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Docetaxel in advanced gastric and gastro-oesophageal cancer.

Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastro-esophageal cancer adenocarcinoma: the V-325 Study Group

Ajani JA, Moiseyenko VM, Tjulandin S et al. Journal of Clinical Oncology, 2007, 25, 3205-3209

Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastro-esophageal adenocarcinoma: the V-325 Study Group

Ajani JA, Moiseyenko VM, Tjulandin S et al. Journal of Clinical Oncology, 2007, 25, 3210-3216

Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research

Roth AD, Fazio N, Stupp R et al. Journal of Clinical Oncology, 2007, 25, 3217-3223

There is a constant demand for oncologists to provide viable treatment options for patients with advanced cancers. In particular, this is the case in gastro-oesophageal cancers, which are the second leading cause of cancer deaths worldwide [1]. Several different chemotherapy regimens are currently used as first-line treatment in advanced disease, with no consensus on optimal treatment.

The aim of chemotherapy for advanced disease is to provide the greatest survival and symptom benefit with the least detriment to patients' lives. Clinical effectiveness, patient tolerance and convenience all influence the patient's quality of life (QoL) and are important factors in deciding palliative treatment. Whereas a better response rate at the expense of a worse toxicity profile is acceptable in curative chemotherapy, the emphasis in palliative treatment is more on maintaining or improving the QoL for patients.

Advanced gastro-oesophageal cancer is defined as non-resectable disease, due to being locally advanced, metastatic or relapsed following radical surgery. Approximately 75-80% of gastric cancer patients have advanced disease. Locally advanced cancer has a better prognosis compared to metastatic or relapsed disease (12-15 months versus 7-10 months) [2].

There are a number of chemotherapeutic agents that may be used to treat advanced gastro-oesophageal cancer, including fluoropyrimidines, platinum-based compounds, taxanes, anthracyclines and topoisomerase 1 inhibitors. In advanced gastro-oesophageal cancer, single-agent chemotherapy provides poor response rates (10-20%) with a median survival of 6-7 months, whereas doublet regimens such as the combination of cisplatin and fluorouracil (CF) provide response rates of 20-30% with a median survival of 7-8 months [3].

Triplet regimens involving epirubicin or docetaxel combined with CF have shown the most promise in clinical trials. Phase III trials have shown response rates of 35-40% and a median survival of 9 months with such combinations [3]. However, the toxicities with triplet combinations are greater than with doublet regimens. The balance achieved between survival, clinical benefit and QoL is therefore of great importance in the treatment selection process.

The V325 study by Van Cutsem et al. is one of the most important recent Phase III trials in first-line treatment of advanced gastro-oesophageal cancer. Docetaxel was used (75 mg/[m.sup.2] on day 1) in combination with cisplatin and fluorouracil (DCF) in 3-weekly cycles, and was compared to CF alone [4]. A total of 445 patients with advanced gastro-oesophageal cancer (97% with metastatic disease) were randomly assigned to the two arms. There were significant improvements in the primary endpoint, time to progression, of 5.6 months with DCF and 3.7 months with CF (P<0.001) and the secondary endpoint, response rate (37% and 25%, respectively; P<0.001). The median survival benefit of DCF over CF (0.6 months) was modest (9.2 with DCF versus 8.6 months with CF; P=0.020), but the 2-year survival rate was more impressive (18.9% with DCF compared to 8.9% with CF).

It is interesting that the median age of the patients in the study was only 55 years (range, 25-79 years) compared to the usual median age of approximately 70 years at diagnosis, suggesting that the results may not be readily translated to the general population of patients with the disease. Also, the toxicity rates reported were substantial; neutropenia 82% and 57% and febrile neutropenia 29% and 12% in the DCF and CF arms, respectively. These rates are higher than those reported in previous studies for advanced gastro-oesophageal disease with alternative regimens. Diarrhoea and peripheral neuropathy were also significantly worse with DCF than CF (19% versus 8%, and 8% versus 3%, respectively; both P<0.05). Stomatitis rates were lower with DCF but not statistically different (21% versus 27%). Approximately half of patients in the DCF arm either were taken off chemotherapy because of toxicity or refused further cycles of treatment. Hospitalisation rates were not presented, but the rates of grade 3/4 infections in patients over 65 years were considerable, with infections being the main cause of chemotherapy-related death in both arms (3-5% of patients).

The V325 study group considered further secondary endpoints, analysing both the clinical benefit and QoL. Various markers were used to determine clinical benefit, primarily the time to deterioration of the Karnofsky performance status (KPS) by one grade. The study population had exceptionally good performance status with 99% having a KPS of 80-100%. Other measures used were time to 5% definitive weight loss, time to worsening of appetite, and various cancer pain indices. QoL was assessed every 8 weeks using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), to help determine time to 5% deterioration of global health status.

The DCF regimen was statistically superior to CF in preserving KPS (6.1 versus 4.8 months; P=0.009). However, the other clinical benefit indicators were not statistically different in the two treatment groups. The QoL analysis demonstrated that DCF was again superior to CF in preserving global health status (median time to 5% deterioration 6.5 versus 4.2 months; P=0.01). The median times to 10%, 20% and 30% deterioration were also statistically favourable for DCF compared with CF.

Despite the maintenance of the patient's clinical status and the small 0.6-month survival benefit for DCF compared with CF, the grade 3/4 toxicity rates need to be considered. In particular, febrile neutropenia would require inpatient management, which would significantly impact on patients' lives. The levels of grade 3/4 toxicities reported in this trial would therefore cause concern in the palliative setting.

The third paper reviewed is a Phase II trial data (119 patients, > 80% metastatic disease) comparing DCF against docetaxel with cisplatin (DC), and epirubicin with cisplatin and fluorouracil (ECF). Single-agent docetaxel had shown promise with response rates of 17-24% [5]. Roth et al. undertook a Phase II study of DC in gastric carcinoma, and reported a response rate of 56%, with a median survival of 9 months [6]. A further phase I/II trial conducted by the same group compared DC (n=48) with DCF (n=41), and showed response rates of 56% and 51%, respectively [7].

ECF has been compared to fluorouracil, doxorubicin and methotrexate (FAMTX), and showed statistically superior response rates, median time to progression and overall survival [8]. Furthermore, the 2003 Cochrane Database meta-analysis showed that the best survival from advanced gastro-oesophageal cancer was achieved with the combination of CF and an anthracycline [3]. Roth et al. (2007) therefore used ECF as the comparator against DC and DCF in their randomised Phase II trial, to determine which docetaxel combination would merit a Phase III study against ECF.

The study objectives included response rates, survival benefits, toxicity profiles and QoL characteristics. Overall response rates were 25% for ECF, 18.5% for DC and 36.6% for DCF. The median overall survival times were 8.3, 11.0 and 10.4 months for ECF, DC and DCF, respectively, whereas the median times to progression were 4.9, 3.6 and 4.6 months, respectively. Grade 3/4 neutropenia rates (59%, 76% and 80% for ECF, DC and DCF, respectively), and the percentage of cycles with neutropenia (35%, 49% and 57% for ECF, DC and DCF, respectively) were reported. Febrile neutropenia occurred in 18% of patients and 4% of cycles, 21% and 7%, and 41% and 15% for ECF, DC and DCF, respectively. Grade 3/4 diarrhoea also occurred in 15% of patients receiving DCF compared to only 6% receiving ECF and 3% receiving DC, which was consistent with a previous Phase II study by Ajani et al. comparing DC with DCF (5% and 20%, respectively) [9]. Other grade 3/4 toxicities were also generally more prevalent in the DCF compared to the ECF arm. Direct comparison between the arms is limited by the nature of the Phase II design, but this gives an indicator of possible findings in an extended study. The QoL data, measured using the EORTC QLQ-C30 showed improvements in scores with ECF, and preservation of scores with the docetaxel regimens.

Of note, Roth et al. (2007) initially used 85 mg/[m.sup.2] docetaxel and a 21-day continuous infusion of fluorouracil in the DCF arm, whereas only 75 mg/[m.sup.2] docetaxel and a shorter 5-day infusion of fluorouracil was used in the V325 study. The authors reported that the docetaxel dose was reduced to 75 mg/[m.sup.2] after the first 29 patients because of the high incidence of febrile neutropenia. The choice of the shorter duration fluorouracil in the V325 study has been previously debated, as the 21-day infusion appeared to demonstrate better activity and lower toxicity in previous ECF trials. It is interesting that the authors report median times to treatment failure (4.3, 3.2 and 3.0 months for ECF, DC and DCF, respectively), which were in contrast to the better overall survival reported with the two docetaxel arms. This is particularly surprising as the patients in the DCF arm had a higher frequency of metastatic disease (95%), compared to the other two arms which had 82% and 83% (DC and ECF, respectively) of patients with metastatic disease.

Other triplet combinations have also been developed concurrently. The REAL-2 trial by Cunningham et al. was a Phase III, 2x2 factorial, randomised comparison of ECF, with substitutions of oxaliplatin (O) for cisplatin and capecitabine (X) for fluorouracil (EOF, ECX and EOX) in the treatment of advanced gastric, gastro-oesophageal junction and oesophageal cancer [10]. The oral capecitabine offered a more convenient option for patients receiving fluoropyrimidine treatment. The study recruited 1002 patients with either squamous cell or adenocarcinoma, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The grade 3/4 toxicities reported in this study (27.6% neutropenia, 7.8% febrile neutropenia, 11.9% diarrhoea and 4.4% peripheral neuropathy with EOX) were lower than with DCF in the V325 study (82% neutropenia, 29% febrile neutropenia, 19% diarrhoea and 8% peripheral neuropathy). EOX also had significantly lower rates of thromboembolic complications compared to ECF (7.5% versus 16.9%, P<0.01) and the median overall survival was longer for EOX than ECF (11.2 versus 9.9 months, P=0.02).

Alternative docetaxel dosing and administration protocols have been investigated in a Phase II setting in advanced gastro-oesophageal disease, to determine whether the survival benefit can be maintained with a concurrent reduction in toxicity profiles. A split-dose docetaxel regimen, where 50 mg/[m.sup.2] is given on days 1, 15 and 29 on an 8-weekly cycle with weekly bolus fluorouracil has been studied by Lorenzen et al. in a group of 60 patients (60% with metastatic disease) [11]. They reported much lower grade 3/4 toxicity rates than in the V325 study; 22% neutropenia, 5% febrile neutropenia, 20% diarrhoea and 3% peripheral neuropathy. It is interesting that the median time to progression and overall survival rates in the metastatic patient cohort were 8.1 and 15.1 months, respectively; these values were higher than those reported in both the V325 and REAL-2 studies. The median patient age was only 53 years, which may influence the results. Tebbutt et al. recently presented data from their Phase II study investigating an alternative schedule for DCF in metastatic gastro-oesophageal cancer, using a weekly docetaxel, cisplatin and protracted intravenous fluorouracil regimen (wDCF) [12]. The median age of the 50 patients receiving wDCF was 62 years, with overall survival of 11.4 months, and a more acceptable toxicity profile than the three-weekly regimen used in the V325 study (grade3/4 toxicities: 10% diarrhoea, 6% neutropenia and 4% febrile neutropenia). The promising results from these trials with split-dose docetaxel regimens of DCF warrant randomised Phase III investigation.

Other roles for docetaxel in advanced gastro-oesophageal cancer have also been investigated. Promising results were seen in a study investigating DC as second-line treatment in patients with metastatic gastric cancer who had received first-line CF and subsequently recurred or progressed. In addition, irinotecan-based combinations are equally encouraging. The next substantial phase of investigation will be to determine the role of biological agents used in combination with these established cytotoxic agents; early Phase II studies have shown great potential. For example, an investigation of the use of cetuximab (an inhibitory monoclonal antibody against the epidermal growth factor receptor) in combination with fluorouracil, leucovorin and irinotecan has shown overall survival rates of nearly 16 months [13].

In conclusion, docetaxel appears to have a significant role in advanced gastro-oesophageal cancer, although we would dispute that the optimal use is in combination with CF using the regimen outlined by Van Cutsem et al. [4]. The toxicity profile appears to significantly impact on patients' daily lives and the large drop-out rate from the DCF arm in the V325 study suggests that these toxicities may not be readily manageable; modification of their regimen, particularly with respect to the docetaxel schedule, would appear to be desirable.

References

[1.] Parkin DM, Bray F, Ferlay J and Pisani P. Estimating the world cancer burden: GLOBOCAN 2000. Int J Cancer, 2001, 94, 153-156.

[2.] Rivera F, Vega-Villegas ME and Lopez-Brea MF. Chemotherapy of advanced gastric cancer. Cancer Treat Rev, 2007, 33, 315-324.

[3.] Wagner A, Grothe W, Haerting J et al. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol, 2004, 24, 2903-2909.

[4.] Van Cutsem E, Moiseyenko VM, Tjulandin S et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: A report of the V325 Study Group. J Clin Oncol, 2006, 24, 4991-4997.

[5.] Einzig AI, Neuberg D, Remick SC et al. Phase II trial of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy: The Eastern Cooperative Oncology Group (ECOG) results of protocol E1293. Med Oncol, 1996, 13, 87-93.

[6.] Roth AD, Maibach R, Martinelli G et al. Docetaxel (Taxotere)cisplatin (TC): an effective drug combination in gastric carcinoma. Swiss Group for Clinical Cancer Research (SAKK) and the European Institute of Oncology (EIO). Ann Oncol, 2000, 11, 301-306.

[7.] Roth AD, Maibach R, Fazio N et al. 5-Fluorouracil as protracted continuous intravenous infusion can be added to full-dose docetaxel (Taxotere)-cisplatin in advanced gastric carcinoma: a phase I-II trial. Ann Oncol, 2004, 15, 759-764.

[8.] Webb A, Cunningham D, Scarffe JH et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol, 1997, 15, 261-267.

[9.] Ajani JA, Fodor MB, Tjuladin SA et al. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol, 2005, 23, 5660-5667.

[10.] Cunningham D, Rao S, Starling N et al. Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: the REAL-2 trial. Proc ASCO, 2006, 24, Abstr. LBA4017.

[11.] Lorenzen S, Hentrich M, Haberl C et al. Split-dose docetaxel, cisplatin and leucovorin/fluorouracil as first-line therapy in advanced gastric cancer and adenocarcinoma of the gastro-oesophageal junction: results of a phase II trial. Ann Oncol, 2007, 18, 1673-1679.

[12.] Tebbutt N, Sourjina T, Strickland A et al. ATTAX: randomised phase II study evaluating weekly docetaxel-based chemotherapy combinations in advanced esophago-gastric cancer, final results of an AGITG trial. Proc ASCO, 2007, 25, Abstr. 4528.

[13.] Pinto C, Di Fabio F, Siena S et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol, 2007, 18, 510-517.

Commentary by Gihan Ratnayake (1) and David Cunningham

(1) Royal Marsden Hospital London and Surrey, Sutton, UK

Correspondence to: David Cunningham (david.cunningham@rmh.nhs.uk)
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Author:Ratnayake, Gihan; Cunningham, David
Publication:Advances in Gastrointestinal Cancer
Article Type:Report
Date:Dec 1, 2007
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