There was no difference in the incidence of postoperative complications between the 2 patient groups [47]. Based on these results, preoperative chemotherapy with cisplatin and 5-FU is strongly recommended and defined as a standard therapy for cStage II or III esophageal cancer [31].
Comparison between preoperative chemotherapy and preoperative chemoradiotherapy was then pursued. There was only one article related to a randomized study by Stahl et al. [48], in which preoperative chemotherapy and preoperative chemoradiotherapy were compared in patients with adenocarcinoma of the esophagogastric junction. The study was censored due to poor accumulation of cases, therefore, failing to show any significant difference in the endpoint (overall survival time), although the 3-year survival rate was significantly prolonged in the preoperative chemoradiotherapy group as compared to the preoperative chemotherapy group, indicating the possible usefulness of preoperative chemoradiotherapy. However, the target disorder was adenocarcinoma of the esophagogastric junction in this study, hence differing from the subject patient group referred to in this CQ; therefore, the results were not considered adequate for recommending preoperative chemoradiotherapy as the standard therapy in Japan at present.
On account of the paucity of evidence for arriving at any conclusion in respect of comparison between preoperative chemotherapy and preoperative chemoradiotherapy, we compared the outcomes of preoperative chemoradiotherapy and surgery alone. There has been no randomized comparative study investigating the significance of preoperative chemoradiotherapy in Japan, whereas in Europe and North America, a number of randomized comparative studies examining the usefulness of surgery alone, in view of the limitation in its ability to provide local control, have been reported since latter half of the 1980s [49,50,51,52,53,54,55,56,57,58,59,60,61]. The CROSS trial reported by Shapiro et al. [61], comparing a preoperative chemoradiotherapy group and a surgery alone group, demonstrated a significant prolongation of the overall survival time in the former group, in which there was a conspicuous prognostic add-on effect of preoperative chemoradiotherapy, particularly for patients with squamous cell carcinoma. A significant improvement of the postoperative survival rate in the preoperative chemoradiotherapy group was shown by a meta-analysis of data comparing preoperative chemotherapy/chemoradiotherapy and surgery, and surgery alone reported by Sjoquist et al. [62].
Four papers on randomized comparative studies investigating the 5-year survival rate as an outcome [58,59,60,61] from among 13 papers dealing with randomized comparative studies of preoperative chemoradiotherapy versus surgery alone conducted in Europe and North America [49,50,51,52,53,54,55,56,57,58,59,60,61] were subjected to a qualitative systematic review and meta-analysis. The results revealed no significant intergroup difference in the 5-year survival rate between the two treatment groups, although a tendency towards prolongation of the survival was seen in the preoperative chemoradiotherapy group. The patient groups in the 4 randomized comparative studies differed in part from the population under question in this CQ, in that they also included cStage I and cStage IV cases and also patients receiving carboplatin or paclitaxel or cisplatin alone as chemotherapy.
As regards the toxicities associated with preoperative treatment, according to Kumagai et al. [63], a meta-analysis revealed no increase in the mortality attributable to any type of preoperative treatment in esophageal cancer patients overall, when preoperative chemotherapy and preoperative chemoradiotherapy were compared with surgery alone. However, the report describes an increase in the postoperative mortality and incidence of treatment-related death in the preoperative chemoradiotherapy group as compared to the surgery alone group when the analysis was limited to patients with esophageal squamous cell carcinoma. According to a report by Klevebro et al. [64], the postoperative mortality and incidence of complications were significantly higher in patients receiving preoperative chemoradiotherapy as compared to those receiving preoperative chemotherapy.
While the current standard treatment in Japan is preoperative chemotherapy with cisplatin and 5-FU, evidence suggests that preoperative chemoradiotherapy is also useful. The JCOG1109 Study, as a randomized study to compare the current standard treatment of preoperative chemotherapy with cisplatin and 5-FU and a 3-drug combined preoperative chemotherapy regimen with the addition of docetaxel and preoperative chemoradiotherapy is currently in progress, and results of the study are anticipated [65].
Both preoperative chemotherapy and preoperative chemoradiotherapy are covered by the national health insurance, and considering, based on the benefit–risk balance, strength of evidence and patient preferences, that in patients with cStage II or III esophageal cancer who are scheduled to receive therapy primarily consisting of surgery:
-
(1)
There is strong evidence to recommend preoperative chemotherapy over postoperative chemotherapy.
-
(2)
There is weak evidence to recommend preoperative chemotherapy over preoperative chemoradiotherapy
CQ10: Is postoperative adjuvant therapy recommended in cStage II or III esophageal cancer patients who have undergone preoperative adjuvant therapy plus surgery?
Recommendation statement
There is weak evidence to recommend against postoperative chemotherapy in cStage II or III thoracic esophageal squamous cell carcinoma patients who have undergone preoperative adjuvant therapy plus surgery (Rate of consensus: 85% [17/20], strength of evidence: D).
Explanatory note
Preoperative chemotherapy plus surgery is currently the standard treatment for cStage II or III esophageal cancer in Japan, as, while surgery plus postoperative chemotherapy was demonstrated to be superior to surgery alone in the JCOG9204 Study [66], the superiority of preoperative chemotherapy to postoperative chemotherapy was demonstrated in the JCOG9907 Study [31]. However, the usefulness of postoperative chemotherapy in patients who have undergone preoperative chemotherapy plus surgery has not yet been sufficiently verified.
A search of the literature in relation with this CQ yielded 315 PubMed articles, 188 Cochrane articles, and 633 ICHUSHI articles through a primary screening, from which secondary screening led to the retrieval of 1 paper dealing with a randomized comparative study [67] and 1 paper dealing with a case–control study [68], which were subjected to a systematic review.
There has been no randomized comparative study published in this regard in Japan, and the 1 paper dealing with a randomized comparative study that was retrieved was from overseas. That study involved comparison of a group of patients with resectable squamous cell carcinoma of the esophagus who received postoperative adjuvant chemotherapy after preoperative chemotherapy plus radical surgery (group A: 175 patients) and a matched group not receiving the postoperative adjuvant therapy (group B: 171 patients), with assessment of the recurrence-free survival time as the primary endpoint. The 5-year recurrence-free survival rate was 35.0% in group A and 19.1% in group B, with a hazard ratio of 0.62 (p < 0.001) [67]. However, the surgical procedures and chemotherapy described in the report differ from those used in Japan, and furthermore, the report contains no description of the preoperative staging of the disease; therefore, we consider that the results of this study are not directly applicable to the clinical practice setting in Japan. Meanwhile, pre- and postoperative chemotherapy is undertaken for the treatment of adenocarcinoma in Europe and North America [69, 70].
In general, the completion rate of postoperative chemotherapy is low owing to the high incidence rate of adverse events [31, 69, 70]; therefore, it cannot be concluded at present that the benefits from postoperative chemotherapy outweigh the risks.
While postoperative chemotherapy is covered by the national health insurance, we have concluded, after taking into consideration the benefit–risk balance, strength of evidence and patient preferences, there is weak evidence to recommend against postoperative chemotherapy in cStage II or III thoracic esophageal squamous cell carcinoma patients who have undergone preoperative adjuvant therapy plus surgery.
CQ11: Is postoperative chemotherapy recommended for cStage II or III esophageal cancer patients who have undergone surgery without preoperative therapy?
Recommendation statement
There is only weak evidence to recommend postoperative chemotherapy for cStage II or III esophageal carcinoma patients with pathologically confirmed lymph node metastasis who have undergone surgery without preoperative therapy (Rate of consensus: 85% [17/20]; strength of evidence: C).
Explanatory note
In Japan, radical surgery after preoperative chemotherapy with cisplatin plus 5-FU is recommended for cStage II or III thoracic esophageal cancer patients, on the basis of data from the JCOG9907 Study. In the clinical practice setting, however, surgery alone or surgery plus postoperative chemotherapy is undertaken for these patients, depending on the patient’s condition, in patients who are practically unable to ingest food due to stenosis or any factor that interferes with chemotherapy. There may be cases, where surgery is undertaken under the diagnosis of cStage I disease, but the disease stage is discovered to be cStage II or III; the need for postoperative chemotherapy should be examined in such cases.
A search of the literature in relation with this CQ yielded 260 PubMed articles, 258 Cochrane articles, and 132 ICHUSHI articles, which were subjected to a primary screening. After secondary screening, 3 reports of randomized comparative studies were subjected to qualitative and quantitative systematic reviews [66, 71, 72]. All of these 3 randomized comparative studies entailed a low risk of bias and were consistent. However, the study populations included pStage IV cases and cases in which vindesine was used in the postoperative chemotherapy regimen. The results revealed no appreciable improvement of the 5-year survival rate with postoperative chemotherapy in any of these randomized comparative studies, and a meta-analysis of the 3 randomized comparative studies also yielded the same results [73].
In the JCOG8806 Study, in which the outcomes were compared between a group that received 2 cycles of postoperative cisplatin + vindesine chemotherapy and a surgery alone group, no significant difference in the 5-year survival rate was observed between the two groups, nor was there any add-on effect of postoperative chemotherapy on the survival rate [71]. In the subsequently conducted JCOG9204 Study, in which the outcomes were compared between a group that received 2 cycles of postoperative cisplatin + 5-FU chemotherapy and a surgery alone group, there was no significant difference in the overall survival rate between the two groups, but a significant prolongation of the 5-year recurrence-free survival time was noted in the former group. The prolongation of the recurrence-free survival time was particularly evident in the pathologically lymph node-positive cases [66], and not observed in the pathologically lymph node-negative cases. In a randomized study of postoperative chemotherapy (comparing the outcomes between a group that received 6–8 cycles of postoperative cisplatin + 5-FU chemotherapy and a surgery alone group) conducted in France, only palliative resection was indicated in about a half of the study population, and there was no significant difference in the median survival time between the two groups, indicating the failure of the postoperative cisplatin + 5-FU chemotherapy to prolong the survival [72]. Meta-analysis of the data from these 3 randomized comparative studies revealed a risk ratio of 0.95 (0.78–1.15) (p = 0.59), failing to indicate any add-on effect of postoperative chemotherapy on the survival rate.
The long-term outcomes of surgery alone in the JCOG clinical studies conducted until date largely surpass those of the surgery + adjuvant therapy reported from Europe and North America; this trend seems to reflect the substantial differences in the viewpoints about lymphadenectomy and in the precision of lymph node dissection between Japan and Europe/North America. This is an issue that requires attention when comparing the clinical study results between Japan and Europe/North America.
Thus, there is no basis to believe that postoperative chemotherapy would bring about improvement of the overall survival rate in patients undergoing curative resection. Postoperative chemotherapy involves treatment-related death, although at a low incidence, and a definite risk of adverse events, as compared to surgery alone; there was 1 case (0.8%) of treatment-related death among the 120 patients enrolled in the JCOG9204 Study. In the same study, anaemia (1.7%), leukopenia (4.2%), granulocytopenia (15.8%), platelet count decreased (2.5%), nausea/vomiting (8.3%), and diarrhoea (2.5%) were reported as Grade ≥ 3 adverse events, and granulocytopenia (2.5%), arrhythmia (0.8%), infection (0.8%) and pyrexia (0.8%) were reported as Grade ≥4 adverse events. Nevertheless, the study also revealed a significant improvement of the recurrence-free survival rate and prolongation of the recurrence-free survival time in the group that received postoperative chemotherapy, particularly in patients with lymph node metastasis confirmed by histopathology. Based on the results reported from Japan, postoperative chemotherapy (cisplatin + 5-FU, 2 cycles) after curative resection (with no preoperative chemotherapy) is considered to be potentially useful for prolongation of the postoperative recurrence-free survival time in lymph node metastasis-positive patients.
While postoperative chemotherapy (cisplatin + 5-FU, 2 cycles) is covered by the national health insurance in Japan, taking into account the benefit–risk balance, strength of evidence and patient preferences, we concluded that there is only weak evidence to recommend postoperative chemotherapy for cStage II or III esophageal carcinoma patients with pathologically confirmed lymph node metastasis who have undergone surgery without preoperative chemotherapy.
CQ12: Is additional chemotherapy recommended for cStage II, III, or IVa esophageal cancer patients who show complete response after chemoradiotherapy?
Recommendation statement
There is only weak evidence to recommend additional chemotherapy could be offered to cStage II, III, or IVa esophageal carcinoma patients who show complete response after radical chemoradiotherapy (Rate of consensus: 90% [18/20]; evidence level: C).
Explanatory note
A search of the literature in relation with this CQ yielded 351 PubMed articles, 22 Cochrane articles, and 144 ICHUSHI articles, along with one additional article. Twenty-five papers were extracted through a primary screening, and four papers were extracted after the secondary screening [22, 35, 74, 75]. There was no report of any study comparing additional chemotherapy vs. follow-up observation in patients showing complete response to chemoradiotherapy. Therefore, we carried out qualitative systematic reviews of the 4 extracted reports of large-scale studies of definitive chemoradiotherapy.
In all 4 studies, the chemoradiotherapy consisted of radiation therapy and concurrent chemotherapy, followed by 2 additional cycles of chemotherapy (cisplatin + 5-FU). In 2 of the studies conducted in Japan, the therapeutic response was rated prior to the additional chemotherapy, the latter given only when the patient showed partial response or complete response to the concurrent chemoradiotherapy. Although no clear evidence was presented, it could be assumed that the incidence of adverse events would increase with additional chemotherapy.
There is no evidence to support additional chemotherapy for patients showing complete response to concurrent chemoradiotherapy, and the significance of such therapy has not been clarified. In past large-scale clinical studies of current chemoradiotherapy, however, 2 cycles of additional chemotherapy were included and are generally recognized as an international standard. Nevertheless, careful consideration should be given, because the risks may outweigh the benefits depending on the patient’s condition. Two cycles of additional chemotherapy are covered by the national health insurance.
Thus, taking into account the benefit–risk balance, strength of evidence, and patient preferences, there is only weak evidence to recommend additional chemotherapy could be offered to cStage II, III, or IVa esophageal carcinoma patients who show complete response to radical chemoradiotherapy.