Anal cancer treatment: Current status and future perspectives

Table 1 Results of different treatment modalities in localized squamous cell anal cancer

	Protocol	CR	CFS	OS	DFS
A	RT	54%[29]	32% lower colostomy-free rate than C[28]	14% higher death rate than C[27]	12.9% higher death and relapse rates at 5 yr than C[27]
B	RT + 5-FU	NA	71%[29]	No significant difference from C	51%[29]
C	RT + 5-FU + Mitomycin	80%[29]89.6% at 26 wk[34]	59%[28]	78.3% at 5 yr[32,33]	67.8%[29,30]to 73%[29]
D	RT + 5-FU + Cisplatin	90.5% at 26 wk[34]	NA	70.7% at 5 yr[31,32]	57.8%[31,32]

NA: Not availiable; RT: Radiation therapy; 5-FU: 5-Fluorouracil; CR: Complete response; CFS: Colostomy-free survival; OS: Overall survival; DFS: Disease free survival.

Table 2 Studies evaluating recent treatment options in locally advanced anal cancer

	Study	Patients, n	Protocol	RR	OS	DFS	CFS
Induction chemotherapy in LAAC	Nilsson et al[36], 2005Population-based series	308 invasive SCAC	- Arm A: Neoadjuvant platinum CT followed by RT alone	CR: 92%	63%	NA	NA
		142 locally advanced	-Arm B: RT with or without Bleomycin	CR: 76% P < 0.01	44% P < 0.05
	Meropol et al[37], 20081 Phase II	45	Induction: 2 28-d cycles (FU + cisplatin) followed by 2 28-d cycles (FU + mitomycin) with concurrent split-course radiation	CR: 82%	68% at 4 yr	61% at 4 yr	50%
	Peiffert et al[38], 20122 Phase III RCT	283	-Arm A: 2 ICT cycles (5-FU + cisplatin) then RCT and standard dose boost (SD: 15 Gy)	NA	NA	NA	69.6%
			-Arm B: 2 ICT, RCT and high dose boost (HD: 20-25 Gy)				82.4%
			-Arm C: RCT and SD boost				77.1%
			-Arm D: RCT and HD boost				72.7%
Combination of MMC and cisplatin in LAAC	Crehange et al[39], 2007 Phase II	21	1st sequence:RT 36 Gy over 4 wk	CR: 90.5%	NA	NA	NA
			2nd sequence: 23.4 Gy over 2.5 wk, gap 16 d
			MMC and CDDP
	Matzinger et al[40], 20093 Phase II	80	RT: 36Gy + 2 wk gap + 23.4 Gy
			-Arm A: MMC + Cisplatin + RT	RR: 91.9%	NA	NA	NA
			-Arm B: MMC + 5-FU + RT	RR: 79.5%
Targeted therapy in LAAC	Olivatto et al[48], 2013 Phase I	21	Cetuximab + RT + 5-FU + cisplatin	pCR: 95%	NA	NA	NA
	Deutsch et al[49], 2013 Phase II	16	Cetuximab + RT + 5-FU + cisplatin	CR: 55%PR: 45%	92% at 1 yr	NA	67% at 1 yr
Cisplatin in LAAC	Eng et al[50], 20134 Retrospective single institution analysis	197 (41% stage II, 46% stage III, 24% N2-N3)	Weekly (20 mg/m2) or daily (4 mg/m2) cisplatin with 5-FU and RT	CR: 94%	86% at 5 yr	81% at 5 yr	88% at 5 yr

¹After induction, 8 CR and 21 PR. A third cycle of FU and cisplatin with radiation boost was given to patients with persistent primary site disease or bulky N2 or N3 disease at presentation;

²Considering the 2 × 2 factorial analysis, the 5-year CFS was 76.5% vs 75% in groups A and B vs C and D, respectively (ICT effect; P = 0.37), and 73.7% vs 77.8% in groups A and C vs B and D, respectively (RT-dose effect; P = 0.067);

³In the first arm, 9 patients discontinued treatment, with 9 grade 3 hematologic effects. In the second arm, 2 discontinued treatment, and no grade 3 hematologic effects were reported;

⁴The local recurrence rate was 11% after the median follow-up of 8.6 yr, and 8% of the patients developed distal metastases. LAAC: Locally advanced anal cancer; MMC: Mitomycin C; RR: Response rate; NA: Not availiable; RT: Radiation therapy; 5-FU: 5-Fluorouracil; CR: Complete response; CFS: Colostomy-free survival; OS: Overall survival; DFS: Disease free survival; RT: Radiation therapy.

Table 3 Recent case reports and case series evaluating treatment in metastatic anal cancer

Study	n	Characteristics of patients	Regimen	Response	Survival
Jhawer et al[71], 2006	20Phase II		MMC, adriamycin, cisplatin followed by bleomycin-CCNU upon progression of disease	60% PR0% CR	15 mo
Golub et al[67], 2011	3P1P2P3	Previously treated with 5-FU and cisplatin	Paclitaxel 175 mg/m2 on D1Ifosfamide 1 g/m2 D1 to D4Cisplatin 75 mg/m2 on D1Every 3 wk	CR in 3 patientsResponse duration6 mo2.5 yr4 mo	Survival since recurrence14 mo30 mo17 mo (patient still alive)
Abbas et al[69], 2011	7	Prior progression on cisplatin and 5-FU	Weekly paclitaxel	1 CR, 3PR,1 SD	12-14 mo1
Kim et al[70], 2013	8	Advanced recurrent	Docetaxel 75 mg/m2 day 1, CDDP 75 mg/m2 day 1 and 5-FU at 750 mg/m(2)/day for 5 d every 3 wk	CR: 50%	OS 62.5% at 12 mo
Khawandanah et al[68], 2014	1	Skin and perianal metastasis	(1) Paclitaxel, ifosfamide, cisplatin (4 cycles) followed by(2) Mitomycin, cetuximab (2 cycles)	(1) Minimal residual disease(2) Mixed response	(1) Progression 5 mo after the end of therapy(2) OS 24 mo; 16 mo after paclitaxel was started
Barmettler et al[45], 2012	1	Liver metastasis, KRAS wild type and EGFR 2 +	FOLFIRI + cetuximab	Partial response after 6 cycles	21 mo
Bamba et al[46], 2012	1	Lung metastasis	3 FOLFOX→3 courses of FOLFOX + panitumumab→5 courses of FOLFIRI + panitumumab	Marked reduction of primary tumor, disappearance of lung metastasis.	The patient underwent low anterior resection.No recurrence after 5 mo
Lukan et al[47], 2009Case report	7	First or subsequent treatment line	Cetuximab alone or with irinotecan first or subsequent line. KRAS mutated in 2/7	PR 3MR 1PD 2 (Mutated kras)SD 1	NA
Nitori et al[72], 2011	1	58-yr-old female	Oral S-1 (120 mg/body; day 1-21) + low dose cisplatin (10 mg/body; day 1-5, 8-12) + RT for 2 cycles then rest for 4 wk	CR of the primary lesion and PR for the metastatic lesions	16 mo

¹Duration of clinical benefit in SD and PR after the initiation of Paclitaxel: 4-6 mo. PD: Progressive disease; PR: Partial response; MR: Minor response; SD: Stable disease; NA: Not availiable.