Ten years of preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation in three consecutive studies.
OBJECTIVE
To compare acute toxicity, tumor response, and sphincter preservation in three schedules of concurrent chemoradiation in resectable transmural and/or node-positive extraperitoneal rectal cancer.


METHODS
Between 1990 and 1999, 163 consecutive patients were treated according to the following combined modalities: FUMIR: between 1990 and 1995, 83 patients were treated with bolus i.v. mitomycin C (MMC), 10 mg/m(2) day 1, plus 24-h continuous infusion i.v. 5-fluorouracil (5-FU) 1,000 mg/m(2) days 1-4, and concurrent external beam radiotherapy (37.8 Gy). PLAFUR-4: between 1995 and 1998, 40 patients were treated with cisplatin (c-DDP) 60 mg/m(2) given as slow infusion (1-4 h) on days 1 and 29, plus 24-h continuous infusion i.v. 5-FU 1,000 mg/m(2), days 1-4 and 29-32 with concurrent external-beam radiotherapy (50.4 Gy). PLAFUR-5: between 1998 and 1999, 40 patients were treated with c-DDP 60 mg/m(2) given as slow infusion (during 1-4 h) on days 1 and 29, plus 24-h continuous infusion i.v. 5-FU 1,000 mg/m(2), days 1-5 and 29-33 with concurrent external-beam radiotherapy (50.4 Gy).


RESULTS
Grade > or = 3 acute toxicity occurred in 14%, 5%, and 17% of patients treated in the FUMIR, PLAFUR-4, and PLAFUR-5 studies, respectively (p = 0.201). In the FUMIR, PLAFUR-4, and PLAFUR-5 studies, clinical response rate was 77%, 70%, and 83%, respectively. Tumor downstaging occurred in 57%, 68%, and 58% of patients, respectively. Pathologic complete response was recorded in 9% (FUMIR), 23% (PLAFUR-4), and 20% (PLAFUR-5) of patients. Sphincter-preserving surgery was feasible in 44% (FUMIR), 40% (PLAFUR-4), and 61% (PLAFUR-5) of patients having a distance between the anal-rectal ring and the lower pole of the tumor of 0-30 mm, and in 95%, 100%, and 100%, respectively, in those having a distance of 31-50 mm. Comparing FUMIR vs. PLAFUR, the clinical response rate was similar in the two series: a partial response was observed in 62/81 (77%) patients with FUMIR treatment, and in 61/80 (76%) patients with PLAFUR treatment. Tumor downstaging was observed in 46/81 (57%) patients and in 50/80 (68%) patients, respectively. The pathologic complete response rate was statistically higher in the PLAFUR series: 7/81 (9%) patients with FUMIR treatment and 17/80 (21%) patients with PLAFUR treatment (p = 0.04). Major downstaging (pT0+ pTmic+ pT1) in the FUMIR group was reported in 12/81 (15%) patients versus 31/80 (39%) patients in the PLAFUR group (p = 0.0006). The anal sphincter was preserved in 63/81 (78%) patients with FUMIR treatment and in 69/80 (86%) patients with PLAFUR treatment. The perioperative morbidity was statistically lower with PLAFUR: a perioperative morbidity was experienced by 20/81 (25%) patients with FUMIR treatment and by 9/80 (11%) patients with PLAFUR treatment (p = 0.042).


CONCLUSIONS
In our experience, higher radiation dose (50.4 Gy vs. 37.8 Gy), a second course of concurrent 5-FU, and the use of c-DDP instead of MMC improved the pathologic response rate without increasing acute toxicity and perioperative morbidity. The use of 5-FU 5-day infusion (PLAFUR-5) resulted in higher toxicity with a similar response rate compared to 4-day infusion (PLAFUR-4).
Valentini
V
V
Cattedra di Radioterapia, Università Cattolica S. Cuore, Rome, Italy. vvalenti@rm.unicatt.it
Coco
C
C
Cellini
N
N
Picciocchi
A
A
Fares
M C
MC
Rosetto
M E
ME
Mantini
G
G
Morganti
A G
AG
Barbaro
B
B
Cogliandolo
S
S
Nuzzo
G
G
Tedesco
M
M
Ambesi-Impiombato
F
F
Cosimelli
M
M
Rotman
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001003:Anal Canal / Q000601:surgery*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D003131:Combined Modality Therapy; D003967:Diarrhea / Q000209:etiology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007970:Leukopenia / Q000209:etiology; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage / Q000009:adverse effects; D009367:Neoplasm Staging; D018579:Patient Selection; D011446:Prospective Studies; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery
D016685:Mitomycin; D005472:Fluorouracil