Quality of life with biweekly docetaxel and capecitabine in advanced gastro-oesophageal cancer

The incidence of distal gastric cancer is decreasing, whereas cancers of the distal oesophagus and gastro-oesophageal junction tend to increase in the Western world [1]. Worldwide, these cancers cause substantial morbidity and mortality. Nearly one million new cases and more than 700,000 deaths due to gastric cancer were estimated to have occurred in 2012, setting gastric cancer the fifth most common cancer and the third most common cause of cancer death [2]. The prognosis of advanced gastro-oesophageal cancer (AGC) remains poor [1, 2]. A substantial proportion of patients presents with or ends up having metastatic disease after initial treatment [3, 4].

Systemic chemotherapy is shown to improve disease outcome in AGC, as compared to best supportive care, with median survival rates reaching 6–9 months [5‐7]. During the past decade, several new-generation cytotoxic agents, including capecitabine, irinotecan, oxaliplatin and docetaxel, have been investigated in the treatment of metastatic gastric cancer [7‐10]. Two previous large phase III trials demonstrated an oral fluoropyrimidine capecitabine not to be inferior to 5-FU in the setting of a platinum-containing doublet or triplet for AGC [8, 9]. Adding docetaxel into the combination of cisplatin and fluorouracil (DCF) was studied in a randomized phase III trial in first-line therapy for AGC. The final results showed improved survival, response rate, and health-related QOL, albeit increased toxicity with DCF [10]. Further, in a phase III open-label, randomized controlled trial in HER2-positive AGC, trastuzumab in combination with chemotherapy significantly improved median overall survival as compared to chemotherapy alone [11]. Recently, VEGFR-2 antagonist ramucirumab was found to improve survival as monotherapy or in combination with paclitaxel in AGC after first-line treatment [12, 13]. However, so far, no survival benefit has been reported in the first-line setting with other novel targeted agents in AGC, in addition of trastuzumab.

In advanced cancer, the primary treatment goals are to prolong survival, relieve symptoms and sustain or improve the quality of life. Thereby, chemotherapy-related toxicity is an important issue when determining the true value of treatment. Patients with AGC are generally elderly and exhibit poor general performance status, which emphasizes the need for effective treatment options and improved control of side effects. On the basis of these considerations, we conducted a phase II trial to determine the feasibility and tolerability of biweekly docetaxel in combination with capecitabine as first-line treatment of patients with AGC.

This prospective phase II trial with a combination of biweekly docetaxel and capecitabine in AGC showed no deterioration of global health status or either physical or social functioning. Importantly, the patients’ quality of life was not compromised during treatment. Moreover, disease-associated symptoms, including eating restrictions and dysphagia, as well as pain and anxiety, were alleviated during study treatment. The regimen was also conveniently delivered on an outpatient setting without a need for central venous access device.

Docetaxel in various combinations has previously been studied in the treatment in AGC, also including QOL assessments [18‐21]. A recent prostate cancer trial reported better time to treatment failure and fewer serious adverse events with two weekly than with three weekly dosing of docetaxel [22]. In AGC, docetaxel combined to cisplatin and fluorouracil resulted in better symptom palliation and improved QOL, as compared to treatment with epirubicin, cisplatin and fluorouracil. Unfortunately, treatment toxicity data for this combination were not readily provided [19]. Previous trials have generally demonstrated improved QOL accompanied with improved efficacy in AGC, despite increased toxicity with docetaxel triplet combinations [10, 18, 19, 21], i.e. treatment efficacy rather than toxicity tends to affect QOL [23]. Importantly, in the current study, the patients’ QOL was not compromised during treatment. Eating difficulties were alleviated during chemotherapy but started deteriorating along with disease progression. Similarly, after commencing therapy, pain was experienced to relieve but intensify again as cancer progressed. Physical functioning remained stable during chemotherapy, while social functioning improved, even despite disease progression. The global health status was maintained or slightly improved during therapy.

Gubanski and colleagues investigated the effect of sequential treatment on QOL. Patients were randomized to start treatment with either docetaxel or irinotecan combined to fluorouracil and leucovorin. After four cycles, the treatment was switched. Chemotherapy was not found to affect the average QOL scores. Instead, patients with a radiological response were able to sustain better QOL as compared to patients with no radiological response [24]. A patient’s perception of expected treatment efficacy might also influence on QOL scores: a substantial proportion of patients may not comprehend their disease unlikely to be curable [25]. Thus, they may be ready to tolerate even serious side effects and yet experience QOL to be maintained.

The results of this study showed the clinical benefit rate to be 60%, including complete (CR) and partial (PR) responses and stabilized disease (SD), and median overall survival of 8.8 months. These findings are parallel to a previous trial of weekly docetaxel together with capecitabine on days 1–14 of a 21-day cycle, showing a comparable response rate of 29%, stable disease of 44% and overall survival reaching 10.7 months [26]. Another study investigating dose-dependent efficacy of docetaxel and capecitabine resulted in improved overall response rates with full dosing of these agents. However, two patients in each cohort experienced grade 3–4 cardiac arrhythmia, one patient pulmonary oedema, and three patients grade 3–4 thrombosis/pulmonary embolism, one of them leading to death [27]. In the current study, no death was directly associated to study treatment. One patient died after the very first infusion of chemotherapy due to rapidly progressing cancer, without any signs of cardiac complications in the autopsy. However, ventricular fibrillation cannot entirely be ruled out, despite of a negative autopsy report. In the current study, only one patient experienced grade 3–4 cardiac arrhythmia.

Our study shows a moderate incidence of grade 3–4 neutropenia, resulting only rarely in neutropenic fever. Nevertheless, infection was the main reason for treatment-related hospitalization. These results are comparable with earlier studies, reporting even higher rates of grade 3–4 neutropenia, in up to 23–80% of patients, febrile neutropenia among 2–12% and grade 3–4 non-neutropenic fever among 2–41% of patients, while hospitalization data are not readily available [19, 26, 27]. The incidence of mild palmo-plantar dysesthesia or hand-foot syndrome (HFS) was previously reported to be 9–42% and that of severe HFS 3–20% [19, 26, 27]. Even though the incidence of HFS in the current study was 45%, no grade 3–4 symptoms were detected. Likewise, mild diarrhoea was frequent but severe diarrhoea a rare event. On the whole, haematologic and non-haematologic toxicities were considered tolerable.

In conclusion, no treatment combination has been proven superior as compared to others in AGC in the palliative setting. Biweekly docetaxel, together with capecitabine is a feasible, outpatient-based, well-tolerated treatment that enables sustaining QOL and alleviating disease-associated symptoms.