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Review

Cancer Research Frontiers. 2016 May; 2(2): 184-199. doi: 10.17980/2016.184

A Systematic Review of the Randomised Phase III Clinical Trials Employing Palliative Chemotherapy in the Management of Advanced Esophagogastric Adenocarcinoma

Amar M Eltweri1, Anne Thomas2, Ashley Dennison1,2, David Bowrey1,2*

1Department of Surgery, University Hospitals of Leicester, LE1 5WW, UK
2Department of Cancer Studies, University of Leicester, LE1 5WW, UK

 

*Corresponding author: Professor David Bowrey, Department of Surgery, Level 6 Balmoral Building, Leicester Royal Infirmary, LeicesterLE1 5WW, UK. Email: djb57@le.ac.uk. Tel: (+44) 0116 258 5247  Fax: (+44) 0116 258 6083

Citation: Amar Eltweri, et al. A Systematic Review of the Randomised Phase III Clinical Trials Employing Palliative Chemotherapy in the Management of Advanced Esophagogastric Adenocarcinoma. Cancer Research Frontiers. 2016 May; 2(2): 184-199. doi: 10.17980/2016.184

Copyright: @ 2016 Amar Eltweri, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing Interests: DJ Bowrey has received departmental grant support from Fresenius-Kabi and Nutricia for work unrelated to the current submission. AR Dennison has received departmental grant support from Fresenius-Kabi and Braun for work unrelated to the current submission. AM Eltweri has received departmental grant support from Fresenius-Kabi for work unrelated to the current submission. AL Thomas declares no competing interests.

Received Nov 2, 2015; Revised Feb 10, 2016; Accepted Mar 4, 2016. Published Apr 30, 2016

 

 

ABSTRACT

Background: Two-thirds of patients with esophagogastric cancer will be treated with palliative intent, with palliative chemotherapy being the most widely applied therapy. Just over half of those scheduled to receive this treatment will complete treatment as planned, with other patients failing to complete either because of disease progression or treatment side effects. The aim of this review was to report response rates, survival and toxicity of palliative chemotherapy for esophagogastric adenocarcinoma.

Methods: Forty-three randomised phase III clinical trials, reporting on 12,945 patients during the years indicate 1990-2016 were evaluated and information on response rate, survival and treatment related toxicity extracted. Thirty-three studies described patients receiving 1st line therapy and ten studies described patients receiving 2nd line therapy.

Results: Combination regimens were the most widely applied treatment worldwide as first line, with response rates in the order of 20-62%, and median overall survival in the order of 7.2-14.1 months. 30-85% of patients went on to receive second line therapy, generally single agent therapy, with reported response rates in the order of 7-22%, and median overall survival in the range 4.0-13.9 months. With the exception of trastuzumab, the effects of biological agents have been largely disappointing. The principal toxicities for chemotherapy were gastrointestinal (0-58%) and neutropenia (1-39% single agent, 12-82% combination therapy).

Conclusions: At the current time, combination therapy remains the standard of care for patients with advanced esophagogastric adenocarcinoma.

Keywords: adenocarcinoma esophagus; adenocarcinoma stomach; biological agents; chemotherapy; outcome measures; palliation

 


INTRODUCTION

The American Cancer Society estimate that each year over 40,000 patients are diagnosed with esophagogastric cancer, and that more than 25,000 patients will die from these cancers (1). Only around one third of these patients will be amenable to radical therapy, with the remaining two thirds receiving palliative oncology treatments, endoscopic therapies, principally stenting, or best supportive care only (2,3).

The UK National Esophagogastric Cancer Audit which evaluated in excess of 20,000 patients with cancer diagnosed during the time period 1st April 2011 and 31st March 2013 found that 36% of patients received curative intent treatment, 44% received palliative intent treatment, and 20% received best supportive care only. The most widely employed palliative intent treatment was chemotherapy (2,3). Of those scheduled to receive palliative chemotherapy, just over half of the patients completed the treatment as planned (53%) (2,3). For the remaining patients, 11% died during treatment, 18% developed progressive disease, 12% developed acute toxicity requiring discontinuation, and in 6% of patients, treatment was stopped at patient request. Older patients (aged over 80 years) and those with poorer performance status were the least likely to complete planned treatment (2,3).

The principal chemotherapy drugs employed over the last two decades have comprised fluoropyrimidine and platinum combinations, either as a two drug regimen (4-10) or as part of a three drug regimen (11-15), with taxanes, popular in the US and anthracyclines, popular in the UK. In recent years, these have been combined with biological agents (16-22).

The aim of the current article was to review in a systematic way, the accrued evidence from published phase III randomised clinical trials (RCTs) of patients with esophagogastric adenocarcinoma treated with palliative chemotherapy. Included studies were those which reported on the outcome measures of interest; response rate, survival and treatment related toxicity. The rationale for restricting the inclusion criteria to phase III RCTs was on the basis that they would constitute the best available evidence.

 

METHODS

Literature search and study identification

A Pubmed search of the English language literature was undertaken employing the following keywords: chemotherapy, palliative, esophageal, stomach and cancer. The inclusion criteria were phase three randomised controlled trials describing patients with advanced esophagogastric or gastric adenocarcinoma being treated with palliative intent using either single agent or combination chemotherapy. The review included articles published between January 1990 and January 2016. Exclusion criteria were combined chemotherapy and radiotherapy regimes, studies reporting exclusively on patients with squamous cell cancer or mixed study populations, where it was not possible to extract information relating to those with adenocarcinoma, and chemotherapy given in a perioperative setting. Outcome measures of interest included the chemotherapy related toxicity, radiological response to treatment, quality of life and survival analysis.  The process and inclusion of eligible papers were independently reviewed by two of the authors (AME, DJB). Radiological response rates were assessed using the RECIST criteria and in some of the early studies, the WHO criteria. Chemotherapy toxicity was assessed using the Common Toxicity Criteria, according to the version in use at the time of the study.

 

RESULTS

The search strategy yielded 132 evaluable articles which were screened for inclusion. Forty three full articles met the inclusion criteria and form the basis of this review (Figure 1). Thirty three of the forty three studies reported on patients receiving first line palliative chemotherapy, and the remaining 10 studies reported on patients who received second line chemotherapy. Heterogeneity between the included studies made it impossible to perform a formal meta-analysis. The combined reports describe the outcome for a total of 12,945 patients. 

 

Summary of studies reporting on 1st line palliative chemotherapy

Table 1 summarises the clinical trials of 1st line palliative chemotherapy. It is evident that a wide variety of drug combinations have been employed, with the majority of studies over the last decade employing two drug combinations. In those studies that compared treatment to best supportive care, overall survival for participants in the latter group was around three months. Response rates for single agent fluoropyrimidine therapy (seven studies) ranged from 9-31%, with higher values observed for S-1 compared to 5-fluorouracil. Overall survival ranged from 7.1-11.4 months.

Response rates for combined fluoropyrimidine / platinum combinations (13 studies) ranged from 20-62% and overall survival ranged from 7.2-14.1 months.  A number of three drug combinations have been employed. Those reporting on fluoropyrimidine / platinum / anthracycline combinations (five studies) have noted response rates ranging from 15-76%, and overall survival ranging from 5-12 months. Heterogeneous drug combinations in other studies limit meaningful conclusions. Head-to-head comparisons of regimens (where significant) indicated superiority of two agents over single agent, of capecitabine over 5-fluourouracil in combination with cisplatin, and of three drug combinations over best supportive care. Earlier studies did not indicate subsequent therapies, but it is evident from Table 1 that many of the first line trial participants in more recently published articles went on to receive subsequent second (and third) line therapy (range 30-85%).

 
Table 2: Summary of the reported phase III randomized clinical trials of 2nd line palliative chemotherapy for advanced esophagogastric adenocarcinoma (highlighted studies are those where significant differences were identified)
TAB2
 
 
Summary of studies reporting on 2nd line palliative chemotherapy

Table 2 summarises those studies reporting on second line chemotherapy. Three of these compared single agent taxane or irinotecan to best supportive care. Observed response rates were generally lower than for first line therapy (range 7-22%), with overall survival ranging from 4.0-13.9 months. By comparison, overall survival with best supportive care ranged from 2.4-5.3 months. Those where significant findings were noted concluded that single agent therapy was superior to best supportive care.

 

Summary of studies reporting on palliative chemotherapy in combination with biological agents

Table 3 summarises those studies that employed biological agents as part of the treatment regimen, With the exception of the ToGA and TyTAN studies which enrolled only patients with proven immunohistochemical expression of the antibody target in tumour tissue, the other studies enrolled unselected participants.

The use of biological agents in the treatment of esophagogastric adenocarcinoma has been largely disappointing, with the exception of Trastuzumab (Herceptin®), a human epidermal growth factor receptor 2 antibody, in patients with tumours expressing the HER-2 gene or protein. The latter was associated with impressive response rates in phase II clinical trials (up to 94%) and notably, the ability to downstage unresectable gastric cancer to potentially resectable disease. The effects have been largely restricted to those patients whose primary cancer has demonstrated HER-2 expression (23-28). In a phase III clinical trial, the use of trastuzumab plus fluoropyrimidine / platinum in patients with HER-2 positive cancers has been demonstrated to improve response rate, quality of life and survival compared to those patients treated with chemotherapy alone (22).

Therapy with the other biological agents has yielded largely negative results, with no superiority over conventional chemotherapy being demonstrated for bevacizumab, cetuximab or panitumumab. Ramucirumab as a second line treatment has been shown to be superior to placebo, with a toxicity profile similar to conventional chemotherapy (29). When combined with paclitaxel as second line therapy, it has been demonstrated to effect a modest improvement in survival at the expense of a higher frequency of grade 3 or 4 toxicity (18). Lapatinib as second line therapy demonstrated a higher response rate when combined with paclitaxel compared to paclitaxel alone, but no significant improvement in survival was demonstrated (16). Two recent studies of rilotumumab have been terminated early for safety reasons.

 

Table 3: Comparison of the reported phase III randomized clinical trials in patients who received palliative chemotherapy with or without biological agents

TAB3

 

Chemotherapy related toxicities

Tables 5 and 6 summarise the reported grade 3 or 4 toxicities, non-hematological (Table 5) and haematological (Table 6). The most commonly observed toxicities were gastrointestinal adverse effects, which occurred in 0-25% with single agent fluoropyrimidine therapy, 0-26% with single agent irinotecan and 0-58% with combination therapy. Neutropenia was noted in 1-11% with single agent fluoropyrimidine therapy, 18-39% with single agent irinotecan, 15-29% with single agent taxane, and 12-82% with combination therapy.

 

Targeted therapy additional side effects

With the exception of the REAL 3 study, the reported toxicities were similar between those treated with and without biological agents. In the REAL 3 study, the use of panitumumab was associated with an increased frequency of grade 3 and 4 toxicity, and as there was no improvement in survival, the study was terminated early. Compared to combination epirubicin, oxaliplatin and capecitabine alone, the addition of panitumumab was associated with higher frequencies of diarrhea (17% vs 11%), skin rash (11% vs 1%), mucositis (5% vs 0%) and hypomagnesaemia (5% vs 0%).

Table 4 summarises the reported toxicities of special interest to the biological drugs used and related mortalities.

 

Table 4: Comparison of the reported grade 3 or 4 toxicities of interest to biological drugs in those receiving and not receiving the drug
TAB4
 

 

Quality of life assessment

Quality of life (QoL) has been reported in seven phase III RCTs comparing two or more treatment regimens (biological agents employed in three) and two comparing single agent therapy with best supportive care (biological agents employed in one) (14,18,29-35). The most widely used questionnaire was the EORTC QLQ-C30 questionnaire and its modules, but the reporting approach was inconsistent in all trials.

In the ToGA study, Satoh et al reported a median time to 10% deterioration in global health score of 10.2 months for patients treated with trastuzumab and chemotherapy compared to 6.4 months for those patients treated with chemotherapy alone. The beneficial effect was more pronounced in those patients whose primary tumour demonstrated high levels of HER-2 protein expression (32). In the V325 study, the authors compared the quality of life in patients receiving either 5-fluorouracil, cisplatin or 5-FU, cisplatin and docetaxel. A 5% deterioration in quality of life from baseline was observed after 4.2 months with dual therapy, and after 6.5 months, with triple therapy. Similar findings were observed when quality of life was assessed using the EQ-5D instrument (11,35).  Curran et al, and Dank et al reported a 5 % deterioration of quality of life after 5.9 and 4.9 months for 5-fluorouracil, cisplatin and 5-fluorouracil, irinotecan combinations respectively (33,36).

Sadighi et al, compared QoL in patients who received 5-fluorouracil, cisplatin, docetaxel to that observed in patients who received 5-fluoruuracil, cisplatin, epirubicin. Both groups showed improvement in their QoL measures compared to baseline scores with the exception of the domains of cognitive functioning, diarrhea and financial aspect of the disease. Those treated with the taxane containing regimen had evidence of a clinically and statistically significance improvement in global QoL (p=0.001), social functioning (p=0.03), emotional functioning (p=0.004), pain (p=0.03) and sleep difficulties (p=0.02) (31).

Ford et al showed statistically superior symptom control for patients who received single agent docetaxel compared to best supportive care (dysphagia, general pain, abdominal pain, nausea and vomiting and constipation) (30). Webb et al, demonstrated superiority of the 5-fluorouracil, cisplatin, epirubicin regimen over 5-fluorouracil, doxorubicin, methotrexate at 24 weeks (p=0.04) (14).

In the REGARD study, no difference in global QoL was identified between patients treated with ramucirumab monotherapy and those treated with placebo (29). In the RAINBOW study, no difference was identified in global quality of life scores between those treated with paclitaxel plus ramucirumab, and those treated with paclitaxel plus placebo (18). Guimbaud et al showed no statistical significant difference in QoL between those treated with capecitabine, cisplatin, epirubicin and those treated with 5-fluorouracil, folinic acid and irinotecan (34).

 

In summary

Two-thirds of patients with esophagogastric cancer will be treated with palliative intent, with palliative chemotherapy being the most applied therapy. Combination regimens are the most widely applied treatment worldwide, with response rates in the order of 20-62% and median overall survival in the order of 7.2-14.1 months. 30-85% of patients will go to have second or third line therapy, with reported response rates in the order of 7-22%, and median overall survival in the range 4.0-13.9 months. With the exception of trastuzumab, the effects of biological agents have been largely disappointing.

 

Abbreviations

5-FU, 5-fluorouracil;

ATE, arterial thromboembolism;

GI, gastrointestinal;

HER2, Human Epidermal Growth Factor Receptor 2;

HTN, hypertension;

NA, not applicable;

NR, not reported;

OS, overall survival;

PFS, progression free survival;

QOL, quality of life;

RCT, randomized controlled trial;

RECIST, Response Evaluation in Solid Tumors;

RR, response rate;

UK, United Kingdom;

US, United States;

VTE, venous thromboembolism;

WHO, World Health Organization

 

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