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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 172-181

Role of palliative chemotherapy and targeted therapy in advanced esophageal and gastroesophageal junction cancers


Department of Medical Oncology, Tata Memorial Hospital; Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

Date of Web Publication20-Dec-2019

Correspondence Address:
Vanita Noronha
Department of Medical Oncology, Tata Memorial Hospital, Dr. Ernest Borges Road, Parel, Mumbai, Maharashtra; Homi Bhabha National Institute (HBNI), Mumbai
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_10_19

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  Abstract 


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 Feb 28];2:172-81. Available from: http://www.crstonline.com/text.asp?2019/2/2/172/273665




  Introduction Top


Esophageal cancer is the 8th most common cancer in the world with a high rate of mortality.[1] 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).[2] The GEJ is a short anatomical area where the lower end of the esophagus joins the stomach.[3],[4] 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.[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.”[6]

Problem statements

The 5-year relative survival in esophageal cancers as a whole continues to be low at around 16.9%.[2] 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.[2] 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.[7],[8] 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.[9] 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.[10] 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 Top


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.

Comparisons

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 Top


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).[11] 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.[12]

What is the activity of various chemotherapeutic agents in esophageal/gastroesophageal junction cancer?

Single-agent regimens

Cisplatin

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.[13] In other studies, cisplatin has led to a response rate of 19%–26%.[14],[15] 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.

Fluoropyrimidine

A response rate of 15% was observed in an Eastern Cooperative Oncology Group (ECOG) study when 5-FU was administered in the palliative setting.[16] Capecitabine and 5-FU produce similar response rate and are considered to have equivalent efficacy[17] 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].[18],[19],[20],[21],[22] 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

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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

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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.[22]

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.[23],[24] 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.[24] 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%.[25],[26],[27] 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%).[27] 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%).[28] However, peripheral neuropathy was an issue with this regimen.[28]

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.[29] 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.[30]

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).[31] 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%.[32] 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.[33] 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.[34] Cisplatin and irinotecan combination is another active regimen in solid tumors which is administered weekly. Based on results from Phase I study,[35] 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]
Table 3: Three drug combinations used in various studies

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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.[36]

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.[37] 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.[38] 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.[38] SCC were excluded from this study.

Docetaxel + cisplatin + 5-FU (DCF)

DCF has also been tried in advanced esophageal cancer in Phase II studies.[39],[40] 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).[41] 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.[42] 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.[43] 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.[44] 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.[45] 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.[46],[47] Gefitinib and erlotinib have been shown to have limited activity in both SCC and adenocarcinoma.[48],[49] 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).[48] 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.[49]

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.[50] 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.[50] However, the same was not proven in Phase III trials where panitumumab (REAL–3)[51] and cetuximab-containing arms failed to improve survival in patients with treatment-naive unresectable or metastatic gastroesophageal adenocarcinoma.[52] 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).[53]

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.[54]

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.[55] The antiproliferative action of the conventional chemotherapeutic agents has disease-stabilizing effect at lesser doses (antiangiogenic) than the conventional doses.[56] Induction of immune response and invoking dormancy in the tumor are the other proposed mechanisms of action of metronomic chemotherapy.[57] 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.[58] 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.[59] 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).[60] 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.[61] 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.[12] The most important areas of improvement were seen in dysphagia and abdominal pain. Weekly paclitaxel has also provided improvement in dysphagia-related scores.[59] 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.[58]

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.[67],[68] 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.[69] 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 Top


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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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