Abstract
Background: The objective of this article was to review randomized clinical trials (RCTs) utilizing pre- and postoperative treatment modalities for esophageal squamous cell carcinoma (ESCC). Materials and Methods: A computerized (MEDLINE) and manual search was performed to identify articles published on this topic between 1984 and 2012. Results: We identified a total of 49 published RCTs, which included a total of 8,785 patients with ESCC. Treatment modalities consisted of pre- (n=38) and postoperative (n=11) chemo-, radio- and chemoradiotherapy. While both preoperative chemotherapy and chemoradiotherapy apparently improve R0 resection, they often result in substantial postoperative morbidity and mortality. Only for preoperative chemoradiotherapy does there seem to be a significant benefit in overall survival. Conclusion: R0 resection remains the only curative therapy for patients with ESCC. While preoperative chemoradiotherapy may improve overall survival, there is still the need for well-designed RCTs, which should include a homogeneous patient collective, to clarify the question of definitive benefit.
Esophageal cancer is the eighth most commonly diagnosed malignant disease and the sixth most common cause of death worldwide (1). While the 5-year survival rates for all patients with esophageal cancer have improved over the last three decades from 5 to 19% (2), many clinical trials have not differentiated between the two major histological subtypes, named squamous cell carcinoma (SCC) and adenocarcinoma, (AC) accounting for more than 98% of all cases (3). This differentiation, however, is of apparent clinical meaning, as these histological subtypes seem to differ regarding epidemiology, pathogenesis, biology, co-morbidity, operative risk and response to specific treatment (4). Interestingly, the incidence of SCCs is declining, whereas that of ACs has markedly increased. In terms of pathogenesis, SCC is mostly associated with a lower socioeconomic status, with alcohol and/or tobacco abuse, resulting in co-morbidities, while excess weight and gastroesophageal reflux disease contribute to the development of AC (4).
Surgical R0 resection remains the therapy of choice for esophageal cancer and should be carried out in specialized high-volume centers to minimize perioperative morbidity and mortality (5). Surgical approaches for esophageal cancer differ between the Western world and especially Asian countries in particular. Ivor-Lewis-type surgery with a two-field lymphadenectomy is preferred in the West (6), whereas a three-field lymphadenectomy is the treatment of choice in Asia (7). The latter undoubtedly results in a higher R0 resection rate, but whether this consistently results in improved survival, remains unanswered. Also unclear is the benefit of laparoscopic and/or thoracoscopic esophagectomy; despite recent promising results (8), further confirmation from well-designed trials is warranted. One of the major problems is the fact that at the time of diagnosis, two-thirds of patients with cancer are considered inoperable due to tumor stage or co-morbidity. In addition, of patients with SCC initially considered operable, only 15-20% will have surgical R0 resection (9), resulting in a long-term survival between 5-20% (10). These unsatisfactory results in SCCs with surgery-alone have led to the introduction of multidisciplinary approaches including pre- and postoperative chemotherapy (CTx), radiotherapy (RT) or chemoradiotherapy (CRT).
In cases of application of preoperative treatment, response assessment using fluorodeoxyglycose positron-emission tomography-computed tomography (FDG PET-CT) may be able to distinguish between responders and non-responders in a non-invasive way (11, 12).
According to the apparent clinical differences, esophageal SCCs and ACs should be analyzed and reported separately, which has prompted us to review the available literature for patients with SCCs to summarize the results of different pre- and postoperative treatment modalities.
Methods
Using a computerized (MEDLINE) and manual search (1984-2011), we have identified a total of 49 published trials on pre- and postoperative treatment modalities, which included a total of 8,785 patients with esophageal SCCs. Only randomized clinical trials (RCT), apart from two retrospective analyses, and an English abstract were included, whereas abstracts from scientific meetings were not considered. Thus a slight degree of publication bias cannot be excluded; in addition, no effort was made to search for unpublished trials or to evaluate information not stated by the authors in the respective papers. Information reviewed included histological verification of SCC; tumor stage; treatment, including dose and schedule of CTx or RT or both; time-to-treatment; number of patients; R0 resection rate; disease-free survival (DFS); progression-free survival (PFS); overall survival (OS); 1-, 2-, 3-, or 5-year survival (as stated by the authors); median follow-up; accrual period; morbidity and mortality.
Results
Preoperative Treatment Modalities
There are many potential theoretical and clinical advantages for pre- over postoperative treatment modalities for patients with esophageal SCCs. These include down-staging/sizing and thus improved possibility for R0 resection, early elimination of possible systemic micrometastases and improvement of local control, morover undamaged blood and/or lymph vessels may allow for more effective drug concentrations in the tumor area. Thus, enhanced radiosensitivity and oxygenation may be achieved. In responding patients, an improved performance status may lead to decreased pre- or postoperative complications. Effective preoperative therapy may minimize the risk of intraoperative seeding, and the efficacy of treatment can be histopathologically-evaluated, which may be important for selecting patients for postoperative therapy (13).
But there can be no light without shadow. Possible disadvantages of preoperative treatment are that non-responders have a delay in surgical procedures, with the possibility of further spread of metastases and the development of drug resistance.
In summary, we have identified a total of 38 trials on preoperative treatment modalities, including a total of 6,835 patients (Table I). Twenty-three of these studies are Western and 15 trials were performed in Asia.
Preoperative chemotherapy versus surgery-alone. Thirteen trials on preoperative CTx versus surgery-alone, including 8 Western (14-21) and 5 Asian trials (22-26) were identified. Taken together, a total of 3,076 patients participated in these trials, 1,338 of whom received preoperative CTx (Table I). All trials used cisplatin-based CTx, in combination with 5-fluorouracil (5-FU)-alone (CF) (16-21, 23, 24), 5-FU plus adriamycin (25), 5-FU plus mitomycin C (26), bleomycin-alone (15), bleomycin plus vinblastine (22) and bleomycin plus vindesine (14), respectively. The preoperative CTx regimens consisted of one (26), two (14, 15, 19, 20, 22-25), or three cycles (16-19), respectively, and approximately two-thirds of patients completed the planned therapy regimens, which were started 2-5 weeks before surgery.
Out of the trials using preoperative CTx consisting of CF, two Western trials revealed no improvement in OS or resectability (16, 18). In the remaining 6 trials, an advantage in OS or DFS was seen in treatment responders undergoing R0 resection (17, 23) and the results were significant in four trials (19-21, 24). One Japanese trial using CF plus adriamycin concluded that preoperative CTx can successfully eradicate micrometastases in responders, resulting in a favorable OS (non-significant) (25). When using mitomycin C instead of adriamycin, the 3-year survival rate of the CTx group was not significantly higher than that of the control group (26). The combination of cisplatin and bleomycin (15) or additional vinblastine (22) did not result in a significant difference in OS, whereas cisplatin, bleomycin and vindesine, used in a small trial, significantly prolonged OS in responders (>20 months) when compared with non-responders (6.2 months) and patients in the control group (8.6 months) (14). In all trials, the toxic effects of CTx were manageable and did not result in an apparent increase of perioperative morbidity. Eight trials explicitly reported on the R0 resection rate (16-21, 23, 26), which did not differ and ranged from 31.7 to 86.6% in the preoperative CTx arm (17, 26) and from 35.0 to 79.7% in the surgery-alone arm (16, 23). R0 resection rate, postoperative morbidity and mortality did not differ substantially between the two treatment groups (16, 17, 23, 26).
While a potential benefit for preoperative CTx is suggested in six studies (four of them showing significant results), these trials are nevertheless difficult to compare due to application of different cytotoxic drugs, number of cycles administered, timing of surgery, surgical techniques and different tumor stages included. Furthermore, the preoperative staging was not adequate in some studies due to the abandonment of CT and endoscopic ultrasound (EUS). Interestingly, no recent trial has used FDG PET-CT to evaluate early-responders. However, an R0 resection rate of 31.7 to 86.6% in individuals undergoing preoperative CTx (17, 26) versus a comparable 35.0 to 79.7% in the surgery-only groups (16, 23), shows an extremely wide range.
A total of eight meta-analyses were published comparing preoperative CTx with surgery-alone, but patients with both histologies were included (Table II) (27-34). Here the role of preoperative CTx is also difficult to interpret and still remains controversial due to different results and trials included. The most important meta-analysis, in terms of SCC, is a recent German publication because, only two out of eight RCTs (n=1707) included AC (55% and 31% of patients included, respectively) (34). The hazard ratio (HR) for OS after preoperative CTx was 0.93 (p=0.368), for R0 resection 1.16 (p=0.006), for morbidity 1.03 (p=0.638) and for mortality 1.04 (p=0.810).
Preoperative radiotherapy versus surgery-alone. The rationale for application of preoperative RT is to improve local tumor control by down-staging and tumor eradication in involved lymph nodes. We identified four Western (15, 35-37) and two Asian RCTs (26, 38) (Table I). Only in one English trial were both histologies (SCC 32%) represented (37). Out of 1,079 patients, a total of 552 were treated with RT. Apart from two RCTs (15, 26), none of the other four trials reported any significant improvement in resectability or OS advantage, but often a higher treatment-related mortality was seen in the combined modality groups. Both of these two RCTs demonstrated a significant 3-year survival rate for RT over surgery-alone. In a meta-analysis of 1,147 patients, mostly with SCCs, with a median follow-up of 9 years, the HR of 0.89 [95% confidence interval (CI)=0.78-1.01] suggests an overall reduction in the risk of death of 11% by RT and a survival benefit of 3% at 2 years and 4% at 5 years (p=0.062), at the cost of higher treatment-related mortality (39).
To date, controversy still exists regarding optimal dosage, fractionation (conventional versus hyperfraction), and timing of surgery after RT. At present, RT should not be used outside of clinical trials based on these data.
Preoperative chemotherapy versus preoperative radiotherapy. Out of 200 Western patients, 94 were treated with CTx and 106 with RT (Table I) (15, 40). The CTx regimen consisted of cisplatin plus bleomycin (15) and in the second trial vindesine was added to the same regimen (40). RT was not comparable, as 55.0 Gy were used in one (40) and 35.0 Gy in the other trial (15). Apart from the different treatment regimens applied, the results also differed in these small RCTs: Whereas one trial detected no difference in OS (40), the other revealed a significantly higher 3-year survival rate for RT (15). Interestingly, the study reporting a survival benefit at three years applied a much lower dose of radiation (35.0 Gy).
Preoperative radiotherapy versus postoperative radiotherapy. One trial directly compared the efficacy of pre- (n=40) versus postoperative RT (n=42) in SCC. No difference in OS but a higher morbidity after preoperative RT was detected (Table I) (41).
Preoperative chemoradiotherapy versus surgery-alone. Since the first trial of preoperative CTx in conjunction with RT versus surgery-alone for SCC was published in 1992 (15), this topic has been extensively studied for resectable locally advanced SCC. Seven Western trials (15, 42-47) and an additional five Asian trials (26, 48-51) were identified (Table I). Out of 1,682 patients included, 778 received CRT. Three trials evaluating CRT also included patients with AC (25-75%) (45-47). Apart from one trial using cisplatin, only (43), most trials applied combination CTx consisting of CF (42, 46-50). Leucovorin plus etoposide (FLEP) (44), vinblastine (45) and mitomycin C (26) were added to CF in one trial each, while one trial used cisplatin plus bleomycin (15) and another paclitaxel (51). In terms of RT, neither the numbers of fractions (10-30), the daily administered doses (1.5-3.7 Gy), nor the total doses (37.0-50.4 Gy) were uniform. To date, no trial has been performed comparing CRT delivered sequentially versus concomitant CRT. In nearly all trials, pre- study staging was suboptimal since EUS was used in only two trials (47, 48) and FDG PET-CT in none of them. Delayed surgery by up to 90 days after CRT in 129 patients with locally-advanced SCC did not influence the outcomes (52).
When preoperative CRT was compared to surgery-alone, one trial showed an advantage in terms of OS, and PFS was improved in only three trials. In a subgroup analysis, only patients with SCC (37%) as opposed to AC (HR=0.47, 95% CI=0.25-0.86 versus HR=1.02, 95% CI=0.72-1.44) had a benefit (46), while a significant improvement for both SCC and AC was seen in the other two analyses (45, 47). Only one trial adding mitomycin C to CF reported a significantly higher 3-year OS for the CRT group when compared to the control (26). WHO grade 3-4 toxicities ranged from 2-80%, R0 resection was significantly greater after CRT (HR=1.15, 95% CI=1.0-1.32, p=0.043), whereas postoperative morbidity was not increased (34).
It is difficult to draw any firm conclusion from these trials due to the relatively small samples, and differences in patients' characteristics, CRT regimens and surgical procedures. Therefore, 11 meta-analyses including both ACs and/or SCCs were subsequently performed in an effort to synthesize these data into larger pools and discover if an OS benefit exists (Table II) (29, 31-34, 53-58). An Australian and a German analysis deserve particular attention in this respect (31, 34). The first evaluated 10 RCTs including 1,209 patients and showed a statistically significant benefit for preoperative CRT with a 19% decreased risk of death (HR=0.81, 95% CI=0.70-0.93, p=0.002) for both SCC and AC, which corresponded to a 13% absolute difference in 2-year SR (31). The second is the most recent analysis and was published in 2011, including 9 RCTs with 1,099 patients and evaluating only SCC. Evidence of significant OS benefit was present in this analysis (HR=0.81: 95% CI=0.7-0.95, p=0.008) (34).
Preoperative treatment modalities.
When comparing seven meta-analyses on CRT starting in the 1990s, there was heterogeneity between the RCTs included with regard to statistical methods, patients characteristics, tumor histologies, diagnoses, staging methods, CRT regimes and surgical techniques (29, 31, 32, 53-55, 57). These factors and the incomparability linked with it, strongly indicate the need for well-designed RCTs in the future (59).
Preoperative versus postoperative chemoradiotherapy. Lv and colleagues conducted an RCT to evaluate pre- (n=80) and postoperative CRT (n=78) in patients with stage II-III tumor (51). There were no significant differences in OS and PFS between the arms (p>0.05). The local recurrence rates in the CRT group were 11.3 versus 14.1%. When comparing complications and toxicities, no significant differences were detected but the findings tended to be in favor of the postoperative CRT group.
Preoperative versus definitive chemoradiotherapy. Because of the known high rate of co-morbidity of patients with potentially resectable SCC, the question of whether preoperative CRT can be replaced by definitive CRT has been studied in an effort to avoid surgery in high-risk populations without compromising outcomes. Three trials of preoperative CRT, including two RCTs (60, 61) and one retrospective non-randomized trial (62) versus definitive CRT are presented in Table I (n=558). In the German RCT, 172 eligible patients were randomized to receive either three cycles of preoperative CRT consisting of 5-fluorouracil, leucovorin, etoposide and cisplatin (FLEP), followed by CRT (cisplatin/etoposide, 40 Gy/2× 1.5 Gy/fraction) with consecutive surgery or FLEP, followed by definitive CRT (at least 65 Gy) (60). Preoperative CRT improved local tumor control in terms of dysphagia (64.3 versus 40.7%) but did not increase OS, or median survival time (16.4 versus 14.9 months, non-significant). The mortality from preoperative CRT was 12.8% compared with 3.5% in the CRT-alone group (p=0.03). R0 resection was obtained in 82% of patients.
In a French RCT, the preoperative regimen consisted of two cycles of CTx with CF before, and for responders, three cycles after randomization and concurrent RT with 46 Gy (and an additional 20 Gy) to a total of 66 Gy (61). Median survival was 17.7 months after preoperative CRT compared with 19.3 months after definitive CRT. There was no significant difference observed concerning OS but the mortality was again significantly higher in the preoperative CRT group (p=0.002). In a retrospective non-randomized Taiwanese trial, either preoperative CF or cisplatin/paclitaxel and concurrent RT with 36 Gy or definitive CRT with the same CTx plus RT with 60 Gy, were administered (62). No statistically significant difference in DFS or OS was detected between the two groups.
Postoperative Treatment Modalities
Widespread dissemination of esophageal cancer is the primary cause of death. The goal of postoperative treatment is to eliminate micrometastases in order to delay or, ideally, prevent recurrence. Potential candidates for postoperative treatment after R0 resection are therefore patients with stage T3-4 and/or lymph node-positive SCCs with a high risk of recurrence. Apart from postoperative therapy-related toxicity and subsequent poor compliance, delay of postoperative treatment due to surgical complications is still a major concern.
In summary, we found a total of 11 RCTs on postoperative treatment modalities and these included 1,950 patients (Table III). Four are Western and seven are Asian RCTs.
Postoperative chemotherapy versus surgery-alone. The use of postoperative CTx in SCC patients has been studied in one Western (63) and two Asian trials (64, 65), and one additional Asian study has evaluated CTx against a historical surgical control group (66). In all four trials including a total of 648 patients, cisplatin-based chemotherapies at different doses, combinations and cycles were used. Mostly due to convalescence, reduced performance status and weakness after surgery and consequently unacceptable toxicity, in almost all trials the planned CTx could not be administered to the full extent. There was no reported significant difference in DFS or OS between CTx and controls, even after stratification for lymph node status (65, 66). These results were confirmed by a meta-analysis from China (67).
Based on these data, postoperative CTx has so far shown no advantage in terms of improving DFS or OS. Therefore, there is no established role for this treatment approach outside of clinical trials.
Postoperative radiotherapy versus surgery-alone. No OS advantage for postoperative RT was seen in three Western (68-70) and two Asian (71, 72) phase III trials that compared RT following resection against surgery-alone in a total of 888 patients (Table III). However, all trials did show increased RT-related complications such as fistulas or adhesions. There was only local disease control with RT, especially in the subgroup of patients who had no curative surgery. Ténière et al. showed a significant decrease in local recurrence in a subgroup of patients with lymph node-negative disease after R0 resection with RT (69). The study conducted by Xiao and colleagues recorded a significant OS benefit (35.1 versus 13.1%, p=0.0027) for patients with lymph node positivity and stage III SCC (72). In addition, a meta-analysis of these trials confirmed the absence of a significant OS advantage when RT was used (55). In summary, it seems reasonable to give postoperative RT only to a subgroup of patients who have positive margins after surgery in order to enhance local control of the disease, in the absence of a demonstrated prolonged OS.
Meta-analyses concerning preoperative therapy modalities.
Postoperative chemoradiotherapy versus surgery alone. In a Chinese trial patients with stage II-III disease were randomized either to postoperative CRT (n=78) or surgery-alone (n=80) (51). With a median follow-up of 45 months for all enrolled patients, significant differences for CRT and surgery for the primary endpoint PFS (37.2 versus 25.9%, p=0.0151) and for 5-year survival (42.3 versus 33.8%, p=0.0176) were detected between the two arms. The local recurrence rates in the CRT group and surgery group were 14.1 and 35% (p<0.05), respectively.
Postoperative treatment modalities.
Postoperative chemotherapy versus postoperative radiotherapy. A Japanese phase III trial compared postoperative RT (50 Gy, 2 Gy/fraction, n=128) with two cycles of postoperative CTx (cisplatin, vindesine, n=128) in patients undergoing potentially curative surgery (Table III) (73). Randomization was done after R0 resection in 256 patients without any postoperative complications. There was no significant difference in tumor recurrence or in 5-year survival between the RT and CTx groups (44% versus 42%).
Discussion
R0 resection in patients with resectable esophageal SCC, who are able to undergo major surgery is currently the only established curative treatment option (74, 75). As resection margins in pathological specimens have been reported to be negative in only two-thirds of patients initially judged as having resectable disease (18), interdisciplinary treatment options may play an important role in improving R0 resections. However, the optimal timing as well as the ideal perioperative treatment option, still remains controversial. The implementation of better staging methods such as CT, EUS and, in particular, FDG PET-CT has allowed for selection of patients who are candidates for immediate surgery-alone and who may potentially benefit from additional therapies to facilitate surgical resection (76). The merit of pre- and postoperative therapy in patients with ESCC was analyzed in several RCTs and was the subsequent subject of various meta-analyses. Judging from the literature, there seems to be no apparent difference in the outcome between Western and Asian RCTs.
Selected upcoming pre- and/or postoperative randomized clinical trials for esophageal cancer.
Based on the collected data of RCTs for postoperative treatment modalities, there has so far been no clear advantage demonstrated for DFS or OS in esophageal SCC. In view of the data published so far, it is valid to conclude that there is no established role for this treatment approach outside of clinical trials.
A point of potential criticism of the meta-analyses on preoperative treatment published to date, which included 6-14 RCTs is the heterogeneity among the included RCTs (including both SCCs and ACs, different stages, time to treatment, treatment regimen, surgical procedure and endpoints) (27-34, 53-58). Most of these individual trials were in fact underpowered, and the large majority were shown to be of debatable merit for various reasons. For example, staging did not include routine CT scanning in older RCTs or EUS and/or FDG PET-CT in the recent RCTs, resulting in a sound stratification according to stage in few studies, and trial design issues (effect tumor size, tumor stage, statistical power, sample size, and study duration) were not rigorously applied. While R0 resection is an important prognostic factor, no detailed information about histological definition of R0 (which differs e.g. between the USA and the UK) was available (75). Furthermore, both main histologies, SCC an AC, are often included and no correction for the additional time gained by pre- or postoperative therapy modality in contrast to surgery-alone was made in any of the RCTs or meta-analyses. If a given pre- or postoperative treatment yields an OS benefit of a few months, but also takes a comparable time-span for recovery from treatment compared with surgery-alone, then the potential benefit would be completely lost (59). It is therefore still debatable whether the small survival benefit seen in these trials outweighs the higher morbidity and mortality caused by such treatment approaches (28, 55). As it is, only meta-analyses published according to the Quality of Reporting of Meta-Analyses statement may be able to detect relevant health care information in the treatment of resectable esophageal SCC (77).
An exception is the meta-analysis by Kranzfelder et al., which focused almost exclusively on SCCs and included nine RCTs involving preoperative CRT and eight RCTs on preoperative CTx. This analysis revealed a significantly higher R0 resection rate for both treatment modalities and a significant OS benefit for preoperative CRT (34). Despite these promising results, it is noteworthy that preoperative therapy can increase the risk of surgical morbidity. In addition, preoperative CRT can lead to an increase in postoperative mortality (43, 44). It is therefore still debatable whether the small OS benefit outweighs the higher mortality caused by such a treatment (28, 55).
Since targeted agents have been found to be beneficial in patients with multiple different tumor entities, there has also been interest in using these agents in patients with esophageal cancer (78, 79). Consequently, possible targets of potential interest, including metalloproteinases, cyclin-dependent kinases, inhibition of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), which is associated with poor prognosis, and epidermal growth factor receptor (EGFR), have been identified in esophageal carcinomas (78). Many feasibility or phase I-II trials of targeted agents-alone or in combination with CTx or RT in inoperable, metastatic esophageal cancer have been reported or are underway (78, 79). The most important study is probably the randomized phase III trial in patients with recurrent or metastatic gastroesophageal AC, where the combination of cisplatin and fluoropyrimidines plus trastuzumab has been tested (ToGA), and a significantly improved OS (13.5 versus 11.1 months, HR=0.74, 95% CI=0.60-0.91, p=0.0048) was reported (80). In spite of these promising results, a positive human epidermal growth factor receptor 2 (HER2) status was only found in 3.9% of esophageal SCCs as opposed to 15.3% of ACs (81, 82).
The current data on pre- and postoperative treatment modalities strongly indicate the need for designing future trials considering the clinical differences between ACs and SCCs and their potential influence on patient response to therapy.
Many phase III RCTs are currently planned or underway and hopefully the upcoming results may contribute to a better understanding over the role of pre- and postoperative treatment for resectable esophageal SCC and help to identify patient subgroups that could benefit from additional therapies in order to improve the disappointing cure rates (Table IV) (83-94).
- Received July 5, 2012.
- Revision received September 25, 2012.
- Accepted September 27, 2012.
- Copyright© 2012 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
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