Capecitabine + oxaliplatin yields high response rate in rectal cancer
Neoadjuvant chemoradiotherapy (CRT) comprising capecitabine and oxaliplatin shows better efficacy over other preoperative CRT regimens in terms of clinical response for locally advanced rectal cancer (LARC), according to a network meta-analysis.
Researchers evaluated eight CRT regimens (fluorouracil [5FU] alone or in combination with oxaliplatin, cisplatin, or irinotecan; capecitabine alone or with oxaliplatin or irinotecan; and irinotecan with S1*) from 14 randomized trials (n=5,599). A total of 3,772 individuals were evaluated for pathologic complete response (pCR), while 4,510 participants were included in the toxicity analysis. [Cancer Manag Res 2019;11:741-758]
The capecitabine-oxaliplatin combination was the most effective regimen in terms of pooled pCR vs 5FU (odds ratio [OR], 3.09, 95 percent confidence interval [CI], 1.08–8.89), capecitabine (OR, 1.52, 95 percent CI, 0.95–2.42), and 5FU-oxaliplatin (OR, 2.22, 95 percent CI, 0.73–6.77).
The order of SUCRA** values by pCR rate was as follows: capecitabine-oxaliplatin (89.9), capecitabine (66.4), irinotecan-S1 (58.5), 5FU-oxaliplatin (50.0), capecitabine-irinotecan (45.2), irinotecan-5FU (33.8), and 5FU-cisplatin (30.8).
Although overall survival (OS) remains the gold standard for measuring efficacy, pCR was used as a primary endpoint to reflect treatment efficacy given the long follow-up time required to evaluate OS, noted the researchers. “Although the percentage of patients who achieve a pCR is not as accurate … as OS, it is commonly used as a rough approximation.”
Moreover, individuals with pCR who adopt a watch-and-wait strategy have the advantage of organ preservation over those who undergo surgery. [Clin Colon Rectal Surg 2017;30:387-394] Thorough surveillance allows for timely salvage surgery in cases of early regrowth and reduces the risk of systemic disease. [Ann Surg 2018;268:955-967] Furthermore, individuals with pCR have been shown to have a higher rate of disease-free survival and a lower rate of recurrence than those without. [Lancet Oncol 2010;11:835-844; Ann Surg Oncol 2007;14:2766-2772]
In terms of safety however, capecitabine-oxaliplatin had higher toxicity rates vs 5FU (OR, 2.46, 95 percent CI, 1.17–5.18) and capecitabine (OR, 2.16, 95 percent CI, 122–3.83).
5FU was the least toxic among other CRT regimens, generating a SUCRA value of 87.3, followed by capecitabine (79.1), irinotecan-5FU (56.8), 5FU-oxaliplatin (38.9), capecitabine-irinotecan (36.6), capecitabine-oxaliplatin (31.4), and irinotecan-S1 (19.8).
While 5FU remains the standard neoadjuvant CRT for LARC and has been proven superior in terms of tumour response and OS, capecitabine mimics the pharmacologic activity of 5FU by converting to 5FU in tumour tissue with the aid of thymidine phosphorylase. [J Clin Oncol 1998;16:301-308] Radiation then stimulates the synthesis of thymidine phosphorylase and generates an improved therapeutic effect when combined with capecitabine. [J Clin Oncol 2002;20:3983-3991]
As capecitabine carries a lower risk of bleeding, infection, and thrombosis as opposed to 5FU due to their route of administration (oral vs IV, respectively), the former may be considered an alternative neoadjuvant therapy for LARC, said the researchers. “Capecitabine may provide a better balance between efficacy and toxic effect compared with 5FU.”
Given the potential limitations (ie, open-label design, inclusion of tumours 15–16 cm from the anal verge, which typically require surgery), further investigation using larger samples is warranted to validate the reliability of the findings, said the researchers.