Chemoradiation therapy with S-1 for primary squamous cell carcinoma of the rectum: report of three cases

We treated three patients with SCC of the rectum in our institution between 2000 and 2013 (Table 1). The therapy for SCC of the rectum was approved by the Toho University Medical Center Omori Hospital Institutional Review Board (No. 26-231). All of the patients were female and complained of rectal bleeding. Colonoscopy revealed a tumor located in the lower rectum, and histological analysis of biopsies taken at the time of colonoscopy indicated SCC. CT and MRI examinations did not detect lesions at any other site. Finally, the lesions were diagnosed as primary SCC of the rectum. The occurrence of SCC in the colon and rectum is much rarer than in that the anus. In particular, the occurrence of two lesions in the rectum is extremely rare. The mechanism of the development of SCC in the rectum remains elusive. Human papillomavirus (HPV) has been associated with many squamous cell carcinomas such as oral, vaginal, esophageal, and anal cancer and so on. It is possible that SCC of the rectum is associated with HPV infection as well, but there are no firm evidences for a cause or relationship between infection with HPV and SCC of the rectum [10,11]. In addition, several cases have been reported in patients with ulcerative colitis [12-15] and in patients with infections including Schistosomiasis [16] and Entamoeba histolytica [17].

Number	Gender	Age	Location	Size (mm)	cStage	RT (gray/fraction)	CT	Adverse events (CTCAE v4.0)	SCC Ag before CRT	SCC Ag after CRT	Operation	Response	Prognosis
1	F	54	Rb	21.5	III B	59.4/33	S-1 alone	None	9.3	0.9	-	CR	Disease-free for 3 years 8 months
2	F	84	Rb	42.6	II A	59.4/33	S-1 alone	None	6.8	0.9	-	CR	Disease-free for 2 years 1 month
3	F	62	Rb-a	44.4	III C	45/25	S-1 alone	Hemorrhage (G-3)	54.3	1.2	PPE	pCR	Bone and liver metastasis at 1 year 2 months
			Rb	125

RT, radiation therapy; CT, chemotherapy; CTCAE, common terminology criteria for adverse events; SCC Ag, squamous cell carcinoma antigen; CRT, chemoradiation therapy; Ra, rectum above the peritoneal reflection; Rb, rectum below the peritoneal reflection; CR, complete response; PPE, posterior pelvic exenteration; pCR, pathological complete response.

Currently, treatment for SCC of the rectum depends on tumor size, location, depth of invasion, lymph node involvement, and the presence of distant organ metastasis. Local excision is appropriate for T1 or selected T2 tumor, and low anterior resection or abdominoperineal resection is required for advanced tumor. Dyson et al. [18], however, reported that prognosis for patients with SCC of the rectum who received surgical treatment was poor. Surgical treatment also accompanies some problems such as surgical site infection, leakage, and urinary/sexual complications. Some researchers have reported several cases treated using CRT as the primary therapy or in conjunction with surgery [14,15,19-24]. Recently, Clark et al. [4], Rasheed et al. [5], and Sturgeon et al. [25] reported the success of CRT in the treatment of SCC of the rectum. Their regimens involved primary 5-FU-based treatment together with either MMC or cisplatin, which were the same regimens as used for SCC of the anus. Additionally, some experimental treatments using CRT with S-1 + cisplatin, S-1 + MMC, and S-1 alone for SCC of the anus have been reported in Japanese studies [26-34]. These studies found that all patients treated using CRT with S-1 alone had an excellent response to treatment (Table 2). S-1 is an oral anticancer drug that has the following benefits. S-1 increases the blood 5-FU concentration by inhibiting the metabolism of 5-FU by means of dihydropyrimidine dehydrogenase (DPD) and shows significant effectiveness to adenocarcinoma with high-DPD activity of the stomach [35-37], pancreas [38,39], biliary tract [40-42], and so on [43,44]. Moreover, S-1 is more effective as a tumor radiation response enhancer than 5-FU [45,46]. In reports by Vezeridis et al. [47] and Maritinez-Gonzalez et al. [20], disease control for SCC of the rectum treated using 5-FU and RT was not sufficient. In our series, RT was delivered at a total dose of 59.4 Gy in 1.8 Gy/fraction 5 days weekly (Monday to Friday) over a period of 33 days, and S-1 (80 mg/m²/day) was given orally during RT. Patients 1 and 2 were able to safely undergo treatment with S-1, whereas patient 3 was not. Regarding the effectiveness of treatment, all patients had an excellent tumor response; there was a complete response in two patients and a partial response in one. Although patient 3 required a posterior pelvic exenteration with advancement flap reconstruction as a salvage therapy, pathological findings revealed no tumor cells in either the resected specimen or the lymph nodes. Therefore, the response rate was 100% in this series. Phan et al. [48] and Lukan et al. [49] have reported on the treatment of refractory SCC of the anus using cetuximab. Molecular-targeted therapy such as cetuximab for SCC with an epithelial growth factor receptor might be useful in the treatment of a refractory SCC, such as that seen in patient 3.

Author		Gender	Age	Location	cStage	RT (Gy)	Chemotherapy	Response	Prognosis
Miyamoto S et al. [26]	2009	F	61	AC	IV	30	S-1 + CDDP	CR	Disease-free for 20 months
Kuga Y et al. [27]	2009	F	76	AC	III	50	S-1 + CDDP	CR	NR
Shiozawa M et al. [28]	2010	F	48	AC	III	60	S-1 + MMC	CR	Disease-free for 2 years 7 months
		F	65	AC	III	55.8	S-1 + MMC	CR	Disease-free for 2 years 4 months
		F	71	AC	III	58.0	S-1 + MMC	CR	Disease-free for 8 months
Hata T et al. [29]	2011	F	53	AC	I	45	S-1 alone	CR	NR
Baba H et al. [30]	2011	F	79	AC	III	66	S-1 alone	CR	Disease-free for 10 months
Nitori N et al. [31]	2011	F	58	AC	IV	30	S-1 + CDDP	NR	Dead at 16 months
Kuroda M et al. [32]	2012	F	81	AC	IV	50.4	S-1 + CDDP	CR	Disease-free for 1 year 3 months
Sato H et al. [33]	2012	F	83	AC	II	60	S-1 alone	CR	Local recurrence at 9 months and dead at 15 months after CRT
Murata K et al. [34]	2012	F	76	AC	II	60	S-1 alone	CR	Recurrence at 2 years

RT, radiation therapy; AC, anal canal; CR, complete response; NR, not reported.