|Year : 2019 | Volume
| Issue : 2 | Page : 172-181
Role of palliative chemotherapy and targeted therapy in advanced esophageal and gastroesophageal junction cancers
Vijai Simha, Vijay Patil, Amit Joshi, Kumar Prabhash, Vanita Noronha
Department of Medical Oncology, Tata Memorial Hospital; Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
|Date of Web Publication||20-Dec-2019|
Department of Medical Oncology, Tata Memorial Hospital, Dr. Ernest Borges Road, Parel, Mumbai, Maharashtra; Homi Bhabha National Institute (HBNI), Mumbai
Source of Support: None, Conflict of Interest: None
Esophageal cancer is an aggressive disease with high mortality and morbidity. Many of the patients present in advanced stages. In such a situation, systemic therapies are the mainstay of therapy both for palliation of symptoms and for meaningful improvement in survival. Preservation of quality of life is an important aspect of management of advanced and metastatic esophageal cancers. In this review article, we summarize the literature available on various systemic treatment options and the benefit in terms of response rates, improvement in survival and quality of life.Available literature on the subject was searched through an online search of the databases for articles in the English language. We describe the various classes of drugs available as evaluated in clinical trials, their response rates, and various drug combination regimens to achieve maximum benefit at the cost of minimum toxicity. Also detailed in the article are the relevant points regarding each chemotherapeutic agent/regimen and the associated response rates, progression free and overall survival. Palliative systemic therapy produces meaningful outcomes and must be considered in every patient with advanced esophageal cancer. This article will help the reader choose amongst the various treatment options and tailor the treatment according to the clinical situation.
Keywords: GEJ, gastroesophageal junction, palliation, esophageal cancer, esophagus, palliative chemotherapy
|How to cite this article:|
Simha V, Patil V, Joshi A, Prabhash K, Noronha V. Role of palliative chemotherapy and targeted therapy in advanced esophageal and gastroesophageal junction cancers. Cancer Res Stat Treat 2019;2:172-81
|How to cite this URL:|
Simha V, Patil V, Joshi A, Prabhash K, Noronha V. Role of palliative chemotherapy and targeted therapy in advanced esophageal and gastroesophageal junction cancers. Cancer Res Stat Treat [serial online] 2019 [cited 2020 Apr 3];2:172-81. Available from: http://www.crstonline.com/text.asp?2019/2/2/172/273665
| Introduction|| |
Esophageal cancer is the 8th most common cancer in the world with a high rate of mortality. There is significant geographical variation in incidence and histology. Squamous cell carcinoma (SCC) occurs commonly in the upper part of the esophagus, and adenocarcinoma occurs in the lower part of the esophagus and gastroesophageal junction (GEJ). The GEJ is a short anatomical area where the lower end of the esophagus joins the stomach., Some trials in gastric cancer also include tumors of the GEJ. According to GLOBOCAN data, the global incidence of esophageal cancer in men is nearly 400,000 per annum with an age-standardized rate (ASR) of 9.3 and 172,335 in females with an ASR of 3.5. India has an ASR of 6.5/100,000 population for males and 4.2/100,000 population for females. This translates to approximately 47,000 new cases each year and 42,000 deaths. There is a regional variation within India with high incidence in the northeastern region which lies within the so-called “esophageal cancer belt.”
The 5-year relative survival in esophageal cancers as a whole continues to be low at around 16.9%. The disease is inoperable at presentation in most patients (70%–80%), due to locally advanced or metastatic nature of the disease, with expected survival of 7–12 months. Even in those patients who undergo curative resection or radical chemoradiation, recurrences occur in approximately 60% of the patients in the 1st year and up to 80% in the 2nd year., Therefore, in the majority of patients with esophageal cancer, palliation is the mainstay of treatment. While the local therapy modalities are effective and can provide symptomatic benefit, they can hardly be used over a sustained period of time and therefore rarely influence long-term/survival outcomes. The systemic treatment modalities, however, have the potential to prolong survival as well as improve disease-related symptoms when used optimally in appropriately selected patients. The goal of palliative chemotherapy in esophageal/GEJ cancer is to palliate symptoms without hampering the quality of life and to attempt to prolong survival. The purpose of this review is to put together contemporary research done in the area of systemic therapies in the management of esophageal cancer including palliative chemotherapy and targeted therapy in advanced esophageal and GEJ cancers.
| Materials and Methods|| |
Our search objective was to retrieve articles that investigate or summarize the role of palliative chemotherapy in advanced or metastatic esophageal or GEJ cancer.
We performed a manual search using the keywords 'palliative chemotherapy,' 'esophageal cancer,' 'advanced esophageal cancer,' 'metastatic esophageal cancer,' and 'gastroesophageal junction cancer' to identify articles describing palliative chemotherapy administered in patients with advanced esophageal/GEJ cancer. Only articles with an English abstract were included, resulting in some degree of publication bias. Chemotherapy was defined as the use of a cytotoxic drug or drug combination, distinct from immunotherapy and targeted therapy.
Participants and interventions
Patients who received chemotherapy or targeted therapy or immunotherapy as novel interventions compared to contemporary standards and best supportive care were included. Combinations of chemotherapy with radiotherapy were excluded.
Our study only dealt with comparisons between systemic therapies and purposefully excluded studies which incorporated local therapies in the study arms. The studies included Phase I/II and Phase III studies, as well as retrospective/nonrandomized trials. The new chemotherapeutic agent/schedule when used, was to be compared to contemporary systemic therapies or best supportive care.
Outcomes and study designs
With each individual drug and study regimens, the response rates, progression free and overall survival (OS) rates are mentioned along with the incidence of important Grade 3 and Grade 4 toxicities.
The search was conducted in the following electronic databases: Medline, Embase, Web of Science, PubMed and Google Scholar.
| Results|| |
From the above search criteria, 40 articles of relevance to the topic were identified. Of these, 10 were randomized trials, 12 were Phase II trials, and 13 were retrospective/nonrandomized trials.
Does palliative chemotherapy prolong overall survival in esophageal/gastroesophageal junction cancer?
There is lack of level 1 evidence to suggest that chemotherapy improves survival over best supportive care in esophageal cancer. Janmaat et al. published a systematic review to evaluate the effects of palliative systemic therapy for esophageal or GEJ cancer. They included 11 studies (6 studies in the first line setting) in 1347 patients for their main comparison, which was the addition of a cytostatic/targeted therapy to an active control arm versus the control arm alone. They demonstrated a median improvement in OS of 1 month; hazard ratio (HR), 0.75 (95% confidence interval [CI] 0.68–0.84); median OS in the arm with additional systemic therapy was 6.7 months versus a median OS of 5.7 months in the arm that included the control agent, with an increase in the incidence of severe treatment-related toxicity, and an improvement in the quality of life with the addition of systemic therapy. Five studies (2 in the first line setting) with 750 patients compared chemotherapy to best supportive care; the median OS in the chemotherapy arm was 4.7 months, and that in the best supportive care arm was 4.2 months, HR, 0.81 (95% CI, 0.71–0.92). Data on prolongation of survival in the second line setting in patients with esophageal/GEJ adenocarcinoma is far clearer; in the COUGAR-02 study, in patients who had failed platinum and 5-fluorouracil (5-FU), docetaxel led to a median OS of 5.2 months versus 3.6 months in patients who received best supportive care, HR 0.67, 95% CI: 0.49–0.92; P = 0.01. Docetaxel increased the toxicities as well.
What is the activity of various chemotherapeutic agents in esophageal/gastroesophageal junction cancer?
After its success in germ cell tumors, single-agent cisplatin was tried in all solid tumors including the upper GI tract. Kantarjian et al. evaluated the role of single-agent cisplatin in 55 patients of upper GI tract cancers (including 12 esophageal cancers) and was able to demonstrate only 6% response rate in this group. In other studies, cisplatin has led to a response rate of 19%–26%., The main toxicity seen with cisplatin was hematological toxicity (19.6%), and gr 3/4 vomiting in 12.5%, gr >2 nephrotoxicity was seen in 9% of patients.
A response rate of 15% was observed in an Eastern Cooperative Oncology Group (ECOG) study when 5-FU was administered in the palliative setting. Capecitabine and 5-FU produce similar response rate and are considered to have equivalent efficacy producing response rates of 20%–30% and median OS of 10.5 versus 9.3 months. The response rates are higher (reaching up to 58%) in adenocarcinoma.
Other single-agent chemotherapy agents
Taxanes, etoposide and irinotecan have also been used and produce response rates in the range of 30%–40% [Table 1].,,,, Predominant toxicity seen with paclitaxel was Grade 1/2 neuropathy (49%) though rate of severe neuropathy was 2%. Other Grade 3/4 toxicities seen with paclitaxel were Grade 3/4 bony pains (5%) and fatigue (2%). Docetaxel caused Grade 3/4 toxicity including infections in 19% and febrile neutropenia in 7% patients. With irinotecan, Grade 3/4 diarrhea in 6% and neutropenia in 5% were the predominant toxicities.
|Table 1: Detailing the most active agents in esophageal cancer, the studies in which they are described the regimens and the response rates seen when used as a single agent|
Click here to view
Combination chemotherapy - 2 drug regimens [Table 2]
|Table 2: Two drug combinations used in esophageal cancer and the response rates and clinical outcomes associated with them|
Click here to view
Combination chemotherapies produce higher responses compared to single agents but do not appear to lead to significant benefit in terms of prolongation of survival and therefore, an optimal regimen for first-line palliative chemotherapy has yet to be clearly established.
Cisplatin and 5-FU
The two-drug combination of cisplatin and 5-FU as continuous infusion has been the common regimen for both SCC and adenocarcinoma of the esophagus.In vitro synergy has been demonstrated between cisplatin and 5-FU in experimental models., In a Japanese study, this combination led to a 33.3% response rate in patients with metastatic, recurrent, or locally advanced incurable SCC of the esophagus. Multiple authors have confirmed the efficacy of cisplatin and 5-FU combination in variable doses and schedules. The response rates with this doublet are between 33% and 55%.,, However, high-dose cisplatin (100 mg/m2) with 5FU (1 g/m2/day for 5 days) was associated with high rates of morbidity (73%-leucopenia) and mortality (6%). The 1-year survival rate was 33.33% with a median survival of 7.46 months (4.73–10.12 months). The authors concluded that the daily continuous infusion of cisplatin was not associated with higher response and lower toxicity than those seen with bolus/multi-bolus regimens.
Oxaliplatin-based combinations (with 5-FU/capecitabine)
In search of less toxic regimens compared to cisplatin + 5-FU, oxaliplatin was considered as a substitute for cisplatin, and capecitabine for infusional 5-FU. In a German study, FOLFOX (oxaliplatin + 5-FU + leucovorin), used for palliative chemotherapy, showed comparable antitumor activity and favorable toxicity profile compared to cisplatin + 5-FU. Oxaliplatin caused significantly less (any grade) anemia (54% vs. 72%), nausea (53% vs. 70%), vomiting (31% vs. 52%), alopecia (22% vs. 39%), fatigue (19% vs. 34%), renal toxicity (11% vs. 34%), and thromboembolic events (0.9% vs. 7.8%). However, peripheral neuropathy was an issue with this regimen.
S1 with cisplatin
S1 is a newer fluoropyrimidine specifically designed to overcome the limitations of intravenous fluoropyrimidine therapies.
S1 + cisplatin as doublet has been compared to infusional 5-FU + cisplatin in a trial that attempted to establish the superiority of S1 over infusional 5-FU. Similar OS (7.9 vs. 8.6 months) was seen in the two arms. The S1 (CS) arm had less toxicity than 5-FU (CF) (Grade 3/4 neutropenia; CS, 18.6% vs. CF, 40.0%), febrile neutropenia (CS, 1.7% vs. CF, 6.9%), Grade 3/4 stomatitis (CS, 1.3% vs. CF, 13.6%), diarrhea (29.2%; vs. CF, 38.4%) and renal adverse events (CS, 18.8% vs. CF, 33.5%). Similar results were confirmed in a Chinese trial too.
Gemcitabine with cisplatin
Gemcitabine and cisplatin have been used in Phase II trials in patients with unresectable or metastatic esophageal adenocarcinoma or SCC: cisplatin (75 mg/m2 on day 1), followed by gemcitabine (1250 mg/m2, days 1 and 8) every 21 days. The initial dose of gemcitabine resulted in significant toxicity concerns resulting in an interim analysis and amendment to the protocol and the dose of gemcitabine was modified to 1000 mg/m2, on days 1 and 8. A total of 45% of patients had a major objective response, and the median survival was 11 months (95% CI, 4.8–17.3 months). Though this regimen has not been compared to 5-FU + cisplatin, it remains one of the viable options.
Taxane with platinum
The combination of paclitaxel + carboplatin has been tried in advanced esophageal cancer and has shown overall response rates of 39%. Median OS was 15.5 months (95% CI: 1.06–1.5). Median progression-free survival (PFS) was 5.3 months (95% CI 0.34-0.5). The common Grade III toxicities observed were neutropenia (14.2%) and neuropathy (3.7%).
Folinic acid, 5-FU, and irinotecan (FOLFIRI) has been compared head-to-head with ECF and has been found to be equivalent to ECF. FOLFIRI has also been tried in locally advanced or metastatic SCC or adenocarcinoma that are resistant to 5-FU-platinum. Overall response rate of 29% with an improvement in dysphagia in 78.6% patients was noted. The median failure free and OS were 3.7 and 6.4 months respectively. Cisplatin and irinotecan combination is another active regimen in solid tumors which is administered weekly. Based on results from Phase I study, the regimen was tested for efficacy in 35 patients with advanced esophageal carcinomas. The combination resulted in 57% major objective responses, median duration of response 4.2 months (1–8.8 months). The median survival was 14.6 months. There was also significant improvement in quality of life with this regimen.
Combination chemotherapy - 3 drugs regimen [Table 3]
5-Fluorouracil + adriamycin + methotrexate
5-FU, adriamycin, and methotrexate (FAMTX) was the only regimen available previously that demonstrated a survival benefit in a randomized trial over 5-FU, adriamycin, and mitomycin-C (FAM). FAMTX lead to superior response rate (41% vs. 9% [P < 0.0001]) and survival (median OS, 42 weeks vs. 29 weeks [P = 0.004]). FAM regimen was associated with a high rate of thrombocytopenia with nadirs accumulating up to grade 4 thrombocytopenia by the end of 4th cycle; however, this adverse event was not observed with FAMTX regimen. The authors concluded (in the year 1991) that the FAMTX protocol should be considered as the reference treatment for advanced esophageal adenocarcinoma.
Epirubicin + cisplatin + 5-fluorouracil
Epirubicin, cisplatin, and continuous 5-FU (ECF) regimen was developed in the UK at the Royal Marsden Hospital and was compared in a randomized trial to FAMTX. The ECF regimen demonstrated superiority over FAMTX in terms of response rates, OS, better toxicity and tolerability profile, quality of life, and cost-effectiveness. Thus, ECF became the new standard of care in advanced cancer of the GEJ in the late 1990s.
5-Fluorouracil + oxaliplatin + irinotecan
5 FU + leucovorin + oxaliplatin + irinotecan (FOLFIRINOX) has been used as a first-line regimen in advanced GE adenocarcinomas in a single arm Phase II study. Doses used were 5-FU 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h with leucovorin 400 mg/m2, irinotecan 180 mg/m2, and oxaliplatin 85 mg/m2. Along with the backbone of FOLFIRINOX, trastuzumab was administered as 6 mg/kg loading dose and then 4 mg/kg every 14 days if patients had human epidermal growth factor receptor 2 positive (HER-2+) cancer. The overall response rate was 78% (38/49) which increased up to 91% in HER2 + tumors. Median PFS was 11.9 months, and median OS was 17.4 months. Dose modification was required in 83% of patients. SCC were excluded from this study.
Docetaxel + cisplatin + 5-FU (DCF)
DCF has also been tried in advanced esophageal cancer in Phase II studies., The regimen consists of docetaxel 35 mg/m2 with cisplatin 40 mg/m2 on days 1 and 15 and 400 mg/m2 5-FU on days 1–5 and 15–19 every 4 weeks. This regimen has shown up to 90% response rates. This was however associated with 30% grade 3/4 neutropenia which is not acceptable in the palliative setting.
Epirubicin + oxaliplatin + capecitabine regimen
Cunningham et al. in a two-by-two design, randomly assigned 1002 patients to receive triplet therapy with epirubicin and cisplatin plus either fluorouracil (ECF) or capecitabine (ECX) or triplet therapy with epirubicin and oxaliplatin plus either fluorouracil (EOF) or capecitabine (EOX). The HR for death was similar in capecitabine and oxaliplatin groups: 0.86 versus 0.92. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. The overall response rate was 40.7% and was similar in all the groups. Oxaliplatin containing groups had significantly lesser neutropenia but significantly more grade 3/4 peripheral neuropathy (8.4%) while grade 3/4 hand-foot syndrome was higher (10.3%) in the capecitabine-containing arm.
5FU-leucovorin + oxaliplatin + docetaxel regimen
The combination of docetaxel, cisplatin, and 5-FU improved efficacy in gastric cancer, in the curative setting. The same combination was evaluated in adenocarcinoma of the stomach and GEJ. Objective responses of 57% were seen with Grade 3 or 4 toxic effects including neutropenia in 26 (48.1%), leukopenia in 15 (27.8%), diarrhea in 8 (14.8%), and fatigue in 6 (11.1%) patients. Toxicity makes the selection of patients for such regimens extremely important.
Two-drug versus three-drug regimen in gastroesophageal junction tumors
The literature from the V325 study (Van Cutsem et al.) which had 20% GEJ tumors suggests that there is an advantage from the 3-drug regimen of docetaxel + cisplatin + 5-FU versus 2-drug regimen of cisplatin + 5-FU with significantly improved time to tumor progression with a 32% risk reduction in progression of disease (log rank P = 0.02) (primary endpoint), OS at 2 years was 18% versus 9% for the three and two drugs respectively, and overall response rate: 81% versus 57% (secondary endpoints), with global health status (quality of life) and Karnofsky performance status (clinical benefit) preserved for a longer time. However, the study only included GEJ tumors and therefore, the evidence best applies to GEJ adenocarcinomas.
Targeted therapies in gastroesophageal junction cancers
Human epidermal growth factor receptor 2-targeted therapies
HER-2 overexpression (as defined as a 3+ score on immunohistochemistry (IHC) or fluorescence in situ hybridization amplified if IHC shows an equivocal score of 2+) is seen in approximately 12.2%–24% of gastric and GEJ tumors respectively. The ToGA trial compared chemotherapy alone (capecitabine/cisplatin + 5-FU) versus chemotherapy with the addition of trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3-weekly) and demonstrated the activity and benefit of trastuzumab in HER-2-overexpressing GEJ cancers, proposing a new standard of care in this cohort. Antitumor response (47.3% vs. 34.5%), PFS (6.7 months vs. 5.5 months), and OS (13.8 months vs. 11.1 months) (HR, 0.74; P = 0.0046) were better in trastuzumab arm compared to chemotherapy-only arms. This benefit was at the cost of no significant increase in the cardiac adverse events and the toxicities seen mainly nausea, vomiting, and neutropenia were due to chemotherapy.
Antiepidermal growth factor receptor-directed therapies
High levels of epidermal growth factor receptor (EGFR) expression have been inversely correlated with outcomes and chemotherapy resistance in esophageal cancers., Gefitinib and erlotinib have been shown to have limited activity in both SCC and adenocarcinoma., Gefitinib did not prolong survival in a Phase III randomized study of 450 patients (the median PFS was 47 days with gefitinib, compared to 35 days with placebo). A German Phase II study used FOLFOX + erlotinib and found the combination to produce objective response rate of 51%, PFS of 5.5 months, and OS of 11 months.
Cetuximab was combined with cisplatin + 5-FU which showed a benefit over the combination of cisplatin + 5-FU in a Phase II trial in SCC of the esophagus. Evaluation of response rates alone may underestimate the overall treatment effect of targeted therapies as blockade of EGFR pathways often results in disease stabilization. Around 75% of patients treated with cetuximab + cisplatin + 5-FU experienced disease stabilization. The median PFS (5.9 vs. 3.6 months) and the median OS (9.5 vs. 5.5 months) both favored the addition of cetuximab. However, the same was not proven in Phase III trials where panitumumab (REAL–3) and cetuximab-containing arms failed to improve survival in patients with treatment-naive unresectable or metastatic gastroesophageal adenocarcinoma. The median survival was 8.8 months with addition of panitumumab versus 11.3 months with chemotherapy (epirubicin + oxaliplatin + capecitabine) alone. Grade 3/4 toxicities included diarrhea (17%), rash (11%), mucositis (5%) and hypomagnesemia (5%).
Targeting angiogenesis pathways
Ramucirumab is a VEGFR-2 receptor antibody, and ramucirumab in combination with paclitaxel was compared with placebo and resulted in superior OS and PFS in advanced GEJ cancers. Both the trials have been done in second line settings. Median OS was 5.2 months (interquartile range [IQR] 2.3-–9.9) in patients in the ramucirumab group and 3.8 months (IQR, 1.7–7.1) in those in the placebo group (HR, 0.776, 95% CI, 0.603–0.998; P = 0.047).
AMG 386 (Trebananib) is an intravenously administered peptide Fc-fusion protein that inhibits angiogenesis by neutralizing the interaction of Ang1/Ang2 with the Tie2 receptor. The combination of trebanib + cisplatin + capecitabine failed to demonstrate improved response or superior disease-free survival.
Metronomic chemotherapy in esophageal cancer
The role of metronomic chemotherapy in esophageal cancer exploits the ability of some chemotherapeutic agents to target the angiogenesis pathway which seems to be active in esophageal cancer. The antiproliferative action of the conventional chemotherapeutic agents has disease-stabilizing effect at lesser doses (antiangiogenic) than the conventional doses. Induction of immune response and invoking dormancy in the tumor are the other proposed mechanisms of action of metronomic chemotherapy. Capecitabine has been shown at reduced fixed dose of 1000 mg daily to produce response rates of 20.9% with median TTP of 3.6 months. Taxanes in lower doses have also been shown to produce antiangiogenic effect and in retrospective studies, 71% of patients had improvement in dysphagia, with a median time to symptom improvement of 9 days. In 72% of patients, the feeding nasogastric tube could be removed. The overall response rate was 49% (complete remission: 4%, partial remission: 45%, and stable disease: 13%). The median PFS was 4.7 months (95% CI, 3.7–5.7 months) and median OS was 7.5 months (95% CI, 3.1–11.8 months). Remarkably, 45% of patients in this series were of ECOG performance status ≥2 and the feeding tube could be removed in 72% of patients after chemotherapy. Thus, the clinical benefit rates and OS appear to be comparable with the conventional doublet and triplet platinum-based chemotherapy. However, data from head-to-head randomized trials are lacking.
Checkpoint inhibitors in esophageal cancer
Anti-programmed death-1 antibody pembrolizumab has been evaluated in KEYNOTE-028 (Phase I study) in patients with SCC and adenocarcinoma of the esophagus failing standard therapies and with programmed death ligand-1 (PD-L1)-positive status. PD-L1 expression (specified by a combined positive score [CPS] of >10) was seen in 45% of all tumors. In the Phase II study, the overall time to response was 4 months and the median duration of response was 15 months (range, 6–26 months). The adverse effects consisted of decreased appetite, drop in lymphocyte count, and rash, and there were no grade 4 adverse effects. The Phase III trial of nivolumab (NCT02569242) which is ongoing will ultimately establish the role of checkpoint inhibitors in advanced esophageal cancer. The Phase III KEYNOTE-181 study compared pembrolizumab versus chemotherapy in the second-line setting. Pembrolizumab was given at 200 mg every 3-weekly for 2 years or until disease progression. The patients were stratified based on the expression of the PD-L1-CPS ≥10; median OS was better with pembrolizumab at 9.3 months versus 6.7 months 6.7 months with a better safety profile compared to chemotherapy (incidence of severe adverse events <10%). Pembrolizumab has been proposed as the new second-line standard of care in advanced esophageal cancer.
Global health-related quality of life and disease-related quality of life have been reported in a few studies, notable of which are from Ford and Gounaris (Cougar-02 Phase III trial) who showed improvements in the overall quality of life apart from providing a survival benefit. The most important areas of improvement were seen in dysphagia and abdominal pain. Weekly paclitaxel has also provided improvement in dysphagia-related scores. Nearly 51% of patients had improvement in dysphagia, and in 32% of the patients, the nasogastric tube could be removed. There was long-term palliation of dysphagia for 2 years which was seen in 17% of patients treated with metronomic capecitabine.
Systemic therapy in patients with compromised PS
There are no data in patients with esophageal cancer with compromised performance status receiving palliative chemotherapy. Most of the guidelines recommend not to use chemotherapy in the palliative management of esophageal cancer in these patients., Patients with ECOG PS ≥3 are underrepresented in studies using metronomic chemotherapy (<10% of the population) and the same conclusions cannot be drawn to this population.
Systemic therapy in older and frail individuals
The Phase II/III data for palliative chemotherapy in esophageal cancer deal mainly with fit patients; frail patients were generally excluded from these studies. Therefore, there is no published evidence to bolster the role of chemotherapy in this population. Hall et al. reported recently the results of the GO2 randomized trial in older and frail patients where patients were randomized to three dose levels of capecitabine and oxaliplatin at 100%, 80% and 60% the doses of oxaliplatin 130 mg/m2 and capecitabine 650 mg/m2 from days 1 to 21 every 3-weekly. They showed that the median PFS (4.1 months, 4.3 months and 4.9 months respectively) and OS (6.7 vs. 7.6 vs. 7.5 months) were similar between the three cohorts. This study (as yet unpublished) provides evidence to treat frail older patients and makes an important point, i.e. that dose and dose-intensity may not be all important in palliative management. However, a totally oral regimen (metronomic) may also be suited for these patients so that the number of health care visits be minimized.
Future prospects and ongoing work
With improving standards of medicine and healthcare, esophageal cancer seen once as a hopeless disease may hold some hope.
There are many options in the systemic therapy of advanced esophageal cancer which can potentially prolong the PFS and OS without compromising the quality of life. Immunotherapy is one of the most actively researched area. Along with immunotherapy, metronomic chemotherapy holds the maximum promise for providing a least toxic yet efficacious solution to this difficult clinical situation. Recent studies also have shown that reduced doses of chemotherapeutics don't compromise the overall outcomes in the frail older patients and treatment recommendations in this population represent an unmet need.
| Recommendations and Conclusions|| |
The options to treat advanced esophageal cancer are plenty but the response rates with individual agents are very low. Therefore, a two or three-drug regimen must be preferably used. Also, most of the chemotherapy studies outlined above have shown stable disease more than partial responses and few instances of complete response have been seen. This suggests that these agents must be used in a judicious manner with very low thresholds for reductions in dose and stoppage of chemotherapy. The intent of treatment should be palliation of symptoms while maintaining the quality of life.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mahboubeh Sadat Yousefi MS, Pourgholam-Amiji N, Afshar M, Otroshi O. Esophageal cancer in the world: Incidence, mortality and risk factors. Biomed Res Ther 2018;5:2504-17.
Zhang Y. Epidemiology of esophageal cancer. World J Gastroenterol 2013;19:5598-606.
Suh YS, Han DS, Kong SH, Lee HJ, Kim YT, Kim WH, et al.
Should adenocarcinoma of the esophagogastric junction be classified as esophageal cancer? A comparative analysis according to the seventh AJCC TNM classification. Ann Surg 2012;255:908-15.
Hasegawa S, Yoshikawa T, Aoyama T, Hayashi T, Yamada T, Tsuchida K, et al.
Esophagus or stomach? The seventh TNM classification for Siewert type II/III junctional adenocarcinoma. Ann Surg Oncol 2013;20:773-9.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Samarasam I. Esophageal cancer in India: Current status and future perspectives. Int J Adv Med Health Res 2017;4:5-10. [Full text]
Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr., Al-Sarraf M, et al.
Chemoradiotherapy of locally advanced esophageal cancer: Long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999;281:1623-7.
Hulscher JB, van Sandick JW, de Boer AG, Wijnhoven BP, Tijssen JG, Fockens P, et al.
Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N
Engl J Med 2002;347:1662-9.
Ramakrishnaiah VP, Malage S, Sreenath GS, Kotlapati S, Cyriac S. Palliation of Dysphagia in Carcinoma Esophagus. Clin Med Insights Gastroenterol 2016;9:11-23.
Halpern AL, McCarter MD. Palliative management of gastric and esophageal cancer. Surg Clin North Am 2019;99:555-69.
Janmaat VT, Steyerberg EW, van der Gaast A, Mathijssen RH, Bruno MJ, Peppelenbosch MP, et al.
Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal junction cancer. Cochrane Database Syst Rev 2017;11:CD004063.
Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, et al.
Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): An open-label, phase 3 randomised controlled trial. Lancet Oncol 2014;15:78-86.
Kantarjian H, Ajani JA, Karlin DA. Cis-diaminodichloroplatinum (II) chemotherapy for advanced adenocarcinoma of the upper gastrointestinal tract. Oncology 1985;42:69-71.
Bleiberg H, Conroy T, Paillot B, Lacave AJ, Blijham G, Jacob JH, et al.
Randomised phase II study of cisplatin and 5-fluorouracil (5-FU) versus cisplatin alone in advanced squamous cell oesophageal cancer. Eur J Cancer 1997;33:1216-20.
Panettiere FJ, Leichman LP, Tilchen EJ, Chen TT. Chemotherapy for advanced epidermoid carcinoma of the esophagus with single-agent cisplatin: Final report on a Southwest Oncology Group study. Cancer Treat Rep 1984;68:1023-4.
Ezdinli EZ, Gelber R, Desai DV, Falkson G, Moertel CG, Hahn RG. Chemotherapy of advanced esophageal carcinoma: Eastern Cooperative Oncology Group experience. Cancer 1980;46:2149-53.
Popa EC, Shah MA. Capecitabine in the treatment of esophageal and gastric cancers. Expert Opin Investig Drugs 2013;22:1645-57.
Ajani JA, Ilson DH, Daugherty K, Pazdur R, Lynch PM, Kelsen DP. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst 1994;86:1086-91.
Ford H, Gounaris I. Docetaxel and its potential in the treatment of refractory esophagogastric adenocarcinoma. Therap Adv Gastroenterol 2015;8:189-205.
Mühr-Wilkenshoff F, Hinkelbein W, Ohnesorge I, Wolf KJ, Riecken EO, Zeitz M, et al.
Apilot study of irinotecan (CPT-11) as single-agent therapy in patients with locally advanced or metastatic esophageal carcinoma. Int J Colorectal Dis 2003;18:330-4.
Sternberg C, Kelsen D, Dukeman M, Leichman L, Heelan R. Carboplatin: A new platinum analog in the treatment of epidermoid carcinoma of the esophagus. Cancer Treat Rep 1985;69:1305-7.
Grünberger B, Raderer M, Schmidinger M, Hejna M. Palliative chemotherapy for recurrent and metastatic esophageal cancer. Anticancer Res 2007;27:2705-14.
Nishiyama M, Yamamoto W, Park JS, Okamoto R, Hanaoka H, Takano H, et al.
Low-dose cisplatin and 5-fluorouracil in combination can repress increased gene expression of cellular resistance determinants to themselves. Clin Cancer Res 1999;5:2620-8.
Hayashi K, Ando N, Watanabe H, Ide H, Nagai K, Aoyama N, et al.
Phase II evaluation of protracted infusion of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: A Japan Esophageal Oncology Group (JEOG) Trial (JCOG9407). Jpn J Clin Oncol 2001;31:419-23.
Sekiguchi H, Akiyama S, Fujiwara M, Nakamura H, Kondo K, Kasai Y, et al.
Phase II trial of 5-fluorouracil and low-dose cisplatin in patients with squamous cell carcinoma of the esophagus. Surg Today 1999;29:97-101.
Caroli-Bosc FX, Van Laethem JL, Michel P, Gay F, Hendlisz A, Forget F, et al.
Aweekly 24-h infusion of high-dose 5-fluorouracil (5-FU)+leucovorin and bi-weekly cisplatin (CDDP) was active and well tolerated in patients with non-colon digestive carcinomas. Eur J Cancer 2001;37:1828-32.
Levard H, Pouliquen X, Hay JM, Fingerhut A, Langlois-Zantain O, Huguier M, et al.
5-Fluorouracil and cisplatin as palliative treatment of advanced oesophageal squamous cell carcinoma. A multicentre randomised controlled trial. The French Associations for Surgical Research. Eur J Surg 1998;164:849-57.
Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, et al.
Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: A study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 2008;26:1435-42.
Ajani JA, Buyse M, Lichinitser M, Gorbunova V, Bodoky G, Douillard JY, et al.
Combination of cisplatin/S-1 in the treatment of patients with advanced gastric or gastroesophageal adenocarcinoma: Results of noninferiority and safety analyses compared with cisplatin/5-fluorouracil in the First-Line Advanced Gastric Cancer Study. Eur J Cancer 2013;49:3616-24.
Li YH, Qiu MZ, Xu JM, Sun GP, Lu HS, Liu YP, et al.
S-1 plus cisplatin versus fluorouracil plus cisplatin in advanced gastric or gastro-esophageal junction adenocarcinoma patients: A pilot study. Oncotarget 2015;6:35107-15.
Millar J, Scullin P, Morrison A, McClory B, Wall L, Cameron D, et al.
Phase II study of gemcitabine and cisplatin in locally advanced/metastatic oesophageal cancer. Br J Cancer 2005;93:1112-6.
Prithviraj GK, Baksh K, Fulp W, Meredith K, Hoffe S, Shridhar R, et al
. Carboplatin and paclitaxel as first-line treatment of unresectable or metastatic esophageal or gastric cancer. Dis Esophagus 2015;28:782-7.
Guimbaud R, Louvet C, Ries P, Ychou M, Maillard E, André T, et al.
Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: A French intergroup (Fédération francophone de cancérologie digestive, fédération nationale des centres de lutte contre le cancer, and groupe coopérateur multidisciplinaire en oncologie) study. J Clin Oncol 2014;32:3520-6.
Assersohn L, Brown G, Cunningham D, Ward C, Oates J, Waters JS, et al.
Phase II study of irinotecan and 5-fluorouracil/leucovorin in patients with primary refractory or relapsed advanced oesophageal and gastric carcinoma. Ann Oncol 2004;15:64-9.
Saltz LB, Spriggs D, Schaaf LJ, Schwartz GK, Ilson D, Kemeny N, et al.
Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors. J Clin Oncol 1998;16:3858-65.
Wils JA, Klein HO, Wagener DJ, Bleiberg H, Reis H, Korsten F, et al.
Sequential high-dose methotrexate and fluorouracil combined with doxorubicin-a step ahead in the treatment of advanced gastric cancer: A trial of the European organization for research and treatment of cancer gastrointestinal tract cooperative group. J Clin Oncol 1991;9:827-31.
Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, et al.
Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997;15:261-7.
Park H, Wang-Gillam A, Suresh R, Rigden CE, Amin MA, Tan BR, et al
. A phase II trial of first-line folfirinox for patients with advanced gastroesophageal adenocarcinoma. J Clin Oncol 2018;36 Suppl 4:89.
Tamura S, Imano M, Takiuchi H, Kobayashi K, Imamoto H, Miki H, et al.
Phase II study of docetaxel, cisplatin and 5-fluorouracil (DCF) for metastatic esophageal cancer (OGSG 0403). Anticancer Res 2012;32:1403-8.
Tanaka Y, Yoshida K, Yamada A, Tanahashi T, Okumura N, Matsuhashi N, et al.
Phase II trial of biweekly docetaxel, cisplatin, and 5-fluorouracil chemotherapy for advanced esophageal squamous cell carcinoma. Cancer Chemother Pharmacol 2016;77:1143-52.
Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al.
Capecitabine and oxaliplatin for advanced esophagogastric cancer. N
Engl J Med 2008;358:36-46.
Al-Batran SE, Hartmann JT, Hofheinz R, Homann N, Rethwisch V, Probst S, et al.
Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: A phase II trial of the arbeitsgemeinschaft internistische onkologie. Ann Oncol 2008;19:1882-7.
Van Cutsem E, Boni C, Tabernero J, Massuti B, Middleton G, Dane F, et al.
Docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer: A randomized phase II study. Ann Oncol 2015;26:149-56.
Tanner M, Hollmén M, Junttila TT, Kapanen AI, Tommola S, Soini Y, et al.
Amplification of HER-2 in gastric carcinoma: Association with topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol 2005;16:273-8.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al.
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-97.
Itakura Y, Sasano H, Shiga C, Furukawa Y, Shiga K, Mori S, et al.
Epidermal growth factor receptor overexpression in esophageal carcinoma. An immunohistochemical study correlated with clinicopathologic findings and DNA amplification. Cancer 1994;74:795-804.
Kitagawa Y, Ueda M, Ando N, Ozawa S, Shimizu N, Kitajima M. Further evidence for prognostic significance of epidermal growth factor receptor gene amplification in patients with esophageal squamous cell carcinoma. Clin Cancer Res 1996;2:909-14.
Dutton SJ, Ferry DR, Blazeby JM, Abbas H, Dahle-Smith A, Mansoor W, et al.
Gefitinib for oesophageal cancer progressing after chemotherapy (COG): A phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol 2014;15:894-904.
Wainberg ZA, Lin LS, DiCarlo B, Dao KM, Patel R, Park DJ, et al.
Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction. Br J Cancer 2011;105:760-5.
Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, et al.
Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: A randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 2009;20:1667-73.
Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, et al.
Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. Lancet Oncol 2013;14:481-9.
Huang ZH, Ma XW, Zhang J, Li X, Lai NL, Zhang SX. Cetuximab for esophageal cancer: An updated meta-analysis of randomized controlled trials. BMC Cancer 2018;18:1170.
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al.
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014;383:31-9.
Eatock MM, Tebbutt NC, Bampton CL, Strickland AH, Valladares-Ayerbes M, Swieboda-Sadlej A, et al.
Phase II randomized, double-blind, placebo-controlled study of AMG 386 (trebananib) in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer. Ann Oncol 2013;24:710-8.
Noronha V, Patil VM, Joshi A, Chougule A, Banavali S, Prabhash K. Potential role of metronomic chemotherapy in the treatment of esophageal and gastroesophageal cancer. Cancer Lett 2017;400:267-75.
Gille J, Spieth K, Kaufmann R. Metronomic low-dose chemotherapy as antiangiogenic therapeutic strategy for cancer. J Dtsch Dermatol Ges 2005;3:26-32.
Noronha V, Krishna MV, Patil V, Joshi A, Banavali SD, Prabhash K. Metronomic therapy: Chemotherapy revisited. Indian J Cancer 2013;50:142-8. [Full text]
He S, Shen J, Hong L, Niu L, Niu D. Capecitabine “metronomic” chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy. Med Oncol 2012;29:100-6.
Joshi A, Noronha V, Pandey A, Patil V, Samar A, Mahajan A, et al.
Outcomes with palliative weekly paclitaxel in advanced, recurrent, and metastatic esophageal cancer – Real world experience. Indian J Med Paediatr Oncol 2018;39:46-51. [Full text]
Doi T, Piha-Paul SA, Jalal SI, Saraf S, Lunceford J, Koshiji M, et al.
Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol 2018;36:61-7.
Shah MA, Adenis A, Enzinger PC, Kojima T, Muro K, Bennouna J, et al.
Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase 3 KEYNOTE-181 study. J Clin Oncol 2019;37 Suppl 15:4010.
Lee JL, Ryu MH, Chang HM, Kim TW, Yook JH, Oh ST, et al.
Aphase II study of docetaxel as salvage chemotherapy in advanced gastric cancer after failure of fluoropyrimidine and platinum combination chemotherapy. Cancer Chemother Pharmacol 2008;61:631-7.
Graziano F, Catalano V, Baldelli AM, Giordani P, Testa E, Lai V, et al.
Aphase II study of weekly docetaxel as salvage chemotherapy for advanced gastric cancer. Ann Oncol 2000;11:1263-6.
Giuliani F, Gebbia V, De Vita F, Maiello E, Di Bisceglie M, Catalano G, et al.
Docetaxel as salvage therapy in advanced gastric cancer: A phase II study of the Gruppo Oncologico Italia Meridionale (G.O.I.M.). Anticancer Res 2003;23:4219-22.
Harstrick A, Bokemeyer C, Preusser P, Köhne-Wömpner CH, Meyer HJ, Stahl M, et al.
Phase II study of single-agent etoposide in patients with metastatic squamous-cell carcinoma of the esophagus. Cancer Chemother Pharmacol 1992;29:321-2.
Ilson DH. Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. Oncology (Williston Park) 2004;18:22-5.
Kitagawa Y, Uno T, Oyama T, Kato K, Kato H, Kawakubo H, et al.
Esophageal cancer practice guidelines 2017 edited by the Japan Esophageal Society: Part 1. Esophagus 2019;16:1-24.
Lordick F, Mariette C, Haustermans K, Obermannová R, Arnold D; ESMO Guidelines Committee. Oesophageal cancer: Esmo clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27:v50-7.
Hall PS, Swinson D, Waters JS, Wadsley J, Falk S, Roy R, et al.
Optimizing chemotherapy for frail and elderly patients (pts) with advanced gastroesophageal cancer (aGOAC): The GO2 phase III trial. J Clin Oncol 2019;37 Suppl 15:4006.
[Table 1], [Table 2], [Table 3]