C. Haie

Overall treatment time in advanced cervical carcinomas : a critical parameter in treatment outcome

PURPOSE To search for possible influence of overall treatment time on the clinical outcome of advanced cervical carcinomas treated with radiation alone. METHODS AND MATERIALS Three hundred and eighty-six patients with Stage IIB and III cervical carcinomas treated with external radiation and intracavitary curietherapy between 1973 and 1983 were entered in the study. A multivariate analysis was carried out on data concerning these patients to determine whether overall treatment time was a prognostic factor. RESULTS Overall treatment time and blood transfusions during treatment were the two most highly significant factors in the multivariate analysis. Loss of local control and overall survival, when treatment exceeded 52 days, was approximately 1% per day in both cases. CONCLUSION These results suggest that overall treatment time might be a highly significant prognostic factor in the treatment outcome of advanced cervical carcinomas. Prospective randomized studies are strongly warranted to confirm this hypothesis.

Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of the cervix treated by radiation therapy results of a retrospective study of 386 patients

A retrospective study was carried out on 386 patients with advanced cervical carcinomas treated with radiation therapy between 1973 and 1983. The influence of hemoglobin concentrations and blood transfusions before and/or during treatment on the occurrence of distant and/or local regional failures were examined in a univariate and multivariate analyses. In the multivariate analysis hemoglobin concentrations were prognostic only during treatment and patients with at least one value below the threshold of 10 gm% had a significantly higher risk of local regional failure than the patients with all their values above the threshold. Moreover 70% of these high risk patients had less than half of their values below the threshold. It is possible that blood transfusions might be beneficial when given before treatment. However, although it was not significant, blood transfusions given during treatment tended to be an adverse prognostic factor suggesting that blood transfusions might not have completely offset acute anemia prior to transfusion. Our study suggests that anemia during treatment, even of short duration might be detrimental to patients.

Combined radiotherapy and surgery: local control and complications in early carcinoma of the uterine cervix — the Villejuif experience, 1975–1984

From January 1975 to December 1984, 441 patients were treated by combined radiotherapy and surgery at the Institut Gustave Roussy (IGR) for Stage IB (288) and II (proximal) (103) carcinoma of the uterine cervix. Standard treatment consisted of pre-operative utero-vaginal brachytherapy (60 Gy) using a mould technique followed by a colpo-hysterectomy and external iliac lymphadenectomy. Overall 5 year actuarial survival for the whole population was 87% and disease-free survival 85%. Loco-regional relapse occurred in 23 patients (5%). Of these, 12 were central pelvic failures, 8 regional failures and 3 combined central and regional failures. There were 36 systemic relapses (8%) of which 12 relapsed concurrently in the pelvis. Five year actuarial pelvic disease-free, disease-free and overall survival was 87, 85 and 87%, respectively, for the whole population. 340 patients developed one or more complications [Grade 1: 198/441 (44%), Grade 2: 121/441 (27%) and Grade 3 or 4: 21/441 (4.7%)]. Five year actuarial survival for the whole population was poorer for histologically node positive than for node negative (89 vs. 55%, p less than 0.0001). Pre-operative brachytherapy followed by surgery can provide good local control with acceptable morbidity in early cervical cancer.

Twenty years experience of interstitial iridium brachytherapy in the management of soft tissue sarcomas

From February 1968 to February 1988, 50 patients above 10 years of age with a soft tissue sarcoma were treated with interstitial brachytherapy, combined with a wide excision. After pathologic review, 48 were included in the final analysis. A pathological grading was made possible in 41, which showed a majority of high grades (2 + 3 = 86%). Patients presented mainly with small (less than 5 cm: 36) or mid-size lesions (greater than 5 cm: 12). The tumor was located in the limbs (32), trunk (9), and head and neck (7). Four patients had metastases at the time of treatment. Brachytherapy was part of the initial treatment in 22 cases, and of a salvage procedure after previous excision(s) combined or not with another form of treatment in 26. A uniform technique of iridium 192 wires after-loaded in plastic tubing was used. Sixty Gy median doses were delivered with brachytherapy alone (44) or combined with external beam (4). Sixteen patients also received an adjuvant chemotherapy. Follow up ranged from 16 months to 20 years (median 82 months). At the time of analysis, two patients (4%) only had failed in the irradiated volume, but the marginal failures rate (14:31%) was unexpectedly high. Seven of the patients who failed (43%) were salvaged by a second similar procedure. The 5-year survival was 62% in non-previously treated patients and 56.5% in previously treated ones (pNS). By multivariate analysis, only the tumor location appeared predictive of LF (p less than 0.01), which in turn was strongly correlated with the metastatic outcome (p less than 0.01). Necroses were observed in 17 cases (35%) and associated with a benign course in most of them. High dose brachytherapy combined with conservative surgery is highly effective in small and mid-size soft tissue sarcomas located in the extremities and head and neck, whereas in trunk and in recurrent tumors, the adjunction of large fields external radiotherapy and/or possibly polychemotherapy appears necessary.

External irradiation plus curietherapy boost in 108 base of tongue carcinomas

From 1960 to 1983, 108 patients underwent an association cobaltherapy plus curietherapy boost for a base of tongue carcinoma. This group included 18 T1 tumors, 39 T2, and 51 T3. Cobaltherapy was delivered to a dose of 45 Gy/4.5 weeks to the primary site and the neck. It was completed by an electron boost or a nodal surgery in case of initial nodal disease. Two techniques of Curietherapy were used: plastic tubes and guide-gutters. As most of these implants have been done before 1975, all the doses have been recalculated on the 85% isodose according to the Paris system. They varied from 22 to 88 Gy. The tolerance of the implantation was excellent. Five-year survival of the whole group is 26%. The local control rate is 85% for T1 tumors, 50% for T2, and 69% for T3. Despite the importance of cumulated doses, a few necrosis were observed. Considering the poor outlook of this cancer, its treatment by exclusive radiotherapy requires very high doses which can only be delivered without major sequellae or complication by a combination of cobaltherapy and curietherapy boost.

Interstitial and external radiotherapy in carcinoma of the soft palate and uvula

Forty-three patients, all male, with limited epidermoid carcinoma of the soft palate and uvula were treated by interstitial implant usually associated with external radiotherapy. Most patients received 50 Gy external irradiation to the oropharynx and neck followed by 20-35 Gy by interstitial iridium-192 wires using either guide gutters or a plastic tube technique. Twelve primary tumors and two recurrences after external irradiation alone had implant only for 65-75 Gy. Total actuarial local control is 92% with no local failures in 34 T1 primary tumors. Only one serious complication was seen. Overall actuarial survival was 60% at 3 years and 37% at 5 years but cause-specific survivals were 81% and 64%. The leading cause of death was other aerodigestive cancer, with an actuarial rate of occurrence of 10% per year after treatment of a soft palate cancer. Interstitital brachytherapy alone or combined with external irradiation is safe, effective management for early carcinoma of the soft palate and uvula but second malignancy is a serious problem.

Results of radiation treatment of medulloblastoma in adults

From 1961 to 1982, 20 adults (greater than 16 years of age) were treated with radiation therapy following surgery for medulloblastoma. All patients received neuro-axis irradiation. Five patients received adjuvant chemotherapy. A 5- and 10-year survival rate of 78 and 55%, respectively, were achieved. Treatment failures were mainly a result of local recurrences, but also of metastases. One patient died of acute myeloid leukemia. One patient developed paraplegia. The survival rate was better in males (2 deaths out of 14) than in females (5 deaths out of 6). All the survivors are free of deficit or sequelae, except the patient with paraplegia.

Conservative treatment for lower gynecological tract malignancies in childrin and adolescents: The Institut Gustave-Roussy experience☆

Between 1972 and 1986, 37 patients with lower genital tract malignancies were treated with intracavitary or interstitial brachytherapy. Thirteen patients presented with clear cell adenocarcinoma, 14 patients with embryonal rhabdomyosarcoma, 6 patients with endodermal sinus tumor, 3 patients with sarcoma, and 1 patient with an undifferentiated tumor. FIGO classification was: Stage I, 16%; Stage II, 47%; and Stage III, 37%. Treatment policy included initial exploratory laparotomy with lymph node biopsy and ovarian transposition, chemotherapy (except in clear cell adenocarcinoma) and/or external radiotherapy prior to interstitial brachytherapy. Chemotherapy consisted of a combination of VAC-Ad (V = vincristine, A = D actinomycin, C = cyclophosphamide, Ad = adriamycin) in rhabdomyosarcoma and sarcomas, and MAC-Ad (M = methotrexate) in endodermal sinus tumor. External radiotherapy was used in seven patients: in one to reduce a bulky clear cell adenocarcinoma (20 Gy) and in six for pelvic nodal involvement (45 Gy). Brachytherapy techniques depended on tumor site and extent, and on the anatomy of the patients. Vulvar tumors were implanted with iridium-192 wires by an afterloading plastic tube technique. Cervical and vaginal tumors were treated with individually tailored moulded vaginal applicators loaded with either cesium-137 or iridium-192, with or without interstitial implants by plastic tube or guide gutter technique. Computerized dosimetry allowed calculation of treatment volumes and doses delivered on the tumor and adjacent critical organs. The prescribed dose (including external radiotherapy) was 60-75 Gy with 1-3 brachytherapy applications of a low dose rate (0.2 Gy/hr). Six patients are dead: one from chemotherapy complication, three of metastases (two sarcomas, one endodermal sinus tumor) and two of pelvic failures and metastases (two clear cell adenocarcinoma). The overall disease free 5-year survival is 72%. Actuarial 5-year local control is 84%, but including salvage is 94%: three (two rhabdomyosarcoma, one clear cell adenocarcinoma) of the five local failures were salvaged by surgery, chemotherapy and/or brachytherapy. Metastases occurred in six patients, one (sarcoma) salvaged by chemotherapy and external radiotherapy. Complications requiring surgery occurred in five patients: two hydronephroses, one urethral stricture, one ileo-cecal obstruction, and one vesicovaginal fistula. Twelve of the 17 patients (71%) over 12 years of age are normally menstruating. Two patients have produced three normal children. This multidisciplinary management of lower gynecological tract tumors including brachytherapy is both conservative and effective.

Whole abdominal irradiation following chemotherapy in patients with minimal residual disease after second look surgery in ovarian carcinoma

From January 1981 through December 1985, 65 patients with epithelial carcinoma of the ovary were treated with the following protocol: surgery, combination chemotherapy, second-look surgery documenting tumor less than or equal to 2 cm, and whole abdominal irradiation. Chemotherapy consisted of a combination of cyclophosphamide, adriamycin, and cisplatinum in 89% of the patients. The median number of cycles was eleven. Second-look surgery documented no residual tumor in 23 patients, microscopic disease in three patients, and macroscopic disease less than or equal to 2 cm in 39 patients. Whole abdominal irradiation was given with an open field technique up to 20 Gy without renal or hepatic shield. A pelvic boost of 15-30 Gy was subsequently added in 17 patients with macroscopic disease in the pelvis at the time of second-look surgery. Fifteen patients received complementary chemotherapy mostly hexamethylmelamine. All but two patients completed whole abdominal irradiation: one refused further radiotherapy after 3 Gy and one developed disease progression with bowel obstruction after 1 Gy. The median follow-up was 69 months. The 3-year and 6-year no evidence of disease survival rates were 60% (95% CI: 48-71) and 33% (95% CI: 21-46), respectively. The 3-year and 6-year recurrence rates were 33% (95% CI: 22-45) and 54% (95% CI: 40-67), respectively. The 3-year and 6-year metastasis rates were 22% (95% CI: 13-34) and 43% (95% CI: 30-58), respectively. A multivariate analysis showed that residual disease after second-look surgery was the only significant prognostic factor with a relative risk of death or local or distant failure of 4.2 (95% CI: 1.9-9.5, p less than 10(-4)). Two patients developed mean-term gastrointestinal complications (small bowel obstructions requiring surgery). Survival remains poor with high level of failure even with aggressive multimodal treatment.

Radical irradiation and misonidazole in the treatment of advanced cervical carcinoma: Results of a phase II trial

Between February 1979 and January 1982, a Phase II study of misonidazole as a radiosensitizer was performed in 34 patients with advanced carcinoma of the uterine cervix. Twenty-nine patients were treated with conventional fractionated radiation and five patients with a twice daily fractionation schedule, 3 days a week. The total dose to the whole pelvis was 5000 cGy delivered in 5.5 weeks. Intracavitary curietherapy delivered an additional boost to the tumor. Misonidazole was given to all patients during external radiation and to 25 patients during intracavitary treatment for a total dose of 11 to 14 g/m2. All patients were followed for at least 28 months after treatment with a median follow-up of 52 months. Misonidazole toxicity included peripheral neuropathy (18%) and central nervous system toxicity (3%). The 3-year survival rate is 74% and the 3-year disease-free survival is 57%. When compared to our historical group survival, 42 and 12% for Stage III and IV, respectively, our data suggest that there is a probable advantage from using misonidazole in advanced carcinoma of the cervix.