Neo-adjuvant Capecitabine/Oxaliplatin with RT for Rectal Cancer
Neo-adjuvant Capecitabine/Oxaliplatin with RT for Rectal Cancer
Abstract & commentary
By William B. Ershler, MD
Synopsis: The combination of capecitabine and oxaliplatin administered concurrently with radiation therapy as preoperative treatment for rectal cancer proves highly effective in producing complete or near-complete pathologically determined responses, and with excellent tolerability.
Source: Carlomagno C, et al. Neo-adjuvant treatment of rectal cancer with capecitabine and oxaliplatin in combination with radiotherapy: a phase II study. Ann Ocology. 2009; 20:906-912.
Preoperative chemoradiation is now standard treatment for stages II-III rectal cancer. Capecitabine (CAP) and oxaliplatin (OX) are synergistic with radiotherapy (RT) and active in colorectal neoplasms.1,2 Several studies and two meta-analyses demonstrated that, compared with surgery alone, preoperative RT significantly reduces the risk of local recurrence and cancer-specific mortality.3,4 Two recent phase III trials demonstrated that the addition of chemotherapy (5-fluorouracil [5-FU] modulated by leucovorin) to preoperative, conventionally fractionated RT alone significantly improves local control, but neither study showed an advantage in terms of survival,5,6 suggesting that more intense chemotherapy may be needed to prevent distant metastases and, therefore, to reduce mortality. The issue of the best timing for chemoradiotherapy (before or after surgery) was addressed in a large, phase III trial conducted by the German Rectal Cancer Study Group, which demonstrated that preoperative treatment halves local recurrence (6% vs. 13%) and significantly reduces (grade 3 or 4) acute toxicity (27% vs. 40%) compared with postoperative treatment.7 A meta-analysis investigated the predictive role of different chemoradiotherapy regimens on the occurrence of a pathological complete response (pCR), and showed that a chemotherapy regimen consisting of continuous infusion of 5-FU or capecitabine (CAP) and a dose of RT > 45 Gy is significantly associated with a higher rate of pCR.8 CAP showed a similar efficacy and a better tolerability compared with the combination of 5-FU + folinic acid (FA), both in metastatic and in adjuvant treatment of colorectal cancer. In patients with locally advanced rectal cancer, preoperative CAP with concomitant RT is effective; in fact, it resulted in down-staging of the primary tumor and/or regional lymph nodes in about 35%-75% of patients and in a pCR in about 10%-20% of cases.9 The addition of oxaliplatin (OX) to 5-FU-FA resulted in a significant improvement in outcome in patients with metastatic colorectal cancer.9 Also, in the adjuvant setting, it significantly prolonged DFS and OS10 of stage III colon cancer patients.
Since both CAP and OX have radio-sensitizing effects and are synergistic in colorectal cancer, research efforts focused on treatment schedules that included both drugs and RT as neo-adjuvant treatment of rectal cancer patients. In 2003, a German phase I/II trial demonstrated the feasibility and the activity of preoperative RT with concurrent CAP and OX in patients with T3-T4 rectal cancer.11 In the phase I part of the study, dose-limiting toxicity was diarrhea, and the recommended dose of OX was 50 mg/m2 in combination with CAP, 825 mg/m2 bid on days 1-14 and 22-35, and 50.4 Gy of RT. All 32 patients enrolled in the phase II part of the trial achieved down-staging of the primary tumor and 19% obtained a pCR. Based on these findings, Carlomagno et al conducted a phase II trial to verify the activity in terms of pCR of the combination of CAP + OX + RT in the preoperative treatment of stages II-III rectal cancer patients. Secondary endpoints were the evaluation of tolerability, recurrence-free survival, and OS.
Forty-six patients were enrolled, and two cycles of CAP 825 mg/m2 bid (days 1-14) and OX 50 mg/m2 (days 1 and 8) every three weeks were given concomitantly with pelvic conformal RT (45 Gy). Patients with a ≥ T3 and/or node-positive rectal tumor were eligible. The pathologic tumor response was defined according to the tumor regression grade (TRG) scale.
Gastrointestinal adverse events were mostly grade 1 or 2; only two patients experienced grade 3 vomiting and diarrhea and six patients had grade 1 peripheral neuropathy. Hematological toxicity was rare. Grade 2 proctitis and anal pain occurred in two patients. Pathological complete response (TRG1) was observed in nine patients (20.9%; 95% CI 8.7%-33.1%); TRG2 in 19 patients (44.2%); TRG3 in 12 patients (27.9%); and TRG4 in three patients (7%). Overall, nine patients recurred: five with distant metastases, one with local recurrence, and three with both local recurrence and distant metastases.
Commentary
Thus, although it remains unclear whether the addition of oxaliplatin will result in improved DFS and OS when compared to fluoropyrimidine alone, it allows R0 resection in most patients and induces a pCR in 20% of patients. Several other phase II trials using capecitabine-oxaliplatin in combination with preoperative radiotherapy have been reported with comparable responses.12-14 However, acute toxicity was quite variable, and seems to depend on treatment schedule. The regimen used in the current trial (i.e., CAP for two weeks followed by one week off and OX at days 1 and 8), combined with 45 Gy of conformal RT, is very active and has excellent tolerability. It also remains to be established which combination of drugs, and for what duration, adjuvant chemotherapy should be administered, but a number of ongoing phase III trials are currently under way that will directly address these questions. Analysis of the current trial at a later date will address whether the addition of oxaliplatin results in improvement in overall survival.
References
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11. Rodel C, et al. Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol. 2003;21:3098-3104.
12. Machiels JP, et al. Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study. Ann Oncol. 2005;16:1898-1905.
13. Rodel C, et al. Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol. 2007;25:110-117.
14. Fakih MG, et al. Phase II study of weekly intravenous oxaliplatin combined with oral daily capecitabine and radiotherapy with biologic correlates in neoadjuvant treatment of rectal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2008;72:650-657.
The combination of capecitabine and oxaliplatin administered concurrently with radiation therapy as preoperative treatment for rectal cancer proves highly effective in producing complete or near-complete pathologically determined responses, and with excellent tolerability.Subscribe Now for Access
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