Neoadjuvant Treatment for Locally Invasive Esophageal Cancer

World J Surg (2017) 41:1719 1725 DOI 10.1007/s00268-017-3959-x SURGICAL SYMPOSIUM CONTRIBUTION Neoadjuvant Treatment for Locally Invasive Esophageal Cancer Wade T. Iams 1 Victoria M. Villaflor 1 Published online: 7 March 2017 Ó Société Internationale de Chirurgie 2017 Abstract Locally advanced esophageal carcinoma has a poor prognosis, and epidemiologic trends show that more patients are being diagnosed with locally advanced esophageal carcinoma and with adenocarcinoma histology. This prompts a review and evaluation of the field regarding standard of care treatment for patients with locally advanced esophageal carcinoma, both adenocarcinoma and squamous cell carcinoma. We review the evidence showing the moderate benefit of neoadjuvant chemoradiation followed by esophagectomy compared to perioperative chemotherapy plus esophagectomy in patients who are good operative candidates. Also, we summarize the emerging clinical trial landscape in the perioperative setting primarily seeking to apply targeted therapies against HER2 (trastuzumab or pertuzumab) or immune checkpoint inhibitors against programmed death 1 (PD-1; pembrolizumab and nivolumab) or programmed death ligand 1 (PD-L1; durvalumab). Understanding the foundations that have determined the current standard of care for patients with locally advanced esophageal carcinoma will aid in interpreting the clinical trial results that will soon appear with the novel treatment strategies. Introduction Each year, over 480,000 new cases of esophageal cancer are diagnosed worldwide [1]. In the USA, the incidence of esophageal adenocarcinoma has surpassed squamous cell carcinoma (SCC), and with the increased use of screening esophagogastroduodenoscopy (EGD) for patients with known Barrett s esophagus, the incidence of metastatic esophageal carcinoma at the time of diagnosis is declining [2]. These epidemiologic shifts bring the importance of optimal treatment of patients with resectable esophageal carcinoma to the fore. In this review, we will discuss what is known about the efficacy of perioperative chemotherapy and neoadjuvant chemoradiotherapy in patients with & Victoria M. Villaflor victoria.villaflor@nm.org resectable esophageal carcinoma. Additionally, we will discuss oncogene targeted and immunotherapy treatments on the horizon. Potential changes in the current treatment paradigm will continue to be pursued because the prognosis for most patients with resectable esophageal carcinoma is poor, with a 5-year survival rate of 15 34% [3 5]. This 5-year overall survival (OS) is impacted by the degree of pathologic tumor response at resection after neoadjuvant therapy, with a 5-year OS of 52% in those achieving a pathologic complete response (CR), 38% in patients with a pathologic partial response (PR), and 19% in patients with no response [5]. The degree of lymph node (LN) positivity at resection also predicts worse outcomes, with[4 positive LNs or a [20% LN positivity ratio predicting significantly decreased OS [6]. Perioperative chemotherapy 1 Division of Hematology/Oncology, Northwestern Feinberg School of Medicine, Arkes Pavilion, 676 North Saint Clair, Suite 850, Chicago, IL 60611, USA The preponderance of evidence shows a benefit of perioperative chemotherapy combined with esophagectomy

1720 World J Surg (2017) 41:1719 1725 compared to esophagectomy alone [4]. A meta-analysis in 2011 supported this conclusion with incorporation of ten randomized controlled trials (RCTs) involving perioperative chemotherapy plus esophagectomy compared to esophagectomy alone. This meta-analysis found a hazard ratio (HR) of benefit in all-cause mortality for perioperative chemotherapy of 0.87 (95% confidence interval (CI) 0.79 0.96) [4]. The most recent phase III clinical trial demonstrating the superiority of perioperative chemotherapy plus esophagectomy compared to esophagectomy alone showed a benefit in OS with perioperative chemotherapy (HR for death of 0.69, 95% CI 0.50 0.95, p = 0.02) and improvement in 5-year OS to 38% in the perioperative chemotherapy group compared to 24% in patients treated with esophagectomy alone [7]. This trial involved 169 patients with adenocarcinoma histology, with primary tumor sites of lower esophagus (11%), esophagogastric junction (64%), and stomach (25%). Half of the patients received 2 3 cycles of preoperative cisplatin and fluorouracil (FU) followed by esophagectomy and 3 4 cycles of the same regimen in the adjuvant setting, and the remainder were treated with esophagectomy alone. A larger phase III RCT, the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial, also demonstrated both an OS (HR for death of 0.75, 95% CI 0.060 0.93, p = 0.009) and 5-year OS benefit in patients treated with perioperative chemotherapy plus esophagectomy compared to esophagectomy alone (5-year OS of 36 vs 23%, respectively) [8]. In the MAGIC trial, 503 patients with gastric or esophageal adenocarcinoma were randomized to either three preoperative and three postoperative cycles of epirubicin, cisplatin, and infusional FU with esophagectomy or esophagectomy alone. Primary tumor sites included the lower esophagus (15%), esophagogastric junction (11%), and stomach (74%). The largest RCT assessing perioperative chemotherapy plus esophagectomy compared to esophagectomy alone was the EC trial (OEO2) conducted by the British Medical Research Council, and this showed a significant improvement in OS (HR for death of 0.79, 95% CI 0.67 0.93, p = 0.004) and 2-year OS rate in patients treated with perioperative chemotherapy (43 vs 34%) compared to esophagectomy alone [9]. Perioperative chemotherapy was two cycles of cisplatin and FU in the preoperative setting, and while this trial involved 802 patients, it included patients with both adenocarcinoma (70%) and SCC (30%) and multiple primary tumor sites (7% upper third of esophagus, 25% middle third of esophagus, 64% lower third of esophagus, and 10% gastric cardia). The largest negative RCT of perioperative chemotherapy plus esophagectomy compared to esophagectomy alone was the North American Intergroup (INT) 0113 trial [10], where the HR for death in the group treated with perioperative chemotherapy was 1.07 (HR 0.87 1.32) and the 3 years OS rates were 23% in the group treated with perioperative chemotherapy plus esophagectomy and 26% in the group treated with esophagectomy alone [10]. Perioperative chemotherapy in this trial was three cycles of preoperative and two cycles of postoperative cisplatin and FU. This trial highlights some of the difficulties in interpreting the RCTs evaluating perioperative chemotherapy. For example, much of the data is outdated, and this clinical trial was conducted between 1990 and 1995. Also, many RCTs include patients with both adenocarcinoma and SCC histology or both gastric and esophageal cancers. This trial of 467 patients with esophageal carcinoma included 51% with adenocarcinoma and 44% with SCC. The aforementioned meta-analysis noted a distinction in the benefit of perioperative chemotherapy by tumor histology, as patients with adenocarcinoma had a more defined benefit (3 RCTs [7, 10, 11] with 946 patients; HR 0.88, 95% CI 0.8 0.96) compared to patients with SCC (9 RCTs [10 18] with 1084 patients; HR 0.92, 95% CI 0.81 1.04) [4]. Overall, the existing RCT evidence shows a benefit to perioperative chemotherapy plus esophagectomy compared to esophagectomy alone in patients with resectable esophageal carcinoma, but this benefit is greater in patients with adenocarcinoma compared to SCC, and it may be influenced in unknown ways by primary tumor location (lower esophagus vs gastric cardia). Neoadjuvant chemoradiotherapy The benefit of neoadjuvant chemoradiation followed by esophagectomy compared to esophagectomy alone has been demonstrated for patients with resectable esophageal carcinoma. Using a neoadjuvant chemotherapy regimen akin to trials of perioperative chemotherapy, the Cancer and Leukemia Group B (CALGB) 9781 trial noted a statistically substantial benefit to neoadjuvant chemoradiotherapy followed by esophagectomy compared to esophagectomy alone, with patients in the neoadjuvant chemoradiation arm experiencing a median OS of 4.48 years compared to 1.79 years in the group treated with esophagectomy alone (p = 0.002) [19]. In this cohort of 56 patients, 75% had adenocarcinoma and 25% had SCC, and patients with primary gastric adenocarcinoma were excluded. In the chemoradiotherapy arm, patients received chemotherapy with cisplatin and FU with concurrent radiotherapy followed by esophagectomy. This trial closed early due to slow accrual, as both patients and investigators were wary of being randomized to treatment with esophagectomy alone. However, the large benefit of neoadjuvant chemoradiotherapy seen in this study set the stage for the CROSS trial [20].

World J Surg (2017) 41:1719 1725 1721 The largest RCT of neoadjuvant chemoradiation followed by esophagectomy compared to esophagectomy alone was the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS), where median OS with neoadjuvant chemoradiation plus esophagectomy was 49.4 months compared to 24 months in the group treated with esophagectomy alone (HR for death 0.66, 95% CI 0.50 0.87, p = 0.003) [3]. In this trial of 366 patients, 75% had adenocarcinoma histology compared to 23% with SCC, and tumor primary sites included the esophagus (76%) and esophagogastric junction (24%). The chemoradiotherapy arm involved treatment of weekly carboplatin and paclitaxel with concurrent radiotherapy followed by esophagectomy. The findings of the CROSS trial are both supported and contradicted by smaller RCTs, taking as examples RCTs published in 1996 [21] and 2001 [22]. In the former example, 113 patients with esophageal adenocarcinoma received either neoadjuvant cisplatin, FU, and concurrent radiotherapy followed by esophagectomy or esophagectomy alone. In the group treated with neoadjuvant chemoradiotherapy, median OS was 16 months compared to 11 months in the group treated with esophagectomy alone (p = 0.01), and 3 years OS rate was 32% compared to 6%, respectively (p = 0.01) [21]. This trial enrolled only patients with adenocarcinoma histology, with tumor primary sites including the middle third of the esophagus (14%), lower third of the esophagus (51%), and gastric cardia (35%). As an example of a negative RCT in this setting, 100 patients with resectable esophageal carcinoma were randomized to either neoadjuvant cisplatin, FU, and vinblastine with radiotherapy followed by esophagectomy or esophagectomy alone, and neither median OS (16.9 months compared to 17.6 months, respectively) nor 3-year OS rate (30% compared to 16%, p = 0.15, respectively) were improved [22]. This negative trial confounds the debate because it included both patients with adenocarcinoma (75%) and SCC (25%) and utilized a distinct neoadjuvant chemotherapy regimen compared to other trials. It was also underpowered to detect a statistically significant difference in OS based on the event rate experienced by patients in the trial, and a trend toward improved OS was noted, particularly in patients experiencing a pathologic CR after neoadjuvant chemoradiation. The 13 RCTs comparing the efficacy of neoadjuvant chemoradiotherapy followed by esophagectomy with esophagectomy alone (1932 patients) were assessed in a recent meta-analysis which showed a survival benefit in patients treated with neoadjuvant chemoradiotherapy (HR for all-cause mortality 0.78, 95% CI 0.70 0.88) [4]. This survival benefit in patients treated with neoadjuvant chemoradiotherapy was consistent in both patients with SCC (9 RCTs [13, 21 28]) and adenocarcinoma (3 RCTs [21, 22, 26]). Overall, the evidence has shown a benefit to neoadjuvant chemoradiation plus esophagectomy compared to esophagectomy alone in patients with resectable esophageal carcinoma, with most clinicians favoring the CROSS regimen of carboplatin and paclitaxel with concurrent radiotherapy if a patient has satisfactory performance status. Direct comparisons of perioperative chemotherapy and neoadjuvant chemoradiotherapy There have only been two RCTs directly comparing neoadjuvant chemoradiotherapy followed by esophagectomy and perioperative chemotherapy plus esophagectomy, with a statistically nonsignificant trend toward superiority of trimodality compared to bimodality therapy [29, 30]. The smaller of the two trials showed no significant difference in median OS comparing neoadjuvant chemoradiotherapy and perioperative chemotherapy in patients with resectable esophageal adenocarcinoma (median OS 32 months with chemoradiotherapy vs 29 months with chemotherapy, p = 0.83) [29]. This was a phase II RCT involving 75 patients treated with either neoadjuvant chemoradiotherapy (cisplatin, FU, and concurrent radiotherapy of 35 Gray starting in cycle two) followed by esophagectomy or two cycles of preoperative cisplatin and FU followed by esophagectomy. This trial included only patients with adenocarcinoma of the esophagus or esophagogastric junction. Explanations for the negative results of this trial include a lower dose of radiation than typically applied in this setting (35 Gy compared to 41.4 Gy in the CROSS trial [3] and 50.4 Gy CALGB 9781 trial [19]) and the small number of patients. Importantly, there was a trend toward improved PFS when patients were treated with chemoradiotherapy compared to chemotherapy (26 months vs 14 months, p = 0.37, respectively). This trend was likely due to the higher rate of pathologic CR (13% with chemoradiation vs 0% with chemotherapy, p = 0.02) after neoadjuvant chemoradiation compared to perioperative chemotherapy. This finding reinforces the favorable prognosis of patients who achieve a pathologic CR after neoadjuvant therapy. The larger of the two trials, the preoperative chemotherapy or radiochemotherapy in esophagogastric adenocarcinoma trial (POET), showed a large but statistically insignificant trend toward 3-year OS benefit in 119 patients treated with either neoadjuvant chemoradiotherapy followed by esophagectomy or perioperative chemotherapy followed by esophagectomy (47.4 vs 27.7%, p = 0.07, respectively) [30]. Patients treated with neoadjuvant chemoradiotherapy experienced a significantly higher pathologic CR rate (15.6 vs 2%). Of note, this trial

1722 World J Surg (2017) 41:1719 1725 involved 19 different centers, with 12 centers enrolling \5 patients, raising concern that lower volume centers may not have achieved analogous outcomes to high volume centers and skewing results toward insignificance. Both groups were treated with chemotherapy in the form of 2 2.5 courses of cisplatin, FU, and leucovorin. One course was a 6-week interval of weekly FU with leucovorin accompanied by biweekly cisplatin. In the group treated with neoadjuvant chemoradiotherapy, patients received two courses of this chemotherapy regimen followed by concurrent chemoradiotherapy with cisplatin and etoposide. The neoadjuvant chemotherapy group was treated with 2.5 courses of the aforementioned cisplatin, FU, and leucovorin regimen. Importantly, due to the prolonged duration of preoperative chemotherapy and chemoradiotherapy, postoperative mortality was increased in the neoadjuvant chemoradiotherapy group compared to the neoadjuvant chemotherapy group, but the increase was not statistically significant (10.2 vs 3.8%, respectively, p = 0.26) [30]. In summary, these data show that there is a trend toward benefit in patients receiving neoadjuvant chemoradiotherapy followed by esophagectomy compared to perioperative chemotherapy plus esophagectomy, but caution should be used in patients who have high perioperative risk due to comorbidities. There are additional studies seeking to better understand the outcome differences between trimodality and bimodality therapy in patients with resectable esophageal carcinoma, such as the ongoing Irish MAGIC versus CROSS study (NCT01726452; MAGIC vs CROSS Upper GI. ICORG 10-14) [20]. Role of adjuvant chemoradiation Adjuvant chemoradiation is typically applied in patients with locally advanced esophageal carcinoma who are upstaged at the time of surgery. In this scenario, adjuvant chemoradiation has RCT-supported evidence for improving OS [31]. A large RCT of 556 patients with resectable gastric or gastroesophageal junction adenocarcinoma showed that patients treated with resection followed by chemoradiation compared to patients treated with resection alone had an improved OS (hazard ratio for death in the surgery alone arm of 1.35, 95% CI 1.09 1.66, p = 0.005) and 3-year OS (50% with adjuvant chemoradiation vs 41% with resection alone) [31]. Primary tumor sites included the gastric antrum (54%), gastric corpus (24%), gastric cardia (20%), and multicentric (2%). Adjuvant chemoradiation was FU and leucovorin with radiation for 5 weeks, followed by two cycles of FU and leucovorin one month after completion of concurrent chemoradiation. Future directions of perioperative chemotherapy While the question of which perioperative chemotherapy regimen to choose remains unsettled (platinum plus taxane or platinum plus fluoropyrimidine with or without an anthracycline), no ongoing clinical trials seek to specifically answer this question [20]. Rather, in the perioperative setting, combinations targeting HER2, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor (VEGFR) in combination with chemotherapy are being tested. The addition of HER2 directed therapy in the perioperative setting is based in part on the clear survival benefit of adding trastuzumab to chemotherapy in patients with metastatic esophageal adenocarcinoma with HER2 overexpression or amplification [32]. The INNOVATION- TRIAL (Integration of trastuzumab, with or without pertuzumab, into perioperative chemotherapy of HER-2 positive stomach cancer) is an ongoing RCT treating patients with resectable, HER2-positive gastroesophageal or gastric adenocarcinoma with both preoperative and postoperative cisplatin and fluoropyrimidine in combination with HER2 blockade with trastuzumab or both trastuzumab and pertuzumab (NCT02205047). Lapatinib is a dual tyrosine kinase inhibitor that targets both the HER2 and EGFR pathways. In a phase II/III RCT, the British Medical Research Council is evaluating the efficacy of lapatinib in combination with perioperative chemotherapy (epirubicin, cisplatin, and capecitabine) in patients with HER2 positive, resectable lower esophageal, esophagogastric junction, or gastric adenocarcinoma. Also included in this trial is an evaluation of bevacizumab in combination with epirubicin, cisplatin, and capecitabine in patients with resectable lower esophageal, esophagogastric junction, or gastric adenocarcinoma (NCT00450203). Future directions of neoadjuvant chemoradiotherapy While adding EGFR-targeted therapy to neoadjuvant chemoradiotherapy has proven excessively toxic without clinical benefit, there are several ongoing studies evaluating the addition of HER2-directed therapy to neoadjuvant chemoradiotherapy in patients with locally advanced esophageal cancer. Also, as of mid-2016, immune checkpoint inhibitors targeting the programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) interaction are entering trials in both the neoadjuvant and adjuvant setting for patients with locally advanced esophageal cancer (NCT02735239, NCT02730546, NCT02743494). The primary limiting factor to adding EGFR antibodies or inhibitors such as cetuximab, panitumumab, or gefitinib to neoadjuvant chemoradiotherapy in patients with locally

World J Surg (2017) 41:1719 1725 1723 advanced esophageal carcinoma has been treatment-related toxicity [33] (NCT00551759; NCT00827671). The publication of the American College of Surgeons Oncology Group (ACOSOG) Z4051 trial demonstrated this toxicity. In this phase II clinical trial, patients received docetaxel, cisplatin, and panitumumab every 2 weeks for 9 weeks while receiving radiotherapy during weeks 5 9. While it was not a direct, randomized comparative trial using the most successful neoadjuvant chemoradiotherapy regimens, patients in this trial did not have improved median OS (19 months) nor 3-year survival rate (38.6%) compared to historical controls, and almost half (48.5%) of the patients experienced at least grade 4 toxicity [33]. Based on these data, adding EGFR-targeted therapy to neoadjuvant chemoradiotherapy is not recommended. In contrast to the addition of EGFR-targeted therapy, the addition of HER2-targeted therapy to neoadjuvant chemoradiotherapy is still under investigation. This therapeutic approach is being applied in the phase III RTOG 1010 clinical trial (NCT01196390). This landmark trial is randomizing patients with locally advanced, HER2 overexpressing esophageal adenocarcinoma to either neoadjuvant chemoradiotherapy with the CROSS regimen of carboplatin and paclitaxel with trastuzumab and radiotherapy, followed by esophagectomy, plus adjuvant trastuzumab for up to 13 cycles versus neoadjuvant chemoradiotherapy with the CROSS regimen and esophagectomy alone (NCT01196390). Results from this trial and an analogous Dutch trial, the trastuzumab and pertuzumab in resectable esophageal adenocarcinoma (TRAP) trial (NCT02120911), are eagerly awaited. In 2016, three checkpoint inhibitor clinical trials targeting the PD-1/PD-L1 axis were launched. AstraZeneca has opened a German clinical trial adding the anti-pd-l1 antibody durvalumab to neoadjuvant capecitabine, oxaliplatin, and radiotherapy in patients with locally advanced esophageal carcinoma (NCT02735239). The Mayo Clinic launched a clinical trial of the anti-pd-1 antibody pembrolizumab in combination with either neoadjuvant chemoradiotherapy per the CROSS regimen or FU, oxaliplatin, and leucovorin (mfolfox6) without radiation in patients with locally advanced gastric or gastroesophageal junction adenocarcinoma (NCT02730546). The latter clinical trial includes the potential for patients to continue to receive pembrolizumab in the adjuvant setting. Finally, Bristol-Myers Squibb has opened a phase III RCT applying nivolumab in the adjuvant setting for patients with resectable esophageal or gastroesophageal junction carcinoma who do not achieve a pathologic CR after neoadjuvant chemoradiation and esophagectomy (CheckMate 577; NCT02743494). None of these checkpoint inhibitor clinical trials are screening patients based on tumor PD-1 or PD-L1 immunohistochemistry findings. Future directions of adjuvant therapy Additions to therapy in the adjuvant setting for patients with locally advanced esophageal carcinoma after neoadjuvant chemoradiotherapy include a clinical trial of the broad tyrosine kinase inhibitor sunitinib after neoadjuvant chemoradiotherapy with cisplatin and irinotecan followed by esophagectomy (NCT00400114), the aforementioned CheckMate 577 trial with nivolumab, or regorafenib after investigator s choice neoadjuvant chemoradiotherapy and esophagectomy (NCT02234180). The findings from these adjuvant targeted and immunotherapy trials will have to be interpreted in the context of the findings from all clinical trials being applied in the neoadjuvant and adjuvant setting. Conclusion The impetus for improvements in the treatment of patients with locally advanced esophageal carcinoma is strong, as this disease has a 5-year survival rate of only 15 34% [3 5]. Currently, standard of care management for patients with locally advanced esophageal carcinoma is neoadjuvant chemoradiotherapy if a patient has a good performance status, most often based on the CROSS regimen [3]. However, neoadjuvant chemoradiation with a platinum plus fluoropyrimidine remains an option, as the POET trial demonstrated similar efficacy with this choice [30]. It is important to note that improvements in survival with neoadjuvant chemoradiation compared to perioperative chemotherapy have not been resounding and have been balanced by perioperative morbidity and mortality in patients who have a difficult time tolerating chemoradiation prior to surgery [30]. For this reason, it is still acceptable to treat patients who are moderate to high risk for surgical complication with perioperative chemotherapy alone, especially patients with adenocarcinoma histology [4]. Also, while adjuvant chemoradiation is not standard of care, there are data to support adjuvant chemoradiation following resection alone in patients with esophageal carcinoma who are upstaged at the time of surgery [31]. Finally, patients with locally advanced esophageal carcinoma are likely to see their neoadjuvant and adjuvant treatment options broaden in the future, as additional targeted therapies such as HER2-directed therapy in patients with HER2 overexpressing adenocarcinoma and immunotherapy are being applied in current clinical trials. As these new clinical trial data emerge, it will be important to consider treatment-related morbidity and the history of conflicting clinical trial data in this setting, as the validation of both perioperative chemotherapy and neoadjuvant chemoradiation in patients with good performance status

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