Neo-adjuvant radiotherapy in rectal cancer

Table 3 Major randomized radiotherapy trials in primary rectal cancer¹

Study	Inclusion time	No of patients	Treatments			Radiation technique2	Increased postop death	Local recurrence			Increased survival	Comments
			Surgery alone	Preop (C)RT	Postop (C)RT			Surgery alone	Preop RT + surgery	Postop RT
Pre-TME era
MRC1[91]	1975-78	824	Yes	5 Gy × 1 2 Gy × 10		AP-PA	No	43%	45% 47%		No	Very low radiation dose, no benefit
EORTC[92]	1976-81	466	Yes	2,3 Gy × 15		AP-PA	No	28%	14%1		No	Decreased local recurrence risk
Bergen[93]	1976-85	169	Yes	1.75 Gy × 18		AP-PA	No	24%	17%		No	Marginally decreased local recurrence risk, comparably low dose
Stockholm I[94]	1980-87	849	Yes	5 Gy × 5		AP-PA	Yes	28%	14%2	-	No	Increased postop death (8% vs 2%), large target, suboptimal technique, decreased local recurrence risk. Increased risk late complications
Uppsala[95]	1980-85	471	-	5.1 Gy × 5	2 Gy × 30	3D-C on RT	No	-	13%1	22%	No	Preop 5 Gy × 5 is better than postop RT (60 Gy). Increased risk of late complications after postop RT
S:t Marks[96]	1980-84	395	Yes	5 Gy × 3		AP-PA	Yes	24%	17%		No	Increased postop death (9% vs 4%)
MRC2[97]	1981-89	279	Yes	2 Gy × 20		AP-PA	No	46%	36%1		No	Slightly reduced risk of local failure, tendency to improved survival (HR = 0.79, 95%CI: 0.6-1.04)
North-West[98]	1982-86	284	Yes	5 Gy × 4		3D-C on RT	No	41%	18%3		No	Decreased local recurrence risk, 10 x 10 cm beams
SRCT[53,55]	1987-90	1110	Yes	5 Gy × 5		3D-C on RT	No	27%	12%3	-	Yes	Decreased local recurrence risk, no increased acute toxicity, some late toxicity after 10-15 yr
Stockholm II[99]	1987-93	557	Yes	5 Gy × 5		3D-RT	Yes	25%	12%3	-	Yes	Overlaps to a large part SRCT, simplified radiation technique, tendency to increased postop mortality (4% vs 1%). Lower local recurrence risk, increased survival as in SRCT. Increased risk of late complications
Post-TME era
EORTC 22921[38]	1993-03	1011	-	RT CRT3	RTCRT	3D-C on RT	No		17% 9%2		No	2 × 2 design, chemotherapy in addition to RT gives fewer local recurrences as first event than RT alone irrespective of whether concomitant (9%) or postoperative (10%), or both (8%), increased toxicity, no increased survival
FFCD 9203[37]	1993-03	742	-	RT CRT		3D-C on RT	No		17% 8%1		No	Preop CRT results in fewer local recurrences than preop RT, increased toxicity, no survival difference
AIO-94[30,100]	1995-02	823	-	CRT	CRT	3D-C on RT	No		6%2	13%	No	Preop CRT is less toxic and gives fewer local recurrences than postop CRT, no difference in survival
TME[54,101]	1996-99	1861	Yes	5 Gy × 5		3D-C on RT	No	11%	5%3		No	No increased postop mortality. Decreased local recurrence risk even with TME, no improved survival, some risk of increased late complications after 5-10 yr
LARCS[39]	1998-03	207	-	RT CRT		3D-C on RT	No		33% 18%1		Yes	The only study in “ugly” rectal cancers, preop CRT gives better local control and better disease and cancer specific survival, tendency towards better survival (66% vs 53% after 5 yr). Increased acute and possibly late toxicity from CRT
MRC-CR07[31]	1998-05	1350	-	5 Gy × 5	CRT if CRM+	3D-C on RT	No		5%2	11%	Yes	Preop 5 Gy × 5 better than postop CRT if CRM+, marginally increased survival. No increase in late complications (3-5 yr)
Polish[33]	1999-02	312	-	5 Gy × 5 CRT		3D-C on RT	No		11% 16%		No	First study that shows less risk of acute toxicity from 5 × 5 compared with preop CRT, no difference in local recurrence and survival or late complications (3-5 yr)
TROG[34]	2001-06	326	-	5 Gy × 5 CRT		3D-C on RT	No		7% 4%		No	Same design as the Polish study, same results

¹Only large studies of relevance for present treatment recommendations are included. Patients with tumours considered to be resectable were included in all studies but one (LARCS). Staging has varied considerably over the years, but most included patients belonged to the intermediate group (bad) except in the LARCS study where most tumours were locally advanced (ugly).

²AP-PA, anterior posterior beams with no blocking, meaning high radiation doses to large normal tissue volumes, 3D-CRT, 3D-conformed radiotherapy, 3 or 4 beams with blocking of normal tissues that did not contain tumour cells. 3D-RT (in the Stockholm II study) means 4 beams but no blocking.

³CRT means chemoradiotherapy with 1.8-2 Gy daily to 45-50.4 Gy. RT means the same radiotherapy as in the CRT arm without chemotherapy. ^aP < 0.05, ^bP < 0.01, ^cP < 0.001. TME: Total (or partial) mesorectal excision; CRT: Chemotherapy.