Preoperative therapy in locally advanced esophageal cancer

Table 1 Salient features of randomized controlled trials addressing the role of preoperative radiotherapy followed by surgery versus surgery alone in the management of esophageal cancer

Ref.	Study period	Treatment	No. of patients	Histology	Complete resection	Local recurrence rate	Operative mortality	5-yr OS	Conclusion
Launois et al[5], 1981	1973-1976	40 Gy RT + Surgery	67	SCC	74%	NA	22.6%	9.5%	No significant benefit of pre-op RT
		Surgery	57	SCC	78%	NA	23.4%	11.5%
Gignoux et al[8], 1987	1976-1982	33 Gy RT + Surgery	NA	SCC	43%	46%	NA	11%	No significant benefit of pre-op RT
		Surgery	NA	SCC	55%	67%	NA	10%
Wang et al[7], 1989	1977-1985	40 Gy RT + Surgery	104	SCC	74%	41%	5%	5%	Higher pre-op RT dose or post-op RT required
		Surgery	102	SCC	65%	34%	6%	30%
Arnott et al[4], 1993	1979-1983	20 Gy RT + Surgery	90	SCC/AC	76%	NA	NA	9%	No benefit of low dose RT
		Surgery	86	SCC/AC	72%	NA	NA	17%
Nygaard et al[6], 1992	1983-1988	35 Gy RT + Surgery	NA	SCC	34%	NA	NA	21%	Beneficial effect of pre-op RT
		Surgery	NA	SCC	32%	NA	NA	9%

SCC: Squamous cell cancer; AC: Adenocarcinoma; RT: Radiotherapy; NA: Not available; OS: Overall survival.

Table 2 Salient features of randomized controlled trials addressing the role of preoperative/perioperative chemotherapy followed by surgery versus surgery alone in the management of esophageal cancer

Trials	Study period	Treatment	No. of patients	Histology	R0 resection	pCR	pN+	Median follow up	LRR	OS (%)	Conclusions
Roth et al[21], 1988	1982-1986	Periop Cisplatin vindesine, bleomycin + S	19	SCC	35%	6%	NS	30 mo	NS	25 (3 yr)	Prolonged OS in responders in perioperative chemotherapy arm with acceptable toxicity and post-op complications
		Surgery	20	SCC	21%	-	NS	30 mo	NS	05 (3 yr)	No improvement in survival in chemotherapy arm
Nygaard et al[6], 1992	1983-1988	Preop Cisplatin, Bleomycin + S	44	SCC	44%	NS	NS	NA	NS	03 (3 yr)
		Surgery	41	SCC	36%	-				09 (3 yr)
Schlag et al[22], 1992	1980's	Preop FC + S	22	SCC	44%	6%	NA	NA	NS	NS	No influence on resectability or OS in chemotherapy arm. Rather, it results in Increase in side effects and postop mortality rate
		Surgery	24	SCC	45%	-	NA	NA	NS	NS
Maipang et al[19], 1994	1988-1990	Preop Cisplatin Vindesine, Bleomycin + S	24	SCC	NS	0%	NS	NA	NS	31 (3 yr)	Better OS in control group. Poorly nourished patients may tolerate smaller dosages of chemotherapy
		Surgery	22	SCC		-		NA		36 (3 yr)
Law et al[18], 1997	1989-1995	Preop FC + S	74	SCC	67%	6.7%	70	NA	12	44 (2 yr)	Significant downstaging and an increased likelihood of R0 resection in chemotherapy arm. No survival difference but responders fared better
		Surgery	73	SCC	35%	-	88		30	31 (2 yr)
Ancona et al[15], 2001	1992-1997	Preop FC + S	47	SCC	90%	13%	NS	30 mo	32	34 (5 yr)	Significantly improved long term survival in patients with pathologic complete response following preoperative chemotherapy
		Surgery	47	SCC	87%	-		30 mo	34	22 (5 yr)
Cunnigham et al[26], 2006 (Magic trial)	1994-2002	Peri-op ECF + S	37/250	AC	69.3%	NA	NS	49	14.4	36.3 (5 yr)	Peroperative chemotherapy decreased tumor size and stage, and significantly improved PFS, OS
		Surgery	36/253	AC	66.4%	-		47	20.6	23 (5 yr)
Kelsen et al[17], (RTOG 8911, US Intergroup 113) 2007	1990-1995	Preop FC + S	213	SCC - 98, AC - 115	63%	2.5%	NS	8.8 yr	25	23 (3 yr)	No improvement in OS in chemotheray arm.Only R0 resection results in long-term survival, regardless of pre-op chemotherapy
		Surgery	227	SCC - 106, AC - 121	59%	-			19	26 (3 yr)
MRC OEO2 trial, 2009 Allum et al[25]	1992-1998	Preop FC + S	400	SCC - 123, AC - 265, Others - 12	60%	4%	58	5.9 yr	11.5	23 (5 yr)	Preop chemotherapy improves survival and should be considered as a standard of care
		Surgery	402	SCC - 124, AC - 268, Others - 10	54%	-	68	6.1 yr	12.2	17 (5 yr)
Ychou et al[23], 2011	1995-2003	Peri-op FC + S	113	AC	84%	3%	67	8.8 yr	12	38 (5 yr)	Peri-op chemotherapy significantly increased R0 resection rate, DFS, and OS
		Surgery	111	AC	73%	-	80		8	24 (5 yr)
Boonstra et al[16], 2011	1989-1996	Preop Cisplatin, Etoposide + S	85	SCC	71%	7%	43	15 mo	19	26 (5 yr)	Significant improvement in OS in chemotherapy arm
		Surgery	84	SCC	57%	-	46	14 mo	25	17 (5 yr)
Ando et al[24], 2012- JCOG 9907	2000-2006	Preop FC + S	164	SCC	96%	2%	65	62 mo	25	55 (5 yr)	Pre-op chemotherapy can be regarded as standard treatment
		Surgery	166	SCC	91%	-	76	NA	31	43 (5 yr)

Periop: Perioperative; SCC: Squamoous cell cancer; AC: Adenocarcinoma; RT: Radiotherapy; NA: Not available; OS: Overall survival; NS: Not stated; ECF: Epirubicin, cisplatin, 5-FU; S: Surgery.

Table 3 Salient features of randomized controlled trials addressing the role of preoperative chemoradiotherapy followed by surgery vs surgery alone in the management of esophageal cancer

Trial	Study period	Treatment	No. of patients	Histology	Completed treatment	R0	pCR	pN+	LRR	Median survival (mo)	OS	Treatment related mortality	DFS median/proportions	Conclusion
Apinop et al[31], 1994	1986-1992	FC + 40 Gy RT + Surgery	35	SCC	26	NA	26.9%	NA	NA	NA	NS	NS	NA	No statistically significant difference in OS, complication rate, mortality
		Surgery	34	SCC	-	NA	-	NA	NA	NA	NS	NS	NA
Le Prise et al[32], 1994	1988-1991	Sequential FC-20 Gy RT-FC + Surgery	41	SCC	39	51.0%		NA	17.9%	10	19.2 (3 yr)	8.5%	7.6 mo	No change in operative mortality or survival time
		Surgery	45	SCC	42	36.0%	-	NA	21.4%	10	13.8 (3 yr)	7%	5 mo
Walsh et al[33], 1996	1990-1995	FC + 40 Gy RT + Surgery	58	AC	53	NA	25%	42	NA	32	37 (3 yr)	3%	NA	Multimodal treatment superior to surgery alone
		Surgery	55	AC	54	NA	-	82	NA	11	07 (3 yr)	2%	NA
Lee et al[34], 2004	1999-2002	FC + 45.6 Gy RT + Surgery	51	SCC	35	100%	43%	37	22.8%	28.2	55 (2 yr)	8.5%	49% (2 yr)	CRT induced high clinical and pathological response, but no statistically significant benefit in OS and DFS
		Surgery	50	SCC	48	87.5%	-	78	10.8%	27.3	57 (2 yr)		51%(2 yr)
Burmeister et al[35], 2005	1994-2000	FC + 35 Gy RT + Surgery	128	45 SCC + 80 AC + 3 others	105	80.0%	16%	43	11%	22.2	NS	4.7%	16 mo	No significant improvement in PFS or OS
		Surgery	128	50 SCC+ 78 AC	110	59.0%	-	67	14%	19.3	NS	5.4%	12 mo
Tepper et al[36], 2008 (CALGB 9781)	1997-2000	FC+ 50.4 Gy RT + Surgery	30	7 SCC + 23 AC	29	84.6%	40%	12	13.7%	53.7	39 (5 yr)	5 yr	28% (5 yr)	Long-term survival advantage supports trimodality therapy as a standard of care
		Surgery	26	7 SCC+ 19 AC	26	88.4%	-	NA	15.3%	21.4	16 (5 yr)	3.8%	15% (5 yr)
Lv et al[37], 2010	1997-2004	2 Cis, Pacli+ 40 gy + Surgery	80	SCC	80	97.4%	NA	NA	11.3%	53	24.5 (10 yr)	3.4%	61.3% (3 yr)	Rational application of pre-op or post-op CRT can improve PFS, OS
		Surgery	80	SCC	80	80.0%	-	NA	35%	36	12.5 (10 yr)	0%	49.3% (3 yr)
Van Hagen et al[38], 2012 (CROSS trials)	2004-2008	5 Pacli, Carbo + 41.4 Gy + Surgery	178	41 SCC + 134 AC + 3 other	168	92.0%	29%	13	3.3%	49.4	47 (5 yr)	5.9%	not reached	Improved survival with acceptable adverse-event rates
		Surgery	188	43 SCC + 141 AC + 4 other	186	69.0%	-	75	9.3%	24	34	6.9%	24.2 mo
Mariette et al[39], 2014	2000-2009	2 Cis, 5FU + Surgery	98	67 SCC + 30 AC+ 1 other	84	93.8%	33.3%	30.8	22.1%	31.8	41 (5 yr)	11.1%	35.6% (5 yr)	No effect on R0 resection rate or survival but enhanced postoperative mortality
		Surgery	97	70 SCC + 27 AC	91	92.1%	-	52.8	28.9%	41.2	33.8	3.4%	27.7% (5 yr)

Periop: Perioperative; SCC: Squamous cell cancer; AC: Adenocarcinoma; RT: Radiotherapy; NA: Not available; OS: Overall survival; NS: Not stated; ECF: Epirubicin, cisplatin, 5-FU; S: Surgery.