|Year : 2018 | Volume
| Issue : 1 | Page : 88-93
Docetaxel/Oxaliplatin/Capecitabine (TEX) triplet followed by continuation monotherapy in advanced gastric cancer
Vikas Ostwal1, Subhadeep Bose1, Bhawna Sirohi2, Bhavesh Poladia1, Arvind Sahu3, Prabhat Bhargava1, Vipul Doshi1, Rohit Dusane4, Chaitali Nashikkar4, Shailesh V Shrikhande5, Anant Ramaswamy1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
3 H M Patel Center for Medical Care and Education, Karamsad, Gujarat, India
4 Statistician (Clinical Research Secretariat), Tata Memorial Hospital, Mumbai, Maharashtra, India
5 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||23-Aug-2018|
Dr. Anant Ramaswamy
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Introduction: Docetaxel/oxaliplatin/capecitabine (TEX) is a commonly used combination chemotherapeutic regimen in advanced gastric cancer (AGC). Application strategies in routine clinical practice are reported in this study. Materials and Methods: Patients diagnosed with AGC, receiving biweekly TEX (docetaxel - 60 mg/m (2)-D1; oxaliplatin - 85 mg/m (2)-D1, and capecitabine 500–625 mg/m (2) orally twice daily for 14 days) between July 2012 and May 2016 were retrospectively analyzed for tolerance, prognostic factors, event-free survival (EFS), and overall survival (OS). The proportion of patients continuing and terminating chemotherapy at various time-points was enumerated. Results: Overall, 208 patients were started on TEX. Median EFS was 6.34 months (95% confidence interval [CI] 5.80–6.87), and median OS was 15.31 (95% CI 12.65–17.96). Post 8 cycles of TEX, further 30 patients (14.4%) were continued on chemotherapy (docetaxel, capecitabine, or TEX) whereas 47 patients (22.6%) were on observation only, and there was a statistically significant difference in the median OS of these two groups (22.55 months vs. 14.89 months; P = 0.028). Raised serum alkaline phosphatase (SAP) levels (>100 U/L) predicted inferior survival (P = 0.006). Conclusion: TEX chemotherapy is a feasible, efficacious triplet regimen that can be used in clinical practice. SAP levels >100 U/L is a poor prognostic factor, as observed in this study. An initial “induction” such as combination chemotherapy regimen followed by monotherapy as continuation requires further evaluation.
Keywords: Continuation chemotherapy, docetaxel, downscaling, palliative chemotherapy, TEX
|How to cite this article:|
Ostwal V, Bose S, Sirohi B, Poladia B, Sahu A, Bhargava P, Doshi V, Dusane R, Nashikkar C, Shrikhande SV, Ramaswamy A. Docetaxel/Oxaliplatin/Capecitabine (TEX) triplet followed by continuation monotherapy in advanced gastric cancer. Indian J Cancer 2018;55:88-93
|How to cite this URL:|
Ostwal V, Bose S, Sirohi B, Poladia B, Sahu A, Bhargava P, Doshi V, Dusane R, Nashikkar C, Shrikhande SV, Ramaswamy A. Docetaxel/Oxaliplatin/Capecitabine (TEX) triplet followed by continuation monotherapy in advanced gastric cancer. Indian J Cancer [serial online] 2018 [cited 2019 Aug 23];55:88-93. Available from: http://www.indianjcancer.com/text.asp?2018/55/1/88/239589
| » Introduction|| |
Palliative chemotherapy in advanced gastric cancers (AGCs) improves survival as well as quality of life, with evidence also suggesting a benefit for combination chemotherapy over monotherapy. Beyond biology and disease burden, there exists a wide geographical variation in combination regimens used across Asia, Europe, and North America. Despite some improvement in survival with HER2-directed therapy, a majority of studies have concentrated on a clutch of drugs in varying combinations with largely similar results.,,,,
One such combination is docetaxel/oxaliplatin/capecitabine (TEX) evaluated in Phase II studies that proved the efficacy and feasibility of this regimen.,,, These studies have utilized both biweekly and thrice-weekly schedules, resulting in varying incidences of adverse events and differential tolerance across studies. A study by Van Cutsem et al. showed a high incidence of adverse events ([TEX cohort] hematological toxicity [Grade 3/4 neutropenia - 64%], fatigue [Grade 3 - 24%], and sensory neuropathy [Grade 3/4 - 10%]), which resulted in 23.8% patients discontinuing treatment due to adverse events and a further 17.3% withdrawing from treatment (entire study cohort). While such a high adverse event rate is unwelcome in the setting of advanced cancers, there is also some evidence to suggest that patients with a good performance status (PS) may benefit from a triplet regimen compared to a doublet regimen in terms of response rates (RRs) and survival., Such a benefit is not without caveats, with the suggested improvement not commiserate with clinically relevant hazard ratios along with a definite increase in toxicity. Strategies to balance the “outcomes versus adverse events/quality of life” conundrum remain a question mark in AGC.
Clinically, relevant prognostic factors have been elucidated in AGC, although they remains underused in clinical practice. A simple tool, consisting of the Eastern Cooperative Oncology Group (ECOG) PS, serum alkaline phosphatase (SAP), and presence of liver metastases and peritoneal metastases, has been constructed based on the data from three clinical trials, although its relevance in the nontrial real-world setting remains to be seen.
With the above background, we evaluated patients with AGC treated at our center with our preferred first-line chemotherapy – the TEX regimen. Our study aims were three-fold – first, to evaluate the performance of this triplet regimen in the nontrial setting with regard to tolerance, adverse events, and outcomes; second, to evaluate the prognostic factors used by Chau et al. in our setting with TEX chemotherapy; and finally, and most importantly, whether we could identify a strategy to administer a triplet regimen in AGC, maximize the benefit associated with a triplet, and then potentially downscale chemotherapy to maintain continuous exposure to chemotherapy while limiting adverse events and dropout rates.
| » Materials and Methods|| |
This study is a retrospective analysis of metastatic gastric cancer patients who were offered palliative chemotherapy with TEX between July 2012 and May 2016 in the Department of Gastrointestinal Medical Oncology, Tata Memorial Hospital, Mumbai. Decisions regarding the metastatic nature of the disease and palliative intent of therapy were made by a gastrointestinal (GI) multidisciplinary joint clinic comprising a dedicated surgical oncologist, medical oncologist, radiation oncologist, pathologist, gastroenterologist, and radiologist.
Patients satisfying all the following criteria were included in analysis:
- Histologically proven gastric cancer
- Definitive evidence of metastatic disease either by scans or a staging laparotomy
- ECOG PS 0–2
- Administered at least one cycle of chemotherapy in our hospital.
All patients were assessed and optimized by the nutrition clinic department. The doses and schedule used for TEX are as follows: docetaxel (T) 50 mg/m2 D1, oxaliplatin (E) 85 mg/m2 D1, and capecitabine 500–625 mg/m2 D1 to D14 (X) with cycles repeated after every 14 days.
Toxicity assessment was done at every patient visit and recorded as per NCI–CTCAE version 4.0. Response to treatment was evaluated clinically on every visit using contrast-enhanced computed tomography scan after four cycles of chemotherapy or earlier as per physician's decision. Responses were calculated by the Response Evaluation Criteria In Solid Tumors (RECIST) criteria, with responses reported as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), where feasible. If RECIST was not calculable, then the response was quantified based on collusion between treating physician and the GI radiologist as follows: CR – disappearance of all baseline lesions; PR – significant regression of lesions at the baseline; SD – no significant regression of baseline lesions and no new lesions; PD – appearance of new lesions or significant increase in baseline lesions. RRs and clinical benefit rate (CBR) were reported as percentages.
Prognostic factors evaluated included the degree of differentiation (poorly differentiated vs. nonpoorly differentiated), site of primary (proximal vs. distal vs. body cancers), ECOG PS (0/1 vs. 2), presence versus absence of liver metastases, presence versus absence of peritoneal disease, raised serum Alkaline phosphatase (SAP) levels versus SAP levels below the upper limit of normal. Patients were also grouped based into cohorts according to a combination of the following factors: ECOG PS ≥2, SAP levels >100, presence of liver metastases, presence of peritoneal metastases, as per the score evaluated by Chau et al.
- No risk factors
- One or two risk factors
- Three or four risk factors.
Event-free survival (EFS) was calculated from the date of diagnosis to the date of progression, cessation of chemotherapy due to adverse events, loss to follow-up, withdrawal from therapy or death (in case of no documented progression). Overall survival (OS) was calculated from the date of diagnosis to the date of death. Patients who continued TEX beyond 6–8 cycles of chemotherapy were compared with patients who stopped the first first-line chemotherapy and were kept on observation in terms of OS (decision based on patient's wish after detailed discussion).
Clinical data collection and statistics
For this study, demographic data and baseline clinical data were collected retrospectively from GI Medical Oncology Information System and electronic medical record system. All data were entered in SPSS Statistics version 21 (IBM) and used for analysis. Descriptive statistics including median, frequency, and percentage for categorical variables was used to describe age, gender distribution, treatment, and response to treatment. Median EFS and OS were calculated using Kaplan–Meier estimates, whereas log rank test was used for univariate comparisons. Multivariate analysis by Cox regression method was done, irrespective of the results of univariate analysis.
| » Results|| |
A total of 208 patients were included in the analysis. The median age was 52 years (range: 23–75), with the majority of patients being male 75% (156/208), and having an ECOG PS of 0/1 91.3% (190/208). The primary lesion was located proximally, distally, and in the body in 17.8% (37/208), 30.8% (64/208), and 42.3% (88/208), respectively. Epicenter of the primary was not identifiable in 9.1% (19/208) of the cases. Common sites of metastases were peritoneum 54.8% (114/208), liver 30.3% (63/2018), lung 8.6% (18/208), and adnexal masses 8.2% (17/208).
Signet ring histology was seen in 38% (79/208) of the patients, and poorly differentiated adenocarcinoma was seen in 70.2% (146/208) of the patients. Based on the prognostic score, no risk factor was seen in 7.2% (15/208), one or two risk factors in 81.3% (169/208), and 3 or more risk factors in 11.5% (24/208) of the patients. Detailed baseline characteristics are listed in [Table 1].
Details of first-line chemotherapy delivery
Patients could receive a median of 7 cycles of TEX with dose reduction required in 48.6% (101/208) of the patients [Table 2].
Response rates and adverse events
On first-line chemotherapy, 1.4% (03/208) achieved a CR, 53.8% (112/208) PR, 25.5% (53/208) SD whereas 14.9% (31/208) had PD as the best response. RRs were 55.2% (115/2018) and CBR was 80.8% (168/208).
With regard to hematological toxicity, the incidence of Grade 3 and Grade 4 neutropenia, anemia, and thrombocytopenia was 19.2% (40/208), 9.6% (20/208), and 1% (02/208) respectively. Common nonhematological adverse events (Grade 3 and Grade 4) included hand-foot syndrome (HFS) 22.5% (47/208), diarrhea 17.7% (37/208), neuropathy 7.2% (15/208), and chemotherapy-induced nausea and vomiting 6.7% (14/208) [Table 3].
Survival and prognostic factors
With a median follow-up of 9.1 months, the median EFS was 6.34 months (95% confidence interval [CI]: 5.80–6.87) [Figure 1]. Median OS for the entire cohort was 15.31 months (95% CI: 12.65–17.96) [Figure 2]. In the cohort of patients able to complete 8 cycles of TEX and achieve a clinical benefit, those who continued chemotherapy (n = 30) had an improved OS compared to patients who ceased chemotherapy (n = 47) (22.55 months vs. 14.89 months; P = 0.028) [Figure 3].
|Figure 3: Kaplan–Meier for overall survival - continuation chemotherapy versus observation|
Click here to view
Of the prognostic factors evaluated for OS, on univariate analysis, patients with SAP level <100 Units/litre compared to patients with SAP >100 had a statistically superior survival (19.35 months vs. 11.92 months; P = 0.006) and had a statistically significant median OS. This difference was maintained on multivariate analysis (P = 0.041). No other factors achieved statistical significance as a prognostic factor.
On analyzing the risk groups for OS, patients with no risk factors, one or two risk factors, and three or four risk factors had a median OS of 32.72 months, 15.31 months, and 10.87 months, respectively. The risk score did not statistically differentiate between the three risk scores (P = 0.167). However, individual pair-wise comparisons between the group with no risk factors and the group with three or more risk factors showed the difference to be statistically significant (P = 0.035) [Table 4].
|Table 4: Prognostic factors, univariate and multivariate analysis for OS|
Click here to view
| » Discussion|| |
The emergence of docetaxel-based triplet regimens for AGC came into increasing use with the V-325 trial showing clinical and survival benefits of docetaxel-cisplatin-5-fluorouracil (5-FU) (DCF) over CF; however, there was an increased incidence of adverse events., However, the increased toxicities associated with DCF regimen made investigators look for modifications of the regimen while attempting to maintain the efficacy of a docetaxel-based triplet. While one step was to use a modified DCF regimen, another was to substitute oxaliplatin for cisplatin and capecitabine for 5-FU. Although Al-Batran et al. showed preferential tolerance to oxaliplatin compared to cisplatin in AGC, the meta-analysis of the REAL-2 and ML-17032 trials suggested better outcomes with capecitabine compared to 5-FU.,
The TEX regimen is used in our institution majorly in patients with ECOG PS 0/1. To our knowledge, our study is the largest featuring the TEX regimen, although it is retrospective in nature.
The low incidences of Grade 3 and Grade 4 neutropenia, febrile neutropenia, and thrombocytopenia (19.2%, 7.6%, and 1%, respectively) are in contrast to be other studies, where these adverse events are likely dose limiting. In contradistinction, the nonhematological adverse events appear the key to evaluation of tolerance to TEX regimen in this study, specifically, HFS (Grade 2/3 - 22.5%), diarrhea (Grade 3/4 - 17.7%), and mucositis (Grade 3/4 - 3.3%).
This is a pointer toward tolerance issues that may develop after initial combination triplet chemotherapy regarding cumulative toxicities. However, it is also known that exposure to triplet chemotherapy (DCF) provides quality of life benefit in AGC despite increased adverse events. One way to combine the best of both methods is by attempting to follow the paradigms used in metastatic colorectal cancers and lung cancer, as shown in the OPTIMOX-1 and PARADIGM trials., An initial phase of multiagent chemotherapy, followed by single-agent chemotherapy, is a strategy worth evaluating. In our study, 30 patients (14.4%) underwent this strategy of initial TEX regimen, followed by single-agent capecitabine or docetaxel. A further 47 patients (22.6%) were potential candidates for this approach but were only considered at progression for further treatment. Despite the small numbers, the statistically and clinically significant difference in OS between the cohorts is encouraging (22.55 vs. 14.89 months) and suggestive of feasibility for evaluation in a clinical trial.
The outcomes with TEX in the real-world setting appear heartening. The median EFS was 6.34 months, and median OS was 15.31 with a median follow-up of 9.1 months. This is comparable to survival seen with previously reported prospective studies.
Prognostic factors constituting an index, as elucidated by Chau et al., were evaluated in our study, however, it did not differentiate patients as per the stratified risk groups. Of the individual factors assessed, only raised levels of SAP predicted for lower OS, which retained significance on multivariate analysis. Raised SAP level is an indicator of tumor burden and not merely reflective of liver metastases, suggestive of biological feasibility of SAP as a prognostic factor.
Our study is an addition to the existing literature on the feasibility of the TEX regimen in a real-world scenario. However, we acknowledge important caveats that accompany a retrospective analysis such as this study. Our study is hypothesis generating in terms of suggestions regarding multiagent chemotherapy followed by downscaling to monotherapy. This requires a properly conducted randomized clinical trial as a research question.
In conclusion, TEX chemotherapy is a feasible, efficacious triplet regimen that can be used in clinical practice but with a close watch on nonhematological adverse events. SAP levels >100 units/liter is a poor prognostic factor in AGC, which has been seen in our study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, et al.
Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010;(3):CD004064.
Kim R, Tan A, Choi M, El-Rayes BF. Geographic differences in approach to advanced gastric cancer: Is there a standard approach? Crit Rev Oncol Hematol 2013;88:416-26.
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.
Okines AF, Norman AR, McCloud P, Kang YK, Cunningham D. Meta-analysis of the REAL-2 and ML17032 trials: Evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer. Ann Oncol 2009;20:1529-34.
Di Lauro L, Vici P, Belli F, Tomao S, Fattoruso SI, Arena MG, et al.
Docetaxel, oxaliplatin, and capecitabine combination chemotherapy for metastatic gastric cancer. Gastric Cancer 2014;17:718-24.
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.
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.
Goel G, Jauhri M, Negi A, Aggarwal S. Feasibility study of docetaxel, oxaliplatin and capecitabine combination regimen in advanced gastric or gastroesophageal adenocarcinoma. Hematol Oncol Stem Cell Ther 2010;3:55-9.
Stein A, Arnold D, Thuss-Patience PC, Moehler M, Grothe W, Seufferlein T, et al.
Docetaxel, oxaliplatin and capecitabine (TEX regimen) in patients with metastatic gastric or gastro-esophageal cancer: Results of a multicenter phase I/II study. Acta Oncol 2014;53:392-8.
Mohammad NH, ter Veer E, Ngai LL, Mali R, van Oijen MG, Laarhoven HW. First-line doublet or triplet chemotherapy for advanced esophagogastric cancer: A systematic review and meta-analysis. Cancer Metastasis Rev 2015;34:429-41.
Diaz-Guardamino IE, Carmona-Bayonas A, Fonseca PJ, Martin AJ, Lorenzo ML, Custodio A, et al
. First-line triplet or doublet chemotherapy for advanced gastric cancer: Analysis of 970 patients from a community practice registry. Ann Oncol 2016; 27 Suppl 6:626.
Chau I, Norman AR, Cunningham D, Waters JS, Oates J, Ross PJ. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer – Pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004;22:2395-403.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, 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;24:4991-7.
Ajani JA, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, et al.
Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: The V-325 Study Group. J Clin Oncol 2007;25:3205-9.
Shah MA, Janjigian YY, Stoller R, Shibata S, Kemeny M, Krishnamurthi S, et al.
Randomized multicenter phase II study of modified docetaxel, cisplatin, and fluorouracil (DCF) versus DCF plus growth factor support in patients with metastatic gastric adenocarcinoma: A study of the US gastric cancer consortium. J Clin Oncol 2015;33:3874-9.
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.
Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al.
OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer – A GERCOR study. J Clin Oncol 2006 20;24:394-400.
Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et al.
PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2013;31:2895-902.
Köhne CH, Cunningham D, Di Costanzo F, Glimelius B, Blijham G, Aranda E, et al.
Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: Results of a multivariate analysis of 3825 patients. Ann Oncol 2002;13:308-17.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]