Irradiation in carcinoma of the vulva: factors affecting outcome.

PURPOSE: This report reviews the increasing role of radiation therapy in the management of patients with histologically confirmed vulvar carcinoma, based on a retrospective analysis of 68 patients with primary disease (2 in situ and 66 invasive) and 18 patients with recurrent tumor treated with irradiation alone or combined with surgery. METHODS AND MATERIALS: Of the patients with primary tumors, 14 were treated with wide local excision plus irradiation, 19 received irradiation alone after biopsy, 24 were treated with radical vulvectomy followed by irradiation to the operative fields and inguinal-femoral/pelvic lymph nodes, and 11 received postoperative irradiation after partial or simple vulvectomy. The 18 patients with recurrent tumors were treated with irradiation alone. Indications and techniques of irradiation are discussed in detail. RESULTS: In patients treated with biopsy/local excision and irradiation, local tumor control was 92% to 100% in Stages T1-3N0, 40% in similar stages with N1-3, and 27% in recurrent tumors. In patients treated with partial/radical vulvectomy and irradiation, primary tumor control was 90% in patients with T1-3 tumors and any nodal stage, 33% in patients with any T stage and N3 lymph nodes, and 66% with recurrent tumors. The actuarial 5-year disease-free survival rates were 87% for T1N0, 62% for T2-3N0, 30% for T1-3N1 disease, and 11 % for patients with recurrent tumors; there were no long-term survivors with T4 or N2-3 tumors. Four of 18 patients (22%) treated for postvulvectomy recurrent disease remain disease-free after local tumor excision and irradiation. In patients with T1-2 tumors treated with biopsy/wide tumor excision and irradiation with doses under 50 Gy, local tumor control was 75% (3 of 4), in contrast to 100% (13 of 13) with 50.1 to 65 Gy. In patients with T3-4 tumors treated with local wide excision and irradiation, tumor control was 0% with doses below 50 Gy (3 patients) and 63% (7 of 11) with 50.1 to 65 Gy. In patients with T1-2 tumors treated with partial/radical vulvectomy and irradiation, local tumor control was 83% (14 of 17), regardless of dose level, and in T3-4 tumors, it was 62% (5 of 8) with 50 to 60 Gy and 80% (8 of 10) with doses higher than 60 Gy. The differences are not statistically significant. There was no significant dose response for tumor control in the inguinal-femoral lymph nodes; doses of 50 Gy were adequate for elective treatment of nonpalpable lymph nodes, and 60 to 70 Gy controlled tumor growth in 75% to 80% of patients with N2-3 nodes when administered postoperatively after partial or radical lymph node dissection. Significant treatment morbidity included one rectovaginal fistula, one case of proctitis, one rectal stricture, four bone/skin necroses, four vaginal necroses, and one groin abscess. CONCLUSIONS: Irradiation is playing a greater role in the management of patients with carcinoma of the vulva; combined with wide local tumor excision or used alone in T1-2 tumors, it is an alternative treatment to radical vulvectomy, with significantly less morbidity. Postradical vulvectomy irradiation in locally advanced tumors improves tumor control at the primary site and the regional lymphatics in comparison with reports of surgery alone.

Prospective phase I/II studies of definitive irradiation and chemotherapy for advanced gynecologic malignancies.

PURPOSE: This is a prospective study to evaluate toxicity and efficacy of concurrent irradiation and three cycles of chemotherapy bolus cisplatin and infusion 5-fluorouracil (5FU) in patients with advanced gynecologic malignancies. MATERIALS AND METHODS: Patients received cisplatin, 50 mg/m2 I.V. rapid infusion, and 5-day continuous infusion of 5FU (750 mg/m2 per day (schedule A); or cisplatin 75 mg/m2 i.v. rapid infusion, and 4-day continuous infusion of 5FU 1,000 mg/m2 per day (schedule B). Schedule A was given to 25 patients in the first 36 months of the study and was changed to schedule B in an additional 42 patients. All patients received irradiation, which usually consisted of 20 Gy whole pelvis, 30-40 Gy split field, and two intracavitary insertions for a total of 80-90 Gy to point A. Primary cervical cancer occurred in 40 patients with 3 having stage IB bulky, 2 with stage IIA, 5 with stage IIB, 2 with stage IIIA, 23 with stage IIIB, 4 with stage IV, and 1 with stage IVB. Recurrent cervical carcinoma after radical hysterectomy occurred in 18 patients. The remainder of the patients consisted of two each with stages III and IV endometrial carcinoma, two with stage III vaginal carcinoma, two with stage III vulvar carcinoma, and one with recurrent vulvar carcinoma. Patients were treated from 1985 through 1992. RESULTS: The 5-year overall survivals for patients with stages IB (bulky)-IIB cervical cancer was 70%, 25% for stages IIIA-IVA, and 39% for patients with recurrent cervical carcinoma. All four patients with endometrial carcinoma have recurred and died. Two patients with vulvar carcinoma are alive and free of disease, and one is dead of intercurrent disease. One patient with stage III vaginal carcinoma is alive and free of disease, while the other recurred and died. No significant differences were observed in the toxicity of the two chemotherapy schedules. There were 9/39 (23%) grade 4 and one fatal complication in those with primary cervical carcinoma. The overall fistulae rate was 11% (4/39) with three patients developing rectovaginal fistulae and one having vesicovaginal fistula. CONCLUSION: Concurrent chemotherapy and irradiation for advanced gynecologic malignancies as administered in this study is highly toxic and fails to demonstrate an obvious survival improvement.

Irradiation alone or combined with surgery in stage IB, IIA, and IIB carcinoma of uterine cervix: update of a nonrandomized comparison.

PURPOSE: Definitive radiation therapy alone or combined with surgery in carcinoma of the uterine cervix yields comparable tumor control and survival in Stages I and IIA when patients are adequately treated with either modality. Our 30-year institutional experience is described. METHODS AND MATERIALS: This is a nonrandomized comparison of treatment results of 415 patients with Stage IB, 137 with Stage IIA, and 340 with Stage IIB carcinoma of the uterine cervix treated with irradiation alone and 197 with Stage IB, 44 with Stage IIA, and 65 with limited Stage IIB treated with pre- or postoperative irradiation and surgery. Irradiation alone consisted of a combination of external beam therapy and intracavitary insertions to deliver doses of 70 to 85 Gy to point A for patients with Stages IB and IIA disease and 80 to 90 Gy for patients with bulky or Stage IIB tumors. For patients treated with irradiation and surgery, various combinations of external beam and intracavitary therapy were used to deliver 60 to 75 Gy to point A. Surgical procedures consisted of radical hysterectomy with or without lymph node dissection in 130 patients with Stage IB, 28 patients with Stage IIA, and 10 patients with limited Stage IIB. Fifty-seven patients had total abdominal or conservative hysterectomy with or without lymph node dissection, and 3 had vaginal hysterectomy. In addition, 51 patients with Stage IIB tumors underwent pelvic lymphadenectomy after definitive irradiation. RESULTS: The 5-year cause-specific survival (CSS) rates for patients with Stage IB nonbulky tumors treated with irradiation alone or irradiation combined with surgery were 90 and 85%, respectively, and the 10-year survival rate was 84% with either modality. In patients with bulky tumors (> 5 cm), the 5-year CSS rates were 61% with irradiation alone and 63% with irradiation plus surgery; at 10 years the rates were 61 and 68%, respectively (p = 0.5). For those with Stage IIA nonbulky tumors, the 5-year CSS rates were 75% with irradiation alone and 83% with combined irradiation and surgery, and 10-year CSS rates were 66 and 71%, respectively. In patients with Stage IIA bulky tumors, the 5-year CSS rates were 69% with irradiation alone and 60% with irradiation plus surgery, and at 10 years, 69 and 44%, respectively (p = 0.05). In patients with Stage IIB nonbulky tumors treated with irradiation alone or combined with surgery, the 5- and 10-year CCS rates were 72 and 65%, respectively; the corresponding survival rates with bulky tumors or bilateral parametrial involvement were 56 and 50%. Incidence of pelvic failures, alone or with distant metastasis, for Stage IB was 10% (43 out of 415) with irradiation alone and 14% (28 of 197) with irradiation plus surgery; for Stage IIA, 17% (23 out of 137) with irradiation alone and 20% (9 our of 44) with irradiation plus surgery; and for Stage IIB, 23% (88 out of 391) with irradiation alone and 29% (4 out of 14) with irradiation plus surgery. Grade 3 sequelae were comparable in both groups (irradiation alone, 5% to 11%; irradiation combined with surgery, 8% to 12%); the differences are not statistically significant. The most frequent major sequelae in 892 patients receiving irradiation only were rectovaginal fistula (13 cases, 1.5%), proctitis (10, 1.1%), small bowel obstruction (16, 1.8%), ureteral stricture (16, 1.8%), and vesicovaginal fistula (8, 0.9%). In 306 patients treated with irradiation plus surgery, the most commonly recorded major sequelae were small bowel obstruction/perforation (13 cases, 4.2%), ureteral stricture (8, 2.6%), vesicovaginal fistula (5, 1.6%), and rectovaginal fistula (4, 1.3%). CONCLUSION: Irradiation alone or combined with surgery yields comparable pelvic tumor control, survival, and morbidity in patients with Stage IB, IIA, and limited IIB carcinoma of the uterine cervix.

Brachytherapy-related complications for medically inoperable stage I endometrial carcinoma.

PURPOSE: The current study was conducted to investigate the incidence and risk factors for medical complications associated with low dose rate brachytherapy in patients with medically inoperable Stage I endometrial cancer treated with irradiation alone. METHODS AND MATERIALS: From 1965 through 1991 at Mallinckrodt Institute of Radiology, 150 implants were performed on 96 patients who were deemed medically unfit for hysterectomy because of advanced age, obesity, and various medical problems. The records of these patients were examined retrospectively to determine the incidence of medical complications that occurred in the first 30 days following the initiation of brachytherapy. The association of risk factors that precluded major surgery and the occurrence of brachytherapy-related complications was examined by logistic regression. RESULTS: Of these 96 patients, 40 patients were older than 75 years, and 31 patients were deemed morbidly obese. Medical problems included hypertension in 45 patients, and diabetes in 37; there was a history of congestive heart failure in 23, stroke in 11, myocardial infarction in 10, and thromboembolism in 8. There were concurrent malignancies in five patients. Implants were performed using intrauterine Simon-Heyman capsules, tandems, and vaginal ovoids in all patients. General anesthesia was used for 98 implants, spinal anesthesia for 26, local anesthesia for 25, and epidural anesthesia for 1. The duration of anesthesia ranged from 30 to 120 min (median, 60 min). The duration of radioisotope application ranged from 11 to 96 h (median, 46 h). Preventive measures included low dose subcutaneous heparin in 55 patients (since 1978), and intermittent pneumatic compression boots in 29 (since 1985). Four patients developed life-threatening complications including myocardial infarction (two patients), congestive heart failure (one patient), and pulmonary embolism (one patient). Two of these four patients died; one with a myocardial infarction and the other with pulmonary embolism. The morbidity rate was thus 4.2% (4 out of 96), and the mortality was 2.1% (2 out of 96). Although the four serious complications occurred within 30 days of the procedure, only one complication and one death occurred during treatment. There was no correlation between occurrence of complications and medical risk factors, type and duration of anesthesia, or type and duration of implant. CONCLUSIONS: There is a low incidence of complications associated with conventional low dose rate brachytherapy. The procedure is well tolerated in patients with medically inoperable Stage I endometrial cancer. In comparison to the predicted serious complication rate of surgery in these patients, the number of life-threatening complications from brachytherapy appears to be quite acceptable.

Radiation therapy in management of carcinoma of the vulva with emphasis on conservation therapy.

BACKGROUND: This report consists of a retrospective analysis of 50 patients with primary invasive and 17 with recurrent histologically confirmed vulvar carcinoma treated with radiation therapy for locoregional disease. METHODS: Of the patients with primary tumors, 13 were treated with wide local excision plus radiation therapy; 13 had radical vulvectomy followed by irradiation to the operative fields and inguinal-femoral/pelvic lymph nodes; 8 received similar postoperative radiation therapy after partial or simple vulvectomy; 16 patients had radiation therapy alone after biopsy; and 17 had recurrent tumors treated with radiation therapy alone. RESULTS: In patients treated with biopsy/local excision, local tumor control was 92-100% in T1-3N0 disease, 40% in similar stages with N1-3, and 27% in recurrent tumors. Among patients treated with partial/radical vulvectomy and radiation therapy, primary tumor control was 90% in those with T1-3 tumors and any nodal stage, 33% in those with any T stage and N3 lymph nodes, and 66% in patients with recurrent tumors. The actuarial 5-year disease-free survival rates were 87% for patients with T1N0 disease, 62% for those with T2-3N0 disease, 30% for those with T1-3N1 disease, and 11% for patients with recurrent tumors; there were no long-term survivors with T4 or N2-3 disease. Four of 17 patients treated for postvulvectomy recurrent disease remain disease-free after local tumor excision and radiation therapy. In patients with T1-2 tumors treated with biopsy/wide tumor excision and radiation therapy with doses less than 50 Gy, the local tumor control was 75% (three of four patients), in contrast to 100% (13 of 13 patients) with 50.01-65 Gy. With T3-4 tumors treated with local excision and radiation therapy, tumor control occurred in none of three patients with doses less than 50 Gy and 66% (six of nine) with 50.01-65 Gy. In patients with T1-2 tumors treated with partial/radical vulvectomy and radiation therapy, local tumor control was 75% (six of eight), regardless of dose level; in T3-4 tumors, it was 67% (four of six patients) with 50-60 Gy and 86% (six of seven) with 65-70 Gy. Differences were not statistically significant. There was no significant dose response for tumor control in the inguinal-femoral lymph nodes, with doses of 50 Gy being adequate for elective treatment of nonpalpable lymph nodes and 60-70 Gy controlling tumor growth in 75-80% of patients with N2-3 nodes when administered postoperatively, after partial or radical lymph node dissection. Significant treatment morbidity included one rectovaginal fistula, one case of proctitis, one rectal stricture, four bone/skin necroses, four vaginal necroses, and one groin abscess. CONCLUSIONS: Wide local tumor excision and radiation therapy or irradiation alone in T1-2 tumors is an alternative treatment to radical vulvectomy in controlling vulvar carcinoma, with significantly less morbidity. In comparison with reported rates for surgery alone, radiation therapy after radical vulvectomy for locally advanced tumors improves tumor control at the primary site and regional lymphatics. Indications and techniques of radiation therapy are discussed.

Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone.

The authors conducted a retrospective analysis of 1178 patients with histologically proven invasive carcinoma of the uterine cervix treated with irradiation alone. The minimum follow-up time was 3 years. The 10-year actuarial pelvic failure rate in Stage IB was 6% for tumors less than 3 cm, 15% for tumors 3 to 5 cm, and 30% for tumors more than 5 cm (P = 0.0018). The 10-year actuarial pelvic failure rate in Stage IIA was 10% for tumors less than 3 cm, 28% for tumors 3 to 5 cm, and 20% for tumors more than 5 cm (P = 0.09). Stage IIB unilateral nonbulky tumors (less than 5 cm) had a 20% pelvic failure rate compared with 28% for bilateral lesions and 35% for unilateral bulky tumors (more than 5 cm) (P = 0.35). In Stage IIB, pelvic failures were greater when disease extended into the lateral parametrium (30%) compared with medial parametrial involvement only (17%) (P = 0.01). In Stage III unilateral nonbulky tumors, the pelvic failure rate was 28% compared with 45% to 50% for unilateral bulky lesions (P = 0.002). Bilateral parametrial disease in Stage IIB did not increase the pelvic failure rate (21% in both subgroups) (P = 0.83), whereas in Stage III, bilateral parametrial involvement was associated with a 48% pelvic failure rate versus 28% for unilateral extension (P less than or equal to 0.01). Five-year disease-free survival (DFS) rates for IB tumors less than or equal to 3 cm was 90% versus 67% for tumors more than 3 cm (P = 0.01). In Stage IIA tumors less than or equal to 3 cm, 5-year DFS was 70% versus 45% for tumors more than 3 cm. Patients with Stage IIB nonbulky tumors (less than or equal to 5 cm in diameter) had better 10-year DFS (65% to 70%) compared with those with bilateral bulky tumors (45% to 55%) (P = 0.10). Stage III patients with unilateral nonbulky tumors had a 55% 10-year DFS compared with 35% to 40% for bulky tumors or bilateral parametrial involvement (P = 0.002). The authors concluded that clinical stage and size of tumor are critical factors in the prognosis, therapy selection, and evaluation of results in carcinoma of the uterine cervix.

Clinical stage I endometrial cancer: prognostic factors for local control and distant metastasis and implications of the new FIGO surgical staging system.

A retrospective analysis is reported in 858 patients with clinical Stage I carcinoma of the endometrium treated definitively with combined irradiation and total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) from January 1960 through December 1986. Most patients received a preoperative intracavitary insertion (3500-4000 mgh to the uterus and a 6500 cGy surface dose to the upper vagina) followed by a TAH-BSO within 1-2 weeks. Some patients received postoperative external beam irradiation (2000 cGy whole pelvis and an additional 3000 cGy to the parametria, with a midline stepwedge) when factors such as deep myometrial invasion were present. Occasionally patients were treated with a preoperative intracavitary insertion and preoperative external beam irradiation (2000 cGy whole pelvis). The 5-year progression-free survivals by FIGO (1988) surgical stage were 93% for IA, 90% for IB, and 91% for Stage IC. An analysis of multiple variables was performed to ascertain their prognostic significance. Factors that significantly affected the 5-year progression-free survivals by univariate analysis were grade (grade 1 = 95%, grade 2 = 88%, grade 3 = 73%; p less than 0.0001), histology (adenoacanthoma = 96%, clear cell = 89%, adenocarcinoma = 89%, papillary = 81%, adenosquamous = 80%; p = 0.04), lower uterine segment involvement (uninvolved = 89%, involved = 73%; p = 0.006), depth of myometrial invasion (no residual tumor = 91%, limited to the endometrium = 96%, less than 1/3 myometrial penetration = 92%, 1/3 - 2/3 = 100%, greater than 2/3 = 50%; p = 0.02), peritoneal cytology (negative = 92%, positive = 56%, p less than 0.0001), uterine serosal involvement (uninvolved = 89%, involved = 55%; p less than 0.0001), vascular space invasion (absent = 89%, present = 75%; p = 0.001), and the presence of extrauterine disease (absent = 90%, present = 64%; p less than 0.0001). A multivariate analysis of these prognostic variables showed that histological grade (p = 0.001), peritoneal cytology (p = 0.004), and uterine serosal involvement were prognostic for local failure and that peritoneal cytology (p less than 0.001), grade (p = 0.001), age (p = 0.002), and extrauterine disease (p = 0.02) were prognostic for the development of distant metastasis.

Impact of dose in outcome of irradiation alone in carcinoma of the uterine cervix: analysis of two different methods.

This is a retrospective analysis of 1211 patients with histologically proven invasive carcinoma of the uterine cervix with a minimum follow-up of 3 years treated with irradiation alone. The pelvic failure rates by stage were 9.6% for IB, 18.6% for IIA, 23% for IIB, 41% for III, and 75% for Stage IVA disease. External beam and intracavitary irradiation doses to point A and pelvic lymph nodes were calculated. In patients with Stage IB and IIA disease there was no significant correlation between doses to these points and pelvic tumor control. In Stage IIB doses of less than 6000 cGy to point A correlated with a high pelvic failure rate (8 of 12, 66.7%) in contrast to doses of 6000 to 9000 cGy (61 of 261, 23.4%) or higher than 9000 cGy (10 of 74, 13.5%) (p less than or equal to 0.01). In Stage III the pelvic failure rate with doses below 6000 cGy to point A was 72% (18 of 25) compared to 39% (71 of 180) for 6000 to 9000 cGy or 35% (27 of 77) with doses above 9000 cGy (p less than or equal to 0.01). TDF calculation of doses was carried out. In Stage IB and IIA there was no significant correlation between TDF to point A and probability of pelvic recurrence. In Stage IIB with TDF below 135, the pelvic recurrence rate was 41.6% (20 of 48) compared to 20% (61 of 305) with higher TDF (p less than or equal to 0.01). In Stage III the pelvic failure rate was 51% with TDF below 160 (70 of 136) in comparison with 29.5% (46 of 156) with higher TDF (p less than or equal to 0.01). Grade 2 sequelae of therapy were noted in about 10% of the patients and grade 3 in 4.7% of patients with Stage IB (18 of 384), 10.2% (12 of 128) with Stage IIA, 9.3% (33 of 353) with Stage IIB, and 8.2% (24 of 293) with Stage III disease. Doses from external beam and intracavitary irradiation to the rectum or the bladder neck were calculated. The actuarial incidence of major rectal or rectosigmoid sequelae was 2% to 4% with doses to the rectum of 6000 to 8000 cGy, 7% to 8% with 8000 to 9500 cGy, and 13% with doses higher than 9500 cGy (p less than or equal to 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical stage I endometrial cancer: results of adjuvant irradiation and patterns of failure.

A retrospective analysis is reported in 858 patients with clinical Stage I carcinoma of the endometrium treated definitively from January 1960 through December 1986 with combined irradiation and total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO). Most patients received a preoperative intracavitary insertion (2500-4000 mgh to the uterus with Heyman capsules and tandem and 6500 cGy surface dose to the upper vagina) followed by a TAH-BSO within 6 weeks. Some patients received postoperative external beam irradiation (2000 cGy whole pelvis and an additional 3000 cGy to the parametria, with a midline stepwedge) when deep myometrial invasion was present. Occasionally patients were treated with preoperative external beam irradiation (2000 cGy whole pelvis) and intracavitary insertion. The 5-year overall survival for all patients was 84.0% compared to an expected survival of 88.8%. The 5-year progression-free survivals were 92% for FIGO clinical Stage IA and 86% for stage IB (p = 0.12). The dose to the uterine fundus from the preoperative intracavitary insertion was found to have a significant correlation with progression-free survival in patients with grade 3 tumors. Those receiving less than 2500 mgh to the uterine cavity had a 48.9% 5-year progression-free survival compared to 62.7% for 2500-3500 mgh and 87.4% for those receiving greater than 3500 mgh. Analysis of sites of failure showed that less than 1% (7/858) failed in the pelvis alone, 3% (30/858) in the pelvis combined with distant sites, and 7% (60/858) developed distant metastasis only. The lateral pelvic sidewall was the most common site of failure within the pelvis (20/37) and intraperitoneal failures (28/90) and lung (21/90) were the most common sites of distant metastasis. The overall severe (grades 2, 3, and 4) complication rate was 2.7% (23/858).

Phase I/II study of definitive radiotherapy and chemotherapy (cisplatin and 5-fluorouracil) for advanced or recurrent gynecologic malignancies. Preliminary report.

Twenty-three patients with advanced gynecologic malignancy were treated with definitive irradiation and synchronous sensitizing chemotherapy (CT) consisting of cisplatin (CDDP), 50 mg/m2 i.v. rapid infusion, and a 5-day continuous infusion of 5-fluorouracil (5-FU), 750 mg/m2/day. A total of three cycles were administered every 3-4 weeks. Fifteen patients had primary cervical epidermoid carcinoma (three bulky stage IIB, one stage IIIA, ten stage IIIB, one stage IV), four had pelvic recurrences of carcinoma of the cervix, two had endometrial adenocarcinomas (stage IV), and two had vulvar epidermoid carcinoma (one stage III and one stage IV). Radiotherapy (RT) for implantable tumors consisted of 2,000 cGy whole pelvis, 3,000-4,000 cGy split field, and two intracavitary or interstitial insertions, resulting in a total dose of 7,500-8,000 cGy to point A. Three courses of CT were delivered simultaneously with irradiation of the central bulk of tumor: during the first week of whole pelvis RT and with each of the two brachytherapy procedures. Nonimplantable tumors were treated with protracted external beam RT (5,500 cGy tumor dose) and three courses of CT during weeks 1, 4, and 7 of RT. Twenty-one of 23 patients completed RT and 18 of 23 patients completed CT as planned, but half had delays in either RT or CT. Grade 2 or 3 late sequelae consisted of leg edema (one patient), proctosigmoiditis (one patient), bowel obstruction (one patient), vesicovaginal fistula (one patient), and pulmonary embolus (two--one fatal). The incidence of grade 2 and 3 sequelae were 18 and 22%, respectively. With 1-3 years of follow-up evaluation, 12 of 23 (52%) patients are free of disease, and 9 of 22 evaluable patients (41%) have had failure within the pelvis. We conclude that high-dose definitive RT can be delivered with synchronous CDDP and 5-FU at the doses given, with acceptable toxicity. Further study is required to evaluate the impact of radiosensitization on tumor control and late morbidity of therapy. Optimization of irradiation and drug doses as well as the best schedules that may enhance the interaction of these two modalities should be further investigated.

Outcome of recurrent cervical carcinoma following definitive irradiation.

This report is a retrospective analysis of 376 patients with recurrent cervical carcinoma, following definitive radiation therapy to 1054 patients with stage IB-IVA carcinoma of the uterine cervix treated at the Radiation Oncology Center, Mallinckrodt Institute of Radiology, from January 1959 through December 1982. The sites of failure after treatment by stage at initial diagnosis were classified as pelvic only (P), pelvic plus distant metastasis (P + DM), or distant metastasis only (DM). The sites of first failure were for stage IB, P = 0.8%, P + DM = 7.4%, DM = 7.9%; for stage IIA, P = 1.7%, P + DM = 14.7%, DM = 17.2%; for stage IIB, P = 10.4%, P + DM = 11.0%, DM = 14.9%; for stage III, P = 15.4%, P + DM = 23.9%, DM = 18.9%; and for stage IV, P = 16.7%, P + DM = 61.1%, DM = 16.7%. The actuarial probability of pelvic failure at 5 years from initial therapy was 8% for stage IB, 16% for stage IIA, 21% for stage IIB, 42% for stage III, and 100% for stage IV. The incidence of distant metastasis at 5 years was 14, 32, 28, 47, and 100% for stages IB, IIA, IIB, III, and IV, respectively. The therapy after failure was surgery, irradiation, irradiation plus surgery, or chemotherapy. There appeared to be no major difference in survival after recurrence by type of treatment or initial stage. The overall survival at 5 years for all untreated patients was 1%. The median survival was evaluated as a function of time to failure after initial treatment. Patients who developed disease more than 36 months after initial treatment had a median survival of 22.5 months. The median survival was 12.1, 7.6, 9.4, and 9.1 months for those failing less than 6, 6-12, 13-24, and 25-36 months after initial treatment. Severe treatment complications occurred in 3.6% (5/140).

Definitive irradiation in carcinoma of the vagina: long-term evaluation of results.

A retrospective analysis of 165 patients with histologically confirmed carcinoma of the vagina is reported. Actuarial disease-free 10-year survival was: Stage 0 (16 patients)--94%, Stage I (50 patients)--75%, Stage IIA (49 patients)--55%, Stage IIB (26 patients)--43%, Stage III (16 patients)--32%, Stage IV (8 patients)--0%. All but one of the in situ lesions were controlled with intracavitary therapy. Of the patients with Stage I disease, 86% showed no evidence of vaginal or pelvic recurrence. Most of them received interstitial or intracavitary therapy or both; the addition of external beam irradiation did not significantly increase survival or tumor control. In Stage IIA (paravaginal extension) 61% of the tumors were controlled with a combination of brachytherapy and external beam irradiation. Ten of 16 Stage III tumors were controlled in the pelvis. Two of the patients with Stage IV disease had no recurrence in the pelvis with relatively high doses of irradiation. The total incidence of distant metastases was 16% in Stage I, 30.6% in Stage IIA, 46.1% in Stage IIB, 62% in Stage III, and 50% in Stage IV. The dose of irradiation delivered to the primary tumor or the parametrial extension was critical in achieving successful results. The incidence of grade 2-3 complications (12%) is correlated with the stage of the tumor and type of treatment given. More effective irradiation techniques including the optimization of dose distribution by judicious combination of external irradiation and interstitial brachytherapy will be necessary to enhance loco-regional tumor control. The high incidence of distant metastases underscores the need for earlier diagnosis and effective systemic cytotoxic agents if survival is to be significantly improved in these patients.

Therapy of ovarian carcinoma: the relationship of dose level and treatment intensity to survival.

Following primary maximal cytoreduction, 71 previously untreated patients with advanced epithelial ovarian carcinoma received at least six courses of combination chemotherapy consisting of cisplatin, doxorubicin, and cyclophosphamide. The cumulative dose (CD) through three (CD3) and six (CD6) courses was calculated for each drug and for all drugs combined. The dose intensity (DI) through three (DI3) and six (DI6) courses was calculated for each drug by dividing CD3 and CD6 by the interval (in weeks) between surgery and the third and sixth course. The interval from surgery to the third or sixth course had no effect on survival. Similarly, there was no significant difference in survival between patients with high and low CD3 or CD6 for any drug or for all drugs combined. Patients with high DI6 for cisplatin, doxorubicin, and all drugs combined survived significantly longer than those with low DI6. The survival difference for patients with high and low DI6 for cyclophosphamide approached, but did not attain, statistical significance at the 0.05 level. The intensity with which combination chemotherapy is administered may have an impact upon survival in patients with ovarian carcinoma.

Adenocarcinoma of the uterine cervix: lack of evidence for a poor prognosis.

A retrospective analysis was performed to evaluate the prognostic significance of histologic type (epidermoid carcinoma versus adenocarcinoma) on local control of disease and on the development of distant metastatic disease in 1239 patients with carcinoma of the uterine cervix treated with radiation therapy alone or surgery and irradiation at the Radiation Oncology Center, Mallinckrodt Institute of Radiology (MIR), Washington University Medical Center, between 1959 and 1982. The 5-year disease-free survival (all stages combined) was 68.0% for 925 patients with epidermoid carcinoma compared to 64.9% for 79 patients with adenocarcinoma treated with irradiation alone (p = 0.34). There was no significant difference in the survival rate when epidermoid carcinoma and adenocarcinoma were compared after stratification by clinical stage except for stage III. The 5-year disease-free survival (all stages combined) was 73.4% for 213 patients with epidermoid carcinoma and 77.0% for 22 patients with adenocarcinoma treated with irradiation plus surgery (p= 0.74). Prognostic variables analyzed by multivariate analysis included age at diagnosis, histology, size of lesion, endometrial extension, lymph node status (as evaluated by lymphangiogram), dose to point A, and surgery. Prognostic variables that were significant (p less than 0.05) for the development of recurrent disease in the pelvis were size of the primary lesion and dose of irradiation to point A. Significant (p less than 0.05) factors for the development of distant metastatic disease were size of the primary lesion and metastatic lymph nodes at the time of diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiation therapy and conservation surgery for primary and recurrent carcinoma of the vulva: report of 40 patients and a review of the literature.

Forty patients with histologically confirmed primary or recurrent vulvar carcinoma were treated with radiation therapy for loco-regional disease. Nineteen of the patients with primary tumors received postoperative radiotherapy (5000 cGy in 6 weeks). Fifteen of the 19 exhibited local tumor control. Five patients with Stage III or IV disease were managed with radiotherapy alone. Four had a complete response with two currently NED. Two patients who received preoperative radiotherapy with local excision are also currently free of disease. The 4-year NED survival for the study population is 100%, 28%, 50%, 0% and 10% for Stage I, II, III, IV and recurrent tumors respectively. The poor results obtained in Stage II tumors is likely due to selection criteria since four of seven patients developed distant metastases. Two of the 14 patients treated for recurrent disease remain NED after local excision of their tumors prior to irradiation. Even though the number of patients is small no dose response for subclinical disease could be found between 4500 and 7000 cGy. Treatment morbidity was acceptable with two patients developing severe long-term complications requiring surgical intervention.

Analysis of pelvic tumor control and impact on survival in carcinoma of the uterine cervix treated with radiation therapy alone.

A total of 1054 patients with histologically confirmed invasive carcinoma of the uterine cervix were treated with radiation therapy alone between 1959 and 1982. All patients are available for a minimum of 3 years follow-up. Radiation therapy consisted of external irradiation to the whole pelvis (1000-2000 cGy) and parametria (for a total of 4000-6000 cGy) combined with two intracavitary radioactive source insertions (6000-7500 cGy to point A). Patients with Stage IIB, III, and IVA have been consistently treated with somewhat higher doses of external irradiation and intracavitary insertions. A small group of 54 patients with Stage IIB or IIIB had pelvic lymphadenectomy following the irradiation (1960-1964). There was a strong correlation between the tumor regression within 30 days from completion of radiotherapy and the incidence of pelvic recurrences or distant metastases for each of the anatomical stages. The 10-year survival rate for Stage IB was 76%, Stage IIA 60%, Stage IIB 45%, and Stage III 25%. Many of the deaths were due to intercurrent disease. Thus, the 10-year tumor-free survival was 80% for Stage IB, 60% for Stages IIA and IIB and 35% for Stage III. In Stage IB total doses of 6000 cGy or higher to point A resulted in 94% pelvic tumor control. In Stage IIA, the pelvic tumor control was 87% with doses of 6000 cGy to point A or higher. However, in Stage IIB the pelvic tumor control was 58% with doses below 6000 cGy, 78% with 6001-7500 cGy and 82% with higher doses. In Stage IIIB the pelvic tumor control was 42% with doses below 6000 cGy, 57% with 6001-7500 cGy and 68% with higher doses. Tumor control in the pelvis was correlated with the following 5 year survivals: Stage IB-95% (353 patients); Stage IIA-84% (116 patients); Stage IIB-84% (308 patients); Stage IIIB-74% (245 patients). The 5-year survival for patients that recurred in the pelvis was 30% for Stage IB, about 15% for Stages IIA-B and only 5% in Stage III. Patients with tumor control in the pelvis had a significantly lower incidence of distant metastases than patients who initially failed in the pelvis (9.3% vs. 58.6% in Stage IB, 21.6% vs 52.6% in Stage IIA, 19.8% vs 16.7% in Stage IIB, and 31.2% vs 50% in Stage III). In Stage IIB the figures were 19.8% and 16.7% because the initial pelvic recurrence was frequently concurrent with distant metastases.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum copper in ovarian carcinoma.

The serum copper and CA 125 levels of 31 patients with epithelial ovarian carcinoma were determined. Serum copper was elevated in seven patients and CA 125 was elevated in 22 patients. A rise in serum CA 125 always was associated with disease progression. In comparison, serum copper fluctuation did not correlate with the natural history of the malignancy. We concluded that serum copper determination has no use in epithelial ovarian carcinoma management.

Results of therapy, analysis of failures, and prognostic factors for clinical and pathologic stage III adenocarcinoma of the endometrium.

A retrospective analysis was performed on 427 patients with clinical stage I, II, and III adenocarcinoma of the endometrium treated definitively with total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) and pre- or postoperative irradiation at our institution from January 1960 through December 1981. Of 310 patients with clinical stage I, 21 (6.8%) and 9 of 90 (10%) clinical stage II patients were found to have pathologic stage III (CS I-II/PS III) tumors. In addition, 27 patients had clinical stage III (CS III) tumors at the time of diagnosis. At 5 years the overall and disease-free survival for all patients with clinical and/or pathologic stage III disease was 43.5 and 46.2%, respectively. The 5-year disease-free survival for CS I/PS III was 67.3% compared to 32.6% for CS II/PS III and 33.4% for CS III. Failure to control the disease in the pelvis occurred in 14.3% of the CS I/PS III patients and in 44.4 and 33.3% of the CS II/PS III and CS III patients, respectively. The appearance of distant metastasis was higher with increasing stage (19.1% for CS I/PS III, 33.3% for CS II/PS III, and 48.1% for CS III). Eighty percent of all failures occurred within 40 months. Grade of the tumor was associated with increasing pathologic stage but not with ability to control the disease in the pelvis. However, there was a tendency for higher grade lesions to fail more often at distant sites.

Medically inoperable stage I adenocarcinoma of the endometrium treated with radiotherapy alone.

Definitive therapy for Stage I adenocarcinoma of the endometrium consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pre- and/or post-operative radiotherapy (RT) is employed in selected patients with poor prognostic factors such as poorly differentiated tumors or deep myometrial invasion by tumor. The results are reported of RT alone in 69 patients with Stage I adenocarcinoma of the endometrium who presented with severe, acute, and chronic medical illnesses which prevented surgical management of their disease. Sixty-three patients (91.3%) were obese or hypertensive. Twenty-seven patients (39.1%) had diabetes mellitus, 16 (23.2%) had congestive heart failure, and the remaining patients had such conditions as stroke (17.4%), coronary artery disease (15.9%), and recent myocardial infarction (13.0%). The median age for this group of patients was 72.0 years compared to 60.0 years for a concurrent group of 304 patients with Stage I adenocarcinoma of the endometrium treated at our institution with combined surgery and RT. RT consisted of intracavitary insertions alone (11 patients), intracavitary plus low dose external beam therapy (9 patients), and intracavitary therapy plus high dose external beam therapy (49 patients, definitive RT). Younger patients and those with poorly differentiated disease were treated more aggressively. The 5- and 10-year overall survival for all patients was 76.8 and 33.3%, respectively. The 5- and 10-year disease-free survival was 88.1 and 82.4%, respectively. The 5-year overall and disease-free survival for the group of 49 patients treated with definitive RT was 85.4% and 88.7% with 15/49 (30.6%) having poorly differentiated tumors. For the definitive therapy group, the 5- and 10-year disease-free survival was 94.3, 92.3, and 78.0% for grades I, II, and III, respectively. Analysis of patterns of failure showed that none of the patients failed in the pelvis alone. Two out of 11 (18.2%) receiving intracavitary therapy alone and 3/49 (6.1%) receiving definitive RT failed in the pelvis with simultaneous distant metastasis (DM). Three patients in the definitive RT group failed with DM only. Severe complications occurred in 8 patients (16%), all of whom received definitive RT.

Carcinoma of the fallopian tube. Management and sites of failure.

Thirty patients with adenocarcinoma of the fallopian tube, treated between 1950 and 1981, were studied. Median age was 55 years, and mean parity was 1.3. Bleeding or discharge occurred as a presenting complaint in 47% of patients, abdominal distention or mass in 50%, and pain in 30%. Lesions were staged using a system analogous to the International Federation of Gynecology and Obstetrics (FIGO) classification for ovarian carcinoma. Nine patients had Stage I disease; 11, Stage II; 7, Stage III; and 3, Stage IV. Histologic differentiation was Grade 1 in 39% of the patients, Grade 2 in 18%, and Grade 3 in 43%. Primary surgical treatment consisted of total abdominal hysterectomy and bilateral salpingectomy in 70% of the patients; 23% had more extensive surgery, whereas 13% had less extensive surgery. Three patients with Stage I tumors were treated with surgery alone, and the remainder received postoperative radiation, chemotherapy, or both. Survival was unrelated to grade, but highly dependent upon stage. Survival at 5 years was 56% for Stage I, 27% for Stage II, 14% for Stage III, and 0% for Stage IV. Four of five patients treated after surgery with a combination of cisplatin, doxorubicin, and cyclophosphamide (PAC) survived at least 3 years. Patterns of initial treatment failure showed 56% with a component of pelvic failure, 50% with a component of upper abdominal failure, and 44% with extraperitoneal metastases as a component of failure. These results suggest the need for aggressive postoperative adjuvant therapy targeted at upper abdominal and distant sites for metastasis in all lesions beyond Stage I.