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Xelox for Second-line Treatment of CUP
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a phase-II study for patients with relapsed or refractory carcinoma of unknown primary, the combination of oxaliplatin and capecitabine was found to be both active and reasonably well tolerated.
Source: Hainsworth JD, et al. Oxaliplatin and capecitabine in the treatment of patients with recurrent or refractory carcinoma of unknown primary site. A Phase 2 trial of the Sarah Cannon Oncology Research Consortium. Cancer. 2010;116:2448–2454.
Carcinoma from an unknown primary site is a fairly common clinical syndrome, accounting for approximately 2%-3% of all cancer diagnoses. Autopsy studies have demonstrated that occult primary lesions within the gastrointestinal tract account for a substantial proportion of CUP.1 Accordingly, early trials of empiric treatment of CUP used regimens developed for gastrointestinal cancers (e.g., 5-FU; doxorubicin, and mitomycin-C [FAM]). Results were modest, at best, but it is notable that, at the time, these combinations were of only marginal success for gastrointestinal malignancies as well. Subsequently, several taxane/platinum regimens have been investigated for first-line CUP treatment, and have typically produced response rates between 30% and 40%.2,3 However, for patients with relapse after initial treatment, or for those who did not respond to initial treatment, second-line combinations have met with little success.
Newer regimens for gastrointestinal malignancies, such as 5-FU, leucovorin and oxaliplatin (FOLFOX), 5-FU, leucovorin and irinotecan (FOLFIRI), and capecitabine and oxaliplatin (XELOX) have improved outcomes as treatment in the adjuvant setting or for patients with metastatic disease.4 However, there is little available information about the use of these combinations as empiric treatment for CUP.
In the current study, Hainsworth and colleagues conducted a community-based phase II trial of combination oxaliplatin and capecitabine (XELOX) in patients with recurrent and/or refractory CUP. For this, patients with histologically confirmed CUP, who had progressive disease despite at least one previous chemotherapy regimen, were treated with oxaliplatin (130 mg/m2 intravenously on day 1) and capecitabine (1000 mg/m2 orally twice daily on days 1-14). Treatment cycles were repeated every 21 days. Patients with objective response or stable disease after two cycles continued treatment for six cycles, or until disease progression.
All patients received full doses of both oxaliplatin and capecitabine during the first cycle, and 44 of the 48 patients (92%) received at least two cycles and, thus, were evaluable. Patients received a median of 12 weeks (four cycles) of treatment (range 3-66 weeks), and 15 patients completed six or more cycles.
Nine of 48 patients (19%) had objective responses to treatment; an additional 22 patients had stable disease at the time of first re-evaluation. Of the nine who had responded, five had exhibited no response to initial chemotherapy. After a median follow-up of 17 months, the median progression-free and overall survivals were 3.7 months and 9.7 months, respectively. This regimen was reasonably well tolerated by most patients. Severe myelosuppression was uncommon; only one patient developed febrile neutropenia, and there were no complications related to thrombocytopenia. However, nausea and vomiting were common (54%), and grade 3 neuropathy was observed in two patients. A total of six patients (12%) discontinued therapy because of toxicity.
The combination of oxaliplatin and capecitabine was found to have activity as a salvage treatment for patients with CUP and, clearly, additional studies are warranted, both as treatment for relapsed or refractory disease, but also as first-line treatment for those with clinical and pathologic features suggesting a primary site in the gastrointestinal tract.
As molecular profiling of cancer samples becomes more available, interventions for CUP are likely to be more directed and less empiric. In fact, such an approach has already been employed. Varadhachary and colleagues at M.D. Anderson, working in collaboration with investigators at the Sarah Cannon Research Institute, have performed a battery of molecular and immunohistochemical analyses on paraffin-embedded tissue from patients with CUP and, for some (particularly those who provided tissue from liver or peritoneal metastases), a colon-cancer profile was apparent (CK20 positive/DK7 negative, CDX2 positive).5 Furthermore, preliminary data indicate that patients with CUP who fit this profile respond well to empiric therapy with FOLFOX plus bevacizumab.6 It is the hopeful expectation that similar examination of metastatic lesions from other primary sites will allow a more educated estimation of the site of primary tumor and, thus, a more focused approach to treatment.
1. Nystrom JS, et al. Metastatic and histologic presentations in unknown primary cancer. Semin Oncol. 1977;4:53-58.
2. Greco FA, et al. Taxane-based chemotherapy for patients with carcinoma of unknown primary site. Cancer J. 2001;7:203-212.
3. Hainsworth JD, et al. Carcinoma of unknown primary site: Treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide. J Clin Oncol. 1997;15:2385-2393.
4. Cassidy J, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26:2006-2012.
5. Varadhachary GR, et al. Carcinoma of unknown primary with a colon-cancer profile- changing paradigm and emerging definitions. Lancet Oncol. 2008;9: 596-599.
6. Varadhachary GR, et al. Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol. 2008;26:4442-4448.