FOLFCIS Treatment and Genomic Correlates of Response in Advanced Anal Squamous Cell Cancer

• Published in: Clinical colorectal cancer 2019-03, Vol.18 (1), p.e39-e52
• Main Authors: Mondaca, Sebastian, Chatila, Walid K., Bates, David, Hechtman, Jaclyn F., Cercek, Andrea, Segal, Neil H., Stadler, Zsofia K., Varghese, Anna M., Kundra, Ritika, Capanu, Marinela, Shia, Jinru, Schultz, Nikolaus, Saltz, Leonard, Yaeger, Rona
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Anus Neoplasms - drug therapy; Anus Neoplasms - genetics; Anus Neoplasms - mortality; Anus Neoplasms - pathology; Biomarkers, Tumor - genetics; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - secondary; Cisplatin; Female; Fluorouracil - administration & dosage; Follow-Up Studies; Genomics - methods; High-Throughput Nucleotide Sequencing - methods; Human papillomavirus; Humans; Leucovorin - administration & dosage; Lymphatic Metastasis; Male; Massively parallel sequencing; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - mortality; Neoplasm Recurrence, Local - pathology; Oxaliplatin - administration & dosage; Platinum; Prognosis; Retrospective Studies; Survival Rate
• ISSN: 1533-0028; 1938-0674
• DOI: 10.1016/j.clcc.2018.09.005

In a series of 53 patients with advanced anal squamous cell cancer, we demonstrate that a modified 5-fluorouracil and cisplatin schedule (FOLFCIS) with lower dose, more frequent administration of cisplatin is effective and well-tolerated. This regimen should be considered a standard treatment option. Human papillomavirus-negative anal squamous cell cancers were less sensitive to platinum-based therapy and exhibited a distinct molecular profile. Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC. We reviewed all patients with advanced anal SCC receiving first-line FOLFCIS chemotherapy – essentially a FOLFOX (leucovorin, fluorouracil, and oxaliplatin) schedule with cisplatin substituted for oxaliplatin – in our institution between 2007 and 2017, and performed deep sequencing to identify genomic markers of response and key genomic drivers. Fifty-three patients with advanced anal SCC (48 metastatic; 5 unresectable, locally advanced) received first-line FOLFCIS during this period; all were platinum-naive. The response rate was 48% (95% confidence interval [CI], 32.6%-63%). With a median follow-up of 41.6 months, progression-free survival and overall survival were 7.1 months (95% CI, 4.4-8.6 months) and 22.1 months (95% CI, 16.9-28.1 months), respectively. Among all patients with advanced anal SCC that underwent sequencing during the study period, the most frequent genomic alterations consisted of chromosome 3q amplification (51%) and mutations in PIK3CA (29%) and KMT2D (22%). No genomic alteration correlated with response to platinum-containing treatment. Although there were few cases, patients with human papillomavirus-negative anal SCC did not appear to benefit from FOLFCIS, and all harbored distinct genomic profiles with TP53, TERT promoter, and CDKN2A mutations. FOLFCIS appears effective and safe as first-line chemotherapy in patients with advanced anal SCC and represents an alternative treatment option for these patients.