Chemoradiation for adenocarcinoma of the anus

PURPOSE: To assess the efficacy and limitations of definitive chemoradiation for adenocarcinoma of the anal canal and to propose a treatment strategy that addresses the limitations of treatment. METHODS AND MATERIALS: Between 1976 and 1998, 16 patients with localized adenocarcinoma of the anal canal were treated with radiotherapy with or without chemotherapy with curative intent. Available histologic slides were reviewed for evidence of primary adenocarcinoma of anal duct origin. The treatment results for these patients were compared with those of a group of patients with epidermoid histologic features who were all treated with definitive chemoradiation (55 Gy with concurrent 5-fluorouracil and cisplatin, n = 92) between 1989 and 1998. The hospital records were reviewed for all patients. Patients with epidermoid carcinoma presented with more advanced primary tumors (42% vs. 19% Stage T3 or greater). All adenocarcinoma patients were treated with radiotherapy (median dose 55 Gy): 11 received concurrent 5-fluorouracil-based chemotherapy and 5 received radiotherapy alone. The initial surgical procedures included abdominoperineal resection, excisional biopsies (n = 5), and local excision (n = 1). Abdominoperineal resection was performed as salvage therapy after local recurrence in 5 patients. The Kaplan-Meier method was used to calculate 5-year actuarial pelvic control, distant disease control, disease-free survival, and overall survival. The median follow-up was 45 months (range 5-196) for patients with adenocarcinoma and 44 months (range 9-115) for patients with epidermoid histologic features. RESULTS: Both local and distant recurrence rates were significantly greater in the adenocarcinoma patients. Of 16 patients with adenocarcinoma, 7 (5-year actuarial rate 54%) had recurrence at the primary site compared with 16 (5-year actuarial rate 18%) of 92 patients with epidermoid histologic features (p = 0.004). Distant disease developed in more patients with adenocarcinoma (5-year actuarial rate 66%) than in patients with epidermoid carcinoma (5-year actuarial rate 10%, p <0.001). The 5-year actuarial disease-free survival and overall survival rate for adenocarcinoma patients was 19% and 64%, respectively, compared with 77% (p <0.0001) and 85% (p = 0.017) for those with epidermoid carcinoma. CONCLUSION: Patients with localized adenocarcinoma of the anus treated with definitive chemoradiation had high rates of pelvic failure and distant metastasis compared with comparably staged patients with epidermoid histologic features treated similarly. On the basis of these limitations, we recommend preoperative chemoradiation followed by abdominoperineal resection to maximize pelvic disease control and consideration of adjuvant chemotherapy to address the problem of micrometastatic disease.     

Adenocarcinoma of the endometrium treated with combined irradiation and surgery: study of 437 patients

PURPOSE: To identify prognostic factors and treatment toxicity in a series of operable endometrial adenocarcinomas. METHODS AND MATERIALS: Between November 1971 and October 1992, 437 patients (pts) with endometrial carcinoma, staged according to the 1988 FIGO staging system (225 Stage IB, 107 Stage IC, 4 Stage IIA, 35 Stage IIB, 30 Stage IIIA, 6 Stage IIIB, and 30 Stage IIIC), underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy without (n = 140) or with (n = 297) pelvic lymph node dissection. The chronology of adjuvant RT was not randomized and depended on the usual practices of the surgical teams. Seventy-nine pts (Group I) received preoperative low-dose-rate uterovaginal brachytherapy (mean dose [MD]: 57 Gy). Three hundred fifty-eight pts (Group II) received postoperative RT. One hundred ninety-six pts received low-dose-rate vaginal brachytherapy alone (MD: 50 Gy). One hundred fifty-eight pts had external beam pelvic RT (MD: 46 Gy) followed by low-dose-rate vaginal brachytherapy (MD: 17 Gy). Four pts had external beam pelvic RT alone (MD: 47 Gy). The mean follow-up from the beginning of treatment was 128 months. RESULTS: The 10-year disease-free survival rate was 86%. From 57 recurrences, only 12 were isolated locoregional recurrences. The independent factors decreasing the probability of disease-free survival were as follows: histologic type (clear-cell carcinoma, p = 0.038), largest histologic tumor diameter >3 cm (p = 0.015), histologic grade (p = 0.008), myometrial invasion > 1/2 (p = 0.005), and 1988 FIGO staging system (p = 9.10(-8)). In Group II, the addition of external beam pelvic RT did not seem to independently improve vaginal or pelvic control. The postoperative complication rate was 7%. The independent factors increasing the risk of postoperative complications were stage FIGO (p = 0.02) and pelvic lymph node dissection (p = 0.011). The 10-year rate for Grade 3 and 4 late radiation complications according to the LENT-SOMA scoring system was 3.1%. External beam pelvic RT independently increased the rate for Grade 3 and 4 late complication (RR: 5.6, p = 0.0096). CONCLUSION: Postoperative external beam pelvic RT increases the risk of late radiation complications. After surgical and histopathologic staging with pelvic lymph node dissection, in subgroup of "intermediate-risk" patients (Stage IA Grade 3, IB-C and II), postoperative vaginal brachytherapy alone is probably sufficient to obtain a good therapeutic index. Results for patients with Stage III tumor are not satisfactory.     

Response to preoperative chemoradiation increases the use of sphincter-preserving surgery in patients with locally advanced low rectal carcinoma

BACKGROUND: Although controversial, some believe that preoperative chemoradiation increases the use of sphincter-preserving surgery in low rectal carcinoma patients. This article investigates the relationship between objective tumor response and sphincter preservation in low rectal carcinoma patients. METHODS: The authors reviewed the records of 238 patients with T3 or T4 low rectal carcinoma (< or = 6 cm from the anal verge) who underwent preoperative pelvic chemoradiation (45 Gy/25 fractions/5 weeks, n = 182 or 52.5 Gy/30 fractions/5 weeks, n = 56 with continuous infusion 5-fluorouracil at 300 mg/m(2), Monday to Friday) followed by mesorectal (n = 223) or local excision (n = 15). A logistic regression analysis was used to analyze the influence of objective tumor response (defined as complete clinical response) and other prognostic factors on sphincter preservation. Because degrees of partial response could not be objectively defined retrospectively, the influence of partial response on sphincter preservation could not be evaluated. RESULTS: Overall, 49% of patients (117 of 238) had sphincter-preserving surgery. The clinical complete response rate was 47%. Independent predictors of sphincter preservation included the year of surgery, tumor distance from the anal verge, circumferential tumor involvement, and response to chemoradiation. The sphincter preservation rate increased over the period of the study (from 28% [December 1989 to December 1992] to 44% [January 1993 to December 1996] to 67% [January 1997 to December 2000]). The difference in the rates of sphincter preservation according to response was most striking among patients with tumors 3 cm or less from the anal verge (44% vs. 22%, P = 0.01). The pelvic disease recurrence rate among patients undergoing sphincter-preserving surgery has been less than 10% since January 1993 and was not statistically different between the groups treated from January 1993 to December 1996 and from January 1997 to December 2000. CONCLUSIONS: There has been an increase in the use of sphincter-preserving surgery without an increase in pelvic disease recurrence over the past decade. Although not necessary for sphincter preservation, clinical response to preoperative chemoradiation independently contributed to sphincter-preserving surgery, particularly in patients with low rectal tumors.     

Anal canal carcinoma: early-stage tumors < or =10 mm (T1 or Tis): therapeutic options and original pattern of local failure after radiotherapy

PURPOSE: To investigate the clinical history, management, and pattern of recurrence of very early-stage anal canal cancer in a French retrospective survey. METHODS: The study group consisted of 69 patients with Stage Tis and T1 anal canal carcinoma < or =1 cm treated between 1990 and 2000 (12 were in situ, 57 invasive, 66 Stage N0, and 3 Stage N1). The median patient age was 67 years (range, 27-83 years). Of the 69 patients, 66 received radiotherapy (RT) and 3 with in situ disease were treated by local excision alone without RT. Twenty-six patients underwent local excision before RT (12 with negative and 14 with positive surgical margins). Of the 66 patients who underwent RT, 8 underwent brachytherapy alone (median dose, 55 Gy), 38 underwent external beam RT (median dose, 45 Gy) plus a brachytherapy boost (median boost dose, 20 Gy), and 20 underwent external beam RT alone (median dose, 55 Gy). RESULTS: Of the 69 patients, 68 had initial local control. Of the 66 patients treated by RT, 6 developed local recurrence at a median interval of 50 months (range, 13-78 months). Four patients developed local failure outside the initial tumor bed. Of the 3 patients with Tis treated by excision alone, 1 developed local recurrence. No relation was found among prior excision, dose, and local failure. The 5-year overall survival, colostomy-free survival, and disease-free survival rate was 94%, 85%, and 89%, respectively. The rate of late complications (Grade 1-3) was 28% and was 14% for those who received doses <60 Gy and 37% for those who received doses of > or =60 Gy (p = 0.04). CONCLUSION: Most recurrences occurred after a long disease-free interval after treatment and often outside the initial tumor site. These small anal cancers could be treated by RT using a small volume and moderate dose (40-50 Gy for subclinical lesions and 50-60 Gy for T1).     

Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: A multicentric phase II study

PURPOSE: The combination of irradiation and total mesorectal excision for rectal carcinoma has significantly lowered the incidence of local recurrence. However, a new problem is represented by the patient with locally recurrent cancer who has received previous irradiation to the pelvis. In these patients, local recurrence is very often not easily resectable and reirradiation is expected to be associated with a high risk of late toxicity. The aim of this multicenter phase II study is to evaluate the response rate, resectability rate, local control, and treatment-related toxicity of preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis. METHODS AND MATERIALS: Patients with histologically proven pelvic recurrence of rectal carcinoma, with the absence of extrapelvic disease or bony involvement and previous pelvic irradiation with doses < or =55 Gy; age > or =18 years; performance status (PS) (Karnofsky) > or =60, and who gave institutional review board-approved written informed consent were treated by preoperative chemoradiation. Radiotherapy was delivered to a planning target volume (PTV2) including the gross tumor volume (GTV) plus a 4-cm margin, with a dose of 30 Gy (1.2 Gy twice daily with a minimum 6-h interval). A boost was delivered, with the same fractionation schedule, to a PTV1 including the GTV plus a 2-cm margin (10.8 Gy). During the radiation treatment, concurrent chemotherapy was delivered (5-fluorouracil, protracted intravenous infusion, 225 mg/m(2)/day, 7 days per week). Four to 6 weeks after the end of chemoradiation, patients were evaluated for tumor resectability, and, when feasible, surgical resection of recurrence was performed between 6-8 weeks from the end of chemoradiation. Adjuvant chemotherapy was prescribed to all patients, using Raltitrexed, 3 mg/square meter (sm), every 3 weeks, for a total of 5 cycles. Patients were staged using the computed tomography (CT)-based F-classification (F0: no side-wall involvement; F1, F2, F3: 1, 2, and 3-4 side-walls involved, respectively). Toxicity was evaluated on the basis of the Radiation Therapy Oncology Group (RTOG) criteria. RESULTS: Fifty-nine patients (38 male, 21 female; median age, 62 years; range, 43-77 years) were enrolled in the study, by 12 different Italian radiotherapy departments. Previous surgery was anterior resection in 45 patients (76.3%) and abdominal-perineal resection in 14 patients (23.7%); previous radiotherapy dosage ranged between 30 and 55 Gy (median, 50.4 Gy); the median interval between prior radiation therapy to the onset of reirradiation was 27 months (range, 9-106 months); 44 patients (74.6%) had received some form of previous chemotherapy (concurrent and/or adjuvant). Fifty-one of 59 patients (86.4%) completed chemoradiation without treatment interruptions: 6 patients (10.2%) had temporary treatment interruption due to toxicity or patient compliance, and 2 patients (3.4%) had definitive treatment interruption. The incidence of Grade 3 lower gastrointestinal acute toxicity was only 5.1%. No patient developed Grade 4 acute toxicity. After chemoradiation, 5 patients (8.5%) had complete response (CR), 21 patients (35.6%) had partial response (PR), 31 patients (52.6%) had no change (NC) and 2 patients (3.4%) showed progressive disease (PD). Overall, the response rate (PR + CR) was 44.1% (95% confidence interval, 29.0-58.9%). Twenty of 24 patients (83.3%) with pelvic pain before treatment had symptomatic response. Tumor resection was performed in 30 of 59 patients (50.8%) including 2 local excisions, 4 anterior resections, 18 abdominoperineal resections, and 6 other. Surgical resection resulted as R0 and R1 in 21 patients (35.6%) and 3 patients (5.1%), respectively. The possibility of radical resection was influenced by tumor response to chemoradiation (PD/NC: 7/33; PR/CR: 14/26; p = 0.009). Thirty-three patients received adjuvant chemotherapy, which was completed in 30 (50.8%). At a median follow-up of 36 months (range, 9-69 months), 28 patients (47.5%) developed local recurrence or tumor progression in the unresected pelvic disease and 18 patients (30.5%) developed distant metastasis. Seven patients showed late toxicity, including 2 skin fibrosis, 2 impotence, 2 urinary complications requiring nephrostomy, and 1 small bowel fistula requiring surgical diversion. Overall median survival was 42 months. Five-year actuarial survival was 39.3%; 66.8% in R0 resected patients and 22.3% in patients treated without surgery or undergoing subtotal tumor removal. Local control and disease-free survival were significantly correlated with the interval between surgical treatment for primary tumor and local recurrence (p = 0.028 and p = 0.003, respectively). Radical resection significantly influenced local control, disease-free survival, and overall survival (p = 0.010, p = 0.010, and p = 0.050 respectively). The multivariate analysis confirmed the impact of surgery-relapse interval on local control (p = 0.016) and disease-free survival (p = 0.002), and confirmed the correlation between R0 surgery with local control and disease-free survival (p = 0.016). CONCLUSIONS: Use of hyperfractionated chemoradiation was associated with a low rate of acute toxicity and an acceptable incidence of late complications. Pain control was excellent. The overall 5-year survival was 39%. Despite 87.4% of patients having F1-3 stage disease, approximately one-third (35%) achieved R0 resection, and two-thirds of patients in this cohort of patients were alive at the 5-year mark. However, further studies using innovative treatment algorithms are warranted to, hopefully, improve the local tumor response and control.     

Endometrial adenocarcinoma treated with combined radiotherapy and surgery: 437 cases]

PURPOSE: To identify prognostic factors and treatment toxicity in a series of operable endometrial adenocarcinomas. PATIENTS AND METHODS: Between November 1971 and October 1992, 437 patients (pts) with endometrial carcinoma, staged according to the 1988 FIGO staging system, underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy without (n = 140) or with (n = 297) pelvic lymph node dissection. The chronology of RT was not randomized and depended on the usual practices of the surgical teams. Group I: 79 pts received preoperative uterovaginal brachytherapy (mean total dose [MD]: 57 Gy). Group II: 358 pts received postoperative RT (196 pts received vaginal brachytherapy alone [MD: 50 Gy], 158 pts had external beam pelvis RT [EPRT] [MD: 46 Gy over 5 weeks] followed by vaginal brachytherapy [MD: 17 Gy], and 4 pts had EPRT alone [MD: 46 Gy over 5 weeks]). The mean follow-up was 128 months. RESULTS: The 10-year disease-free survival rate was 86%. From 57 recurrences, 12 were isolated locoregionally. Multivariate analysis showed that independent factors decreasing the probability of disease-free survival were: histologic type (clear cell carcinoma, p = 0.038), largest histologic tumor diameter > 3 cm (p = 0.015), histologic grade (p = 0.008), myometrial invasion > 1/2 (p = 0.0055), and 1988 FIGO staging system (p = 9.10(-8)). In group II, the addition of EPRT did not seem to improve locoregional control. The postoperative complication rate was 7%. The independent factors increasing the risk of postoperative complications were FIGO stage (p = 0.02) and pelvic lymph node dissection (p = 0.011). The 10-year rate for grade 3 and 4 late radiation complications according to the LENT-SOMA scoring system was 3.1%. EPRT independently increased the 10-year rate for grade 3 and 4 late radiation complications (R.R.: 5.6, p = 0.0096). CONCLUSION: EPRT increases the risk of late radiation complications. After surgical and histopathologic staging with pelvic lymph node dissection, in a subgroup of intermediate risk patients (stage IA grade 3, IB-C and II), postoperative vaginal brachytherapy alone is probably sufficient to obtain a good therapeutic index. Results for patients with stage III tumor are not satisfactory.     

Intraoperative radiation therapy in resected pancreatic carcinoma: long-term analysis

PURPOSE: The combination of external radiotherapy (RT) plus intraoperative radiotherapy (IORT) in patients with pancreatic cancer is still debated. This study presents long-term results (minimum follow-up, 102 months) for 26 patients undergoing integrated adjuvant RT (external RT+IORT). METHODS AND MATERIALS: From 1990 to 1995, a total of 17 patients with pancreatic cancer underwent IORT (10 Gy) and postoperative external RT (50.4 Gy). Preoperative "flash" RT was included for the last 9 patients. The liver and pancreatic head received 5 Gy (two 2.5-Gy fractions) the day before surgery. In the subsequent period (1996-1998), 9 patients underwent preoperative concomitant chemoradiation (39.6 Gy) with 5-fluorouracil, IORT (10 Gy), and adjuvant chemotherapy. RESULTS: Preoperative chemoradiation was completed in all patients, whereas postoperative therapy was completed in 13 of 17 patients. All 26 patients underwent pancreatectomy (25 R0 and one R1 resections). One patient died of postoperative complications (3.8%) not related to IORT. The 9 patients undergoing concomitant chemoradiation were candidates for adjuvant chemotherapy; however, only 4 of 9 underwent adjuvant chemotherapy. At last follow-up, 4 patients (15.4%) were alive and disease free. Disease recurrence was documented in 20 patients (76.9%). Sixteen patients (61.5%) showed distant metastasis, and 5 patients (19.2%) showed local recurrence. The incidence of local recurrence in R0 patients was 4 of 25 (16.0%). The overall 5-year survival rate was 15.4%. There was significant correlation with overall survival of tumor diameter (p=0.019). CONCLUSIONS: The incidence of local recurrence in this long follow-up series (19.2%) was definitely less than that reported in other studies of adjuvant RT (approximately 50%), suggesting a positive impact on local control of integrated adjuvant RT (IORT+external RT).     

Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal

PURPOSE: To evaluate our data concerning the prognostic factors for locoregional control, survival, late complications, and sphincter conservation in a series of epidermoid cancers of the anal canal without clinical evidence of metastasis. METHODS AND MATERIALS: Between June 1972 and January 1997, 305 patients were treated with curative-intent radiotherapy (RT). The T stage according to the 1987 International Union Against Cancer classification was T1 in 26, T2 in 141, T3 in 104, and T4 in 34. Forty-nine patients had nodal involvement at presentation. The pretreatment anal function score, according to our in-house system, was 0 for 22 patients, 1 for 182, 2 for 74, 3 for 7, and 4 for 11 patients; for 9 patients, scores were unavailable. The treatment started with external beam radiotherapy (EBRT) in 303 patients (median dose 45 Gy). After a rest period of 4-6 weeks, a boost of 20 Gy was delivered by EBRT in 279 patients and by interstitial (192)Ir brachytherapy in 17 patients. Seven patients received only one course of EBRT (mean dose 49.5 Gy), and 2 patients were treated with interstitial (192)Ir brachytherapy alone (55 Gy and 60 Gy). Concomitant chemotherapy (5-fluorouracil and either mitomycin C or cisplatin) was delivered to 19 patients. The mean follow-up was 103 months (median 84). RESULTS: At the end of RT, the local tumor clinical complete response rate was 96% for T1, 87% for T2, 79% for T3, and 44% for T4. Of the 61 locally progressive tumors, 27 (44%) were salvaged with abdominoperineal resection. The rate of local tumor relapse was 12%. Among 37 local tumor relapses, 20 (54%) were salvaged with abdominoperineal resection and one with interstitial (192)Ir brachytherapy. The overall local control rate (with or without salvage local therapy) was 84%. The local control rate with good anal function (score 0 or 1) was 56.5%. Of 181 available patients with their anus preserved, 94% had good anal function. For a subgroup of 15 patients with a tumor length of <2 cm and without nodal involvement, the clinical complete response rate after RT completion was 100%, the local control rate with or without local salvage treatment was 100%, and among 13 available patients with their anus preserved, the anal function score was good in 12 patients (92%). The 10-year disease-free survival rate was 74%. After multivariate analysis, three independent predictive factors significantly influenced disease-free survival: the interval between the two courses of RT (>38 days vs. < or =38 days, p = 0.0025), pretreatment anal function score (0 vs. 1 vs. 2 vs. 3 vs. 4, p = 4.4.10(-6)), and clinical complete response after RT completion (no complete response vs. complete response, p = 2.5.10(-14)). CONCLUSION: We confirm the excellent results with RT in T1 and T2 lesions. However, to improve survival without colostomy with good anal sphincter function, chemoradiotherapy should be preferred for tumors > or =2 cm in length and for locally advanced tumors.     

Operable Stages IB and II cervical carcinomas: a retrospective study comparing preoperative uterovaginal brachytherapy and postoperative radiotherapy

PURPOSE: To evaluate our data concerning prognostic factors and treatment toxicity in a series of operable cervical carcinomas. METHODS AND MATERIALS: Between May 1972 and January 1994, 414 patients with cervical carcinoma, staged according to the 1995 FIGO staging system (286 Stage IB1, 38 Stage IB2, 56 Stage IIA, and 34 Stage IIB with 1/3 proximal parametrial involvement), underwent radical hysterectomy with (n = 380) or without (n = 34) bilateral pelvic lymph node dissection (N+: n = 68). Group I included 168 patients who received postoperative radiation therapy (RT): 64 patients had low-dose-rate vaginal brachytherapy with a median total dose (MTD) of 50 Gy; 93 patients had external beam pelvic RT (EBPRT) with an MTD of 45 Gy over 5 weeks, followed by low-dose-rate vaginal brachytherapy (MTD: 20 Gy); and 11 patients had EBPRT alone (MTD: 50 Gy over 6 weeks). Group II included 246 patients treated with preoperative low-dose-rate uterovaginal brachytherapy (MTD: 65 Gy); 32 of these 246 patients also received postoperative EBPRT (MTD: 45 Gy over 5 weeks) delivered to the parametria and pelvic nodes. Mean follow-up from the beginning of treatment was 106 months. RESULTS: First events included isolated locoregional recurrences (35 patients), isolated distant metastases (27 patients), and locoregional recurrences with synchronous metastases (13 patients). The 10-year disease-free survival (DFS) rate was 88% for Stage IB1, 44% for Stage IB2, 65% for Stage IIA, and 48% for Stage IIB. Multivariate analysis showed that independent factors influencing the probability of DFS were as follows: cervical site (exocervical or endocervical vs. both endo- and exocervical, relative risk [RR]: 1.77, p = 0.047), vascular space invasion (no vs. yes, RR: 1.95, p = 0.041), age (>51 years vs. 1 cm: 83% vs. 41%, respectively, p = 0.001). The overall postoperative complication rate was 10% in Group I and 9% in Group II (p = 0.7). The rate of postoperative ureteral complications requiring surgical intervention was lower in Group I than in Group II (0.6% vs. 2.3%, respectively, p = 0.03). The overall 10-year rate for Grade 3 and 4 late radiation complications was 10.4%. Postoperative EBPRT significantly increased the 10-year rate for Grade 3 and 4 late radiation complications (yes vs. no: 22% vs. 7%, respectively, p = 0.0002). CONCLUSION: The prognosis for patients with cervical carcinoma was not influenced by the sequence of adjuvant RT (preoperative uterovaginal brachytherapy vs. postoperative RT) for Stages IB, IIA, and IIB with 1/3 proximal parametrial involvement. However, postoperative EBPRT increased the risk of late radiation complications.     

Effective pelvic symptom control using initial chemoradiation without colostomy in metastatic rectal cancer

PURPOSE: To assess pelvic chemoradiotherapy (CXRT) without colostomy as a component of the multidisciplinary management of patients presenting with metastatic rectal cancer. METHODS AND MATERIALS: Eighty patients with synchronous distant metastases from rectal cancer were treated with initial CXRT. Hypofractionated radiotherapy was administered usually with concurrent 5-FU (92%, 300 mg/m(2)/day, M-F). Three-field belly-board technique was used in 89%. Group 1 had CXRT alone (n = 55). Group 2 (n = 25) patients were selected for primary disease resection, and sometimes HAI chemotherapy (n = 10) or hepatic resection (n = 5). Subsequently, 78% received systemic chemotherapy. RESULTS: Symptoms from primary tumor resolved in 94%. Endoscopic complete clinical response rate was 36%. Two-year survival (11% vs. 46%, p < 0.0001) and symptomatic pelvic control (PC, 81% vs. 91%, p = 0.111) were higher in Group 2, but colostomy-free rate (CFR) was lower (79% vs. 51% p = 0.02). CFR was 87% in Group 1 patients managed initially without fecal diversion (n = 50). Examining all patients using multivariate analysis, pelvic pain at presentation (p < 0.00001), BED (biologic equivalent dose at 2 Gy/fraction) < 35 Gy (p = 0.077), and poor differentiation (0.079) predicted worse PC. Poor differentiation (p = 0.017) and selection for CXRT alone (p < 0.0001) predicted worse survival. There were 4 RTOG of Grade 3 or greater acute complications, 5 severe perioperative complications, and no significant late treatment-related complications. CONCLUSION: Durable PC can be safely achieved without colostomy in most patients presenting with primary rectal cancer and synchronous systemic metastases using hypofractionated pelvic chemoradiation. A BED greater than 35 Gy is recommended. Selected patients appear to benefit from resection of primary disease. Higher doses should be investigated in patients with pelvic pain.     

Operable stage IB and II cancer of the uterine neck: retrospective comparison between preoperative utero-vaginal curietherapy and initial surgery followed by radiotherapy]

PURPOSE: To identify prognostic factors and treatment toxicity in a series of operable stages IB and II cervical carcinomas. PATIENTS AND METHODS: Between May 1972 and January 1994, 414 patients (pts) with cervical carcinoma staged according to the 1995 FIGO staging system underwent radical hysterectomy with (n = 380) or without (n = 34) bilateral pelvic lymph node dissection. Lateral ovarian transposition to preserve ovarian function was performed on 12 pts. The methods of radiation therapy (RT) were not randomised and depended on the usual practices of the surgical teams. Group I: 168 pts received postoperative RT (64 pts received vaginal brachytherapy alone [mean total dose (MD): 50 Gy], 93 pts had external beam pelvis RT (EBPRT) [MD: 45 Gy over 5 weeks] followed by vaginal brachytherapy [MD: 20 Gy], and 11 pts had EBPRT alone [MD: 50 Gy over 6 weeks]. Group II: 246 pts received preoperative utero-vaginal brachytherapy [MD: 65 Gy], and 32 of theses 246 pts also received postoperative EBPRT [MD: 45 Gy over 5 weeks] delivered to the parametric and the pelvic lymph nodes with a midline pelvic shield. The mean follow-up was 106 months. RESULTS: The 10-year disease-free survival (DFS) rate was 80%. From 75 recurrences, 35 were isolated locoregional. Multivariate analysis showed that independent factors decreasing the probability of DFS were: both exo and endocervical tumour site (p = 0.047), lymph-vascular space invasion (p = 0.041), age < or = 51 yr (p = 0.013), 1995 FIGO staging system (stage IB1 vs stage IIA, p = 0.004, stage IB1 vs stage IB2, p = 0.0009, and stage IB1 vs stage IIB with 1/3 proximal parametrical infiltration, p = 0.00002), and histological pelvic involved lymph nodes (p = 0.00009). Methods of adjuvant RT did not influence the probability of DFS (group I vs group II, p = 0.10). The postoperative complication rate was 10.2% in group I and 8.9% in group II (p = 0.7) but the postoperative urethral complication rate necessitating surgical intervention with reimplantation was lower in group I than in group II (0.6% vs 2.3%, respectively, p = 0.03). The 10-year rate for grade 3 and 4 late radiation complications according to the LENT-SOMA scoring system was 10.4%. EPRT significantly increased the 10-year rate for grade 3 and 4 late radiation complications (yes vs no: 22% vs 7%, respectively, p = 0.0002). CONCLUSION: In our series, the methods of adjuvant RT (primary surgery vs preoperative uterovaginal brachytherapy) do not seem to influence the prognosis of the stage IB, IIA, and IIB (with 1/3 proximal parametrical involvement only) cervical carcinomas. The postoperative EPRT applied according to histopathological risk factors after surgical treatment increases the risk of late radiation complications.     

High-dose whole abdominal and pelvic irradiation for treatment of ovarian carcinoma: long-term toxicity and outcomes

PURPOSE: To evaluate the role of high-dose whole abdominal and pelvic irradiation (WART) in the treatment of epithelial ovarian carcinoma. METHODS AND MATERIALS: A retrospective review was performed on 71 patients with Stage I-III ovarian carcinoma who were treated with WART using an open field technique after total abdominal hysterectomy and bilateral oophorectomy with or without omentectomy. Whole abdominal doses greater than typically recommended were used in a series of patients to enhance local control and to decrease abdominal recurrence. None of the patients had received chemotherapy before RT. Thirty-one patients received Alkeran or cyclophosphamide and two received cisplatin-based chemotherapy after WART. The median whole abdominal dose was 36 Gy (range 9-45.5), delivered in a median of 30 fractions (range 8-46). A pelvic boost was delivered using AP-PA fields during whole abdominal RT to a total midline pelvic dose of 200 cGy/d. The median pelvic dose was 51 Gy (range 16-59). The right lobe and a portion of the left lobe of the liver were shielded with custom blocks at a median dose of 25 Gy (range 9-41). The kidneys were shielded either AP-PA or PA from the first day of RT. The median dose to the kidneys was 19 Gy (range 4-30). RESULTS: The 5-year overall survival rate was 93%, 48%, and 29% for Stage I, II, and III patients, respectively. On multivariate analysis, stage and the extent of residual disease were independent prognostic factors. The 5- and 10-year overall survival rate for the 46 patients in the intermediate-risk group was 61% and 54%, respectively. For this group, a total abdominal dose of > or /=36 Gy was associated with a longer overall survival independent of stage, grade, and the amount of residual disease. This was most likely due to a significant reduction in the incidence of abdominal recurrence in patients receiving >36 Gy to the whole abdomen (18% vs. 49%, p = 0.006). Multivariate analysis revealed that grade (p = 0.023) and abdominal dose (p = 0.018) were independent factors influencing the rate of abdominal recurrence. Pelvic recurrence was rare as a first site of failure (6%). Twenty-one percent (n = 15) of the patients developed Grade 3 or 4 (Radiation Therapy Oncology Group [RTOG] criteria) chronic small or large bowel toxicity. Eleven percent of all patients had a small bowel obstruction requiring surgery. A whole abdominal dose >30 Gy and a pelvic dose >50 Gy were associated with a significant increase in small bowel obstruction (p = 0.01) independent of other factors. Chronic Grade 3 or 4 (Common Toxicity Criteria) anemia, thrombocytopenia, and leukopenia were seen in 7%, 1%, and 4% of the patients, respectively. Transient liver enzyme elevation was common (62%). Two patients had Grade 3 (RTOG) hepatic toxicity. Grade 3 or 4 renal toxicity (RTOG) was observed in 4%, and 2 patients (3%) were diagnosed with pelvic insufficiency fractures that were managed conservatively. CONCLUSION: Survival after RT for ovarian carcinoma rivals that achieved with systemic chemotherapy. The results of this study suggest a possible dose-control relationship between the whole abdominal dose and the risk of abdominal recurrence; however, a higher rate of small bowel obstruction was observed when greater abdominal doses and greater pelvic doses were combined. Careful attention to balancing toxicity and efficacy is imperative if RT is to have a future role in the treatment of this disease.     

The addition of continuous infusion 5-FU to preoperative radiation therapy increases tumor response,leading to increased sphincter preservation in locally advanced rectal cancer

PURPOSE: To compare the outcome from preoperative chemoradiation (CXRT) and from radiation therapy (RT) in the treatment of rectal cancer in two large, single-institutional experiences. PATIENTS AND METHODS: Between 1978 and 1995, 403 patients with localized, nonmetastatic, clinically staged T3 or T4 rectal cancer patients were treated with preoperative RT alone at two institutions. Patients at institution 1 (n = 207) were treated with pelvic CXRT exclusively, and patients at institution 2 were treated (except for 8 given CXRT) with pelvic RT alone (n = 196). In addition, a third group (n = 61) was treated with CXRT at institution 2 between 1998 and 2000 after a policy change. Both institutions delivered 45 Gy in five fractions as a standard dose, but institution 2 used 20 Gy in five fractions in selected cases (n = 26). At both institutions, concurrent chemotherapy consisted of a continuous infusion of 5-fluorouracil (5-FU) at a dosage of 1500 mg/m(2)/week. The end points were response, sphincter preservation (SP), relapse-free survival (RFS), pelvic disease control (PC), and overall survival (OS). RESULTS: Median follow-up was 63 months for all living patients at institution 1 and in the primary group of institution 2. Multivariate analysis of the patients in these groups showed that the use of concurrent chemotherapy improved tumor response (T-stage downstaging, 62% vs. 42%, p = 0.001, and pathologic complete response, 23% vs. 5% p < 0.0001), but did not significantly improve LC, RFS, or OS. Follow-up for the secondary group at institution 2 was insufficient to allow the analysis of these endpoints. In the subset of patients receiving 45 Gy who had rectal tumors < or /=6 cm from the anal verge (institution 1: n = 132; institution 2 primary: n = 79; institution 2 secondary: n = 33), there was a significant improvement in SP with the use of concurrent chemotherapy (39% at institution 1 compared with 13% in the primary group at institution 2, p < 0.0001). A logistic regression analysis of clinical prognostic factors indicated that the use of concurrent chemotherapy independently influenced SP in these low tumors (p = 0.002). This finding was supported by a 36% SP rate in the secondary group at institution 2. Thus SP increased after the addition of chemotherapy at institution 2. CONCLUSIONS: The use of concurrent 5-FU with preoperative radiation therapy for T3 and T4 rectal cancer independently increases tumor response and may contribute to increased SP in patients with low rectal cancer.     

Intraoperative presacral electron boost following preoperative chemoradiation in T3-4Nx rectal cancer: initial local effects and clinical outcome analysis.

BACKGROUND AND PURPOSE: To analyze early results of a single institution experience using adjuvant intraoperative electron radiation therapy (IOERT) presacral boost in locally advanced rectal cancer following preoperative chemoradiation.Materials and methods: In a 63 month period (March 1995-June 2000), 100 consecutive T(3-4)N(x) rectal cancer patients were treated with preoperative chemoradiation (45-50 Gy plus oral Tegafur or 5-Fluorouracil continuous intravenous infusion), radical surgery and IOERT presacral boost (mean dose, 12.5 Gy; range, 10-15 Gy). Adjuvant chemotherapy (5-FU-leucovorin: 4-6 cycles) was given to 52 patients. The median age was 63 years, and 39 patients were >or=70 years old (65 males). Clinical staging was performed with computed tomography (94%) and/or endorectal ultrasound (71%) categorizing 90 cT(3), 10 cT(4), 20 cN(x), and 36 cN(+). Abdomino-perineal resection was performed in 41 cases. RESULTS: The IOERT cancellation rate was 6%. With a median follow-up of 23 months in IOERT treated patients, three developed pelvic recurrence: one anastomotic and one in the posterior vaginal wall (simultaneously with distant metastatic disease); and one presacral (in-field IOERT) as the only site of initial failure. Distant metastasis has been observed in 14 patients (exceptionally in pT(0-1) downstaged patients: 1/20; 5%). Overall treatment tolerances, including neoadjuvant and surgical segments, were acceptable. The actuarial 4-year estimations of local control, disease-free and overall survival are 94, 75 and 65%, respectively. CONCLUSIONS: IOERT electron boost to the presacral region is feasible to integrate systematically in the intensive combined treatment of locally advanced rectal cancer, including neoadjuvant chemoradiation segment. Topography of pelvic recurrences identified 2/3 relapses located in non-IOERT boosted anatomic intrapelvic sites: posterior vaginal wall and anastomotic suture. Presacral recurrence in locally advanced rectal cancer seems to be of low incidence, in a non-subspecialized academic surgical practice coordinated with a multidisciplinary oncology evaluation context, if an IOERT boost is included as a component of treatment together with preoperative chemoradiation.     

A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer

We sought to evaluate the efficacy and safety data of a combination regimen using weekly irinotecan in combination with capecitabine and concurrent radiotherapy (CapIri-RT) as neoadjuvant treatment in rectal cancer in a phase-II trial. Patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive irinotecan (50 mg m(-2) weekly) and capecitabine (500 mg m(-2) bid days 1-38) with a concurrent RT dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the completion of chemoradiation. A total of 36 patients (median age 62 years; m/f: 27:9) including three patients with local recurrence were enclosed onto the trial. The median distance of the tumour from the anal verge was 5 cm. The main toxicity observed was (NCI-CTC grades 1/2/3/4 (n)): Anaemia 23/9/-/-; leucocytopenia 12/7/7/2, diarrhoea 13/15/4/-, nausea/vomiting 9/10/2/-, and increased activity of transaminases 3/3/1/-. One patient had a reversible episode of ventricular fibrillation during chemoradiation, most probably caused by capecitabine. The relative dose intensity was (median/mean (%)): irinotecan 95/91, capecitabine 100/92). Thirty-four patients underwent surgery (anterior resection n=25; abdomino-perineal resection n=6; Hartmann's procedure n=3). R0-resection was accomplished in all patients. Two patients died in the postoperative course from septic complications. Pathological complete remission was observed in five out of 34 resected patients (15%), and nine patients showed microfoci of residual tumour (26%). After a median follow-up of 28 months one patient had developed a local recurrence, and five patients distant metastases. Three-year overall survival for all patients with surgery (excluding three patients treated for local relapse or with primary metastatic disease) was 80%. In summary, preoperative chemoradiation with CapIri-RT exhibits promising efficacy whereas showing managable toxicity. The local recurrence and distant failure rates observed after a median 28 months are low compared with standard 5-fluorouracil based therapy.     

Saving bladders with brachytherapy: implantation technique and results

PURPOSE: To analyze and report the treatment results of brachytherapy for solitary bladder cancer in the Arnhem Radiotherapy Institute. METHODS AND MATERIALS: Between January 1983 and October 1998, 63 patients with a solitary bladder tumor were treated with a combination of transurethral resection, external beam radiotherapy (EBRT), and interstitial radiotherapy. The indications for bladder-conserving treatment were tumor < or =5 cm, T1G3 (n = 14), T2G2 (n = 8), T2G3 (n = 37), and T3a (n = 4). The prescribed implant dose was either 55 Gy (range 50-65 Gy) in combination with small pelvis external beam RT, 3-4 fractions of 3.5 Gy (n = 58), or 30 Gy in combination with 20 fractions of 2 Gy external beam radiotherapy (n = 5). Brachytherapy was performed with 2-8 137Cs needles until 1995 (n = 48) and 2-5 afterloading catheters (192Ir) since 1996 (n = 15). Follow-up cystoscopies were performed at 3-month intervals during the first 2 years, then every 6 months for 3 years, and annually after the fifth year. The median follow-up was 4.9 years. RESULTS: Twenty patients developed local recurrences, of which 6 were "true in-implant recurrences," 12 were in second bladder locations, and 2 were urethral recurrences. All recurrences developed within 2.5 years after treatment. Of these 20 patients, 13 underwent cystectomy: 6 stayed disease-free, 1 died of postoperative complications, 2 developed regional metastases, and 4 developed distant metastases. The 5-year disease-specific survival rate was 80% for patients with Stage T1 and 60% for those with Stage T2 disease. The local control rate was 70% in the whole patient population and 80% after salvage cystectomy. Forty-four bladders were saved. Acute complications were seen in 14 patients, and no significant late complications occurred. CONCLUSION: Using this treatment technique, a high cure rate with conservation of the bladder and only minor toxicity can be obtained in a selected patient population having a solitary tumor < or =5 cm.     

Is extended volume external beam radiation therapy covering the anastomotic site beneficial in post-esophagectomy high risk patients?

BACKGROUND AND PURPOSE: To assess the impact of extended volume radiation therapy (RT) with anastomotic coverage on local control in high risk post-operative esophageal cancer patients. PATIENTS AND METHODS: This is a retrospective study of high risk (T(3), T(4), nodes positive, with or without margin involvement) post-operative esophageal cancer patients treated at London Regional Cancer Centre from 1989 to 1999. After esophagectomy, all patients received adjuvant combined modality therapy consisting of four cycles of fluorouracil-based chemotherapy, and loco-regional RT with or without coverage of the anastomotic site. RT dose ranged from 45 to 60 Gy at 1.8-2.0 Gy/fraction with treatment fields tailored to the pathologic findings and location of the anastomosis. CT planning was used in all patients to design spinal cord sparing beam arrangements. First relapse rate (first incidence of an event), disease specific survival and overall survival were calculated by Chi-Square, Log-Rank, and Kaplan-Meier (K-M) methods. RESULTS: During the study period, 72 patients had underwent esophagectomy and were considered for adjuvant chemoradiation therapy. Three patients were excluded due to disease progression prior to therapy. The 69 remaining patients formed the study cohort for the present analysis. The median age of the study group was 60 years (range 35-82 years). Pathologic stage distribution (AJCC 1997 staging) was T(2,3) N(1) in 94% patients, 65% of the cases were adenocarcinoma and had undergone transhiatal esophagectomy (86%) with positive/close margins in 34 (49%) patients. Median follow-up was 30.5 months (range 3.4-116.3 months). Two- and 5-year actuarial overall survivals rates were 50 and 31%, respectively. First relapse rate after adjuvant therapy was 63.7% (n = 44) and median time to relapse was 27.2 months. Anastomosis recurrence rates were 29% with small volume and 0% with extended volume RT (P = 0.041). Local and regional relapse occurred in 74.2% of patients treated with small volume RT compared to 15.4% in patients treated with extended volume RT (P < 0.001). After adjusting for resection margin status, the local control benefit of extended volume RT remained significant (P = 0.003). Treatment interruptions and late gastrointestinal toxicity were not significantly increased with the use of extended volume RT. CONCLUSIONS: A significant decrease in local and regional relapse without added late toxicity was achieved with the use of extended volume RT encompassing the anastomotic site post-operatively in high risk esophageal cancer patients.     

Preliminary analysis of RTOG 9708: Adjuvant postoperative radiotherapy combined with cisplatin/paclitaxel chemotherapy after surgery for patients with high-risk endometrial cancer

PURPOSE: Patients with completely resected high-risk endometrial cancer have a risk of disease recurrence even with the addition of adjuvant pelvic radiotherapy (RT). A Phase II study was completed by the Radiation Therapy Oncology Group to assess the safety and toxicity of chemotherapy when combined with pelvic RT for these patients. METHODS AND MATERIALS: Eligibility requirements included a total abdominal hysterectomy and bilateral salpingo-oophorectomy with Grade 2 or 3 endometrial adenocarcinoma with >50% myometrial invasion, stromal invasion of the cervix, or pelvic-confined extrauterine disease. This study was designed to administer 4500 cGy in 25 fractions to the pelvis, along with cisplatin (50 mg/m(2)) on Days 1 and 28. Vaginal brachytherapy with a low-dose-rate applicator (1 x 20 Gy to the surface) or high-dose-rate applicator (3 x 6 Gy to the surface) was performed after external beam RT. Four courses of cisplatin (50 mg/m(2)) and paclitaxel (175 mg/m(2)) were given at 4-week intervals after RT completion. RESULTS: Forty-six patients were entered between October 1997 and April 1999. Two patients were ineligible (one with previous bladder cancer and one who had undergone surgery >8 weeks before the start of RT). Follow-up ranged from 6.9 to 48.8 months (median, 28.7 months). The disease was Stage III, II, and I in 66%, 16%, and 18% of patients, respectively. Two patients were not assessable because of incomplete treatment data. The protocol completion rate was 98% (41 of 42 assessable patients). Acute toxicity during RT/chemotherapy was Grade 1 in 27%, Grade 2 in 43%, Grade 3 in 27%, and Grade 4 in 2%. During adjuvant chemotherapy, the toxicity was Grade 1 in 7%, Grade 2 in 7%, Grade 3 in 21%, and Grade 4 in 62%. Severe toxicity was primarily hematologic. Chronic toxicity was Grade 1 in 20%, Grade 2 in 39%, Grade 3 in 16%, and Grade 4 in 2%, including 1 patient with a Grade 4 small bowel complication. At 24 months, the pelvic recurrence, regional recurrence, distant recurrence, disease-free survival, and overall survival rate was 2%, 3%, 17%, 83%, and 90%, respectively. CONCLUSION: This treatment protocol demonstrated an excellent treatment completion rate and expected toxicity. Longer follow-up is needed to assess the outcome. To assess the efficacy of this adjuvant treatment program, a Phase III trial (Radiation Therapy Oncology Group 9905) was designed with high-risk uterine-confined disease to be randomized between pelvic RT alone and pelvic RT with chemotherapy.     

Definitive radiotherapy for patients with isolated vaginal recurrence of endometrial carcinoma after hysterectomy

PURPOSE: To determine the outcome of patients after radical radiotherapy (RT) for isolated vaginal recurrence of endometrial carcinoma and to determine the clinical and pathologic predictors of outcome. METHODS AND MATERIALS: We reviewed the records of 91 patients treated at our institution between 1960 and 1997 with radical RT for vaginal recurrence after definitive surgery for endometrial carcinoma. Thirty-one percent of the patients received external beam RT (EBRT) alone, 12% received brachytherapy alone, and 57% received a combination. The median dose of radiation was 75 Gy (range 34-122). All end points were measured from the time of the first recurrence. The median duration of follow-up after recurrence was 58 months (range 1-289). RESULTS: The 2- and 5-year local control (LC) rate and overall survival rate was 82% and 75% and 69% and 43%, respectively. The median time from initial diagnosis of endometrial cancer to death from disease was 38 months. On univariate analysis, a dose to the relapse site of > or =80 Gy and EBRT plus brachytherapy vs. single-modality therapy were significant predictors of improved LC. On multivariate analysis, only the type of treatment correlated significantly with LC (p = 0.03). On univariate analysis, Grade 1 or 2 vs. Grade 3 tumor and EBRT plus brachytherapy vs. single-modality therapy were significant predictors of improved overall survival. CONCLUSION: RT provides excellent LC of isolated vaginal recurrences of endometrial carcinoma, particularly when high doses are given using a combination of EBRT and brachytherapy. However, distant metastases frequently develop despite local disease control, contributing to a 5-year overall survival rate of <50%. For patients who have an isolated vaginal recurrence, the time from initial diagnosis of endometrial cancer to death from disease is usually >3 years. For this reason, in studies of adjuvant RT, long-term follow-up is required to permit evaluation of the impact of treatment on survival.