Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT): A review of 47 cases.

OBJECTIVE: Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare disease with a poor prognosis. SCCOHT has recently been shown to be associated with SMARCA4 gene mutations as well as molecular and genetic similarities to malignant rhabdoid tumors (MRT). The objective of our study is to describe the clinical characteristics, treatment modalities and outcomes of 47 patients with SCCOHT. METHODS: We performed a retrospective analysis of 47 patients with SCCOHT evaluated at MD Anderson Cancer Center between 1990 and 2014. Medical records were reviewed for demographic information, pathologic findings, treatment regimens and outcomes. RESULTS: Median age at diagnosis was 30 years (range 5-46). All patients underwent surgery with unilateral salpingo-oophorectomy (USO) performed in 26 patients (55%), and hysterectomy with bilateral salpingooophorectomy (BSO) in 21 patients (45%). Sixteen patients (34.0%) had stage I disease, six (12.8%) stage II, 23 (48.9%) stage III, and two patients (4.3%) had stage IV disease. Information on adjuvant treatment was available for 43 patients: 83.3% received chemotherapy alone, 9.5% chemotherapy followed by radiotherapy, 2.4% chemoradiation, and 4.8% did not receive any adjuvant therapy. Median follow-up was 13.2 months (range, 0.1 to 210.7) with a median overall survival of 14.9 months. Multi-agent chemotherapy and radiotherapy were associated with a better prognosis. CONCLUSION: Our findings suggest that aggressive therapy including multi-agent chemotherapy and possibly radiotherapy may extend survival. Further study is needed to improve outcomes in these patients including the adoption of systemic therapies used in MRT as well as the development of novel agents targeting specific mutations.

Adjuvant surgery after radiotherapy.

Investigators disagree about the role of adjuvant hysterectomy after irradiation of bulky stage IB cervical carcinomas, although the benefit of combined treatment has never been clearly demonstrated. Studies that have correlated outcome with initial tumor diameter suggest that central recurrences are rare after irradiation of tumors less than 5 cm in diameter, leaving little room for improvement with additional local treatment. Early studies suggested that adjuvant hysterectomy may improve pelvic disease control for patients with bulky endocervical tumors, but these results may have reflected the selection of tumors with relatively favorable characteristics for combined treatment. Several studies have suggested that central pelvic disease can be controlled in more than 90% of patients with bulky endocervical tumors if they are treated with adequate doses of irradiation. Although published studies are somewhat limited by their retrospective designs, the available data do not support the added cost and morbidity of adjuvant hysterectomy in the routine treatment of patients with bulky early stage cervical carcinomas.

Decreased bone growth arrest in weanling rats with multiple radiation fractions per day.

The relative growth arrest caused by fractionated irradiation delivered in single or multiple daily fractions was studied in weanling rats. Twenty-two day old male rats were treated to a total dose of either 20 or 25 Gy in five consecutive days to the distal femoral and proximal tibial epiphyses of the right and left leg. For each dose three treatment groups were followed for longitudinal tibial growth as measured on serial radiographs: (a) no treatment, (b) 5 fractions in 5 days or (c) 10 fractions in 5 days. Tibial length was significantly greater in the legs treated with twice-daily fractions (TDF) as compared with single daily fractions (SDF) with 23% and 27% sparing of growth arrest (at 200 days) in legs treated to total doses of 20 and 25 Gy respectively (p less than 0.001). This appeared to result from a continuously greater rate of growth during the first 40-50 days following TDF irradiation as compared with SDF. These data suggest that hyperfractionation may provide a means of reducing growth deficits in children when skeletal growth centers must be included in the irradiated volume.

FIGO stage IIIA carcinoma of the uterine cervix.

Between 1955 and 1988, 44 patients with FIGO Stage IIIA carcinoma of the cervix were treated with radiotherapy at The University of Texas M. D. Anderson Cancer Center. This represents only 3% of the 1473 Stage III cervical carcinoma patients treated at M. D. Anderson during this time period. The 5- and 10-year actuarial survival rates of patients with Stage IIIA disease were 37% and 34%, respectively. The actuarial pelvic disease control rate was 72% at 5 and 10 years. Of the 23 patients who experienced a recurrence of their disease, 10 had a recurrence in the pelvis only, 11 had distant metastases only, and two had recurrences in the pelvis and distantly. Two factors, parametrial disease extension and discontinuous involvement of the lower third of the vagina were important predictors of prognosis. The 5-year survival rate of 27 patients with parametrial involvement was 25% compared with 56% for the 17 patients without parametrial disease (p = 0.05). The 5-year survival rate of 13 patients with discontinuous ("skip") lesions in the lower third of the vagina was 15% compared with 48% for 31 patients who presented with direct extension of disease to the lower vagina (p = 0.05). This was because of a high rate of distant disease recurrence in patients with skip lesions since pelvic control rates were similar for both groups. No patient who presented with both parametrial extension and discontinuous vaginal involvement survived 5 years. In contrast, patients with lesions that extended directly from the cervix to involve the lower vagina without involving the parametrium had an excellent 5-year survival rate of 73%.

Pharmacokinetics and toxicology of continuously infused nitroimidazoles.

The pharmacokinetics and toxicology of misonidazole (MISO) and SR-2508 given by continuous intraperitoneal infusion were studied in female C3H mice. The survival (time to death) of animals receiving continuous infusions of SR-2508 and MISO was compared and related to plasma concentration, rate of infusion and total amount of drug delivered. Brain and plasma concentrations were determined by HPLC. For SR-2508, plasma concentration was directly proportional to the infusion rate. However, as the infusion rate of MISO was doubled, the plasma concentration of MISO increased approximately 6-fold, reflecting a substantial increase in the apparent half-life. The brain/plasma concentration ratio in animals infused for up to 6 days with SR-2508 remained constant, at approximately 0.09. For MISO the product of the plasma concentration and survival time (area under the curve (AUC) was constant and equal to approximately 50-mM-hrs. In contrast, the survival of animals infused with SR-2508 could not be directly related either to the AUC of plasma concentration X time or AUC brain concentration X time. At plasma concentrations of 0.08-1.5 mM, animals receiving SR-2508 survived approximately 3 times as long as animals exposed to a comparable plasma concentration of MISO. At higher plasma concentration (and infusion rates), the toxicity of SR-2508 relative to that of MISO was much greater. Even at the lowest infusion rates employed in this study, the survival of mice receiving SR-2508 was much shorter than would have been predicted if the toxicity of these two drugs were solely related to the integral brain exposure. The low brain/plasma concentration ratio of SR-2508 was maintained throughout long continuous exposures. Under these conditions the toxicity of the two drugs was not directly related to the integral brain exposure dose. Possible future clinical applications of continuously infused nitroimidazoles are discussed.

Quantification of intracavitary brachytherapy parameters and correlation with outcome in patients with carcinoma of the cervix.

PURPOSE: To quantify the M. D. Anderson criteria for acceptable implant geometry; to relate our system of intracavitary radiotherapy (ICRT) prescription to Manchester and ICRU reference doses; and to correlate these parameters with outcome measures. METHODS AND MATERIALS: The relationships between intracavitary applicators and normal structures were measured directly from localization films of 808 applications performed in 396 patients who completed definitive treatment for cervical cancer between 1990 and 1994. The distances between applicators and tissue landmarks and the doses to Manchester and normal tissue reference points were correlated with outcome. RESULTS: The median distance from the tandem to the sacrum was 4.0 cm, or one-third the distance from the pubis to the sacrum. The mean distance between the vaginal ovoids and cervical marker seeds was 7 mm, and the median distance between the tandem and the posterior edge of the ovoids was 50% of the ovoid length. In 92% of insertions, vaginal packing was posterior to or within 5 mm of a line that passed through the posterior edge of the ovoids, parallel to the tandem. The median doses to Point A and rectal, bladder, and vaginal surface reference points were 87 Gy, 68 Gy, 70 Gy, and 125 Gy, respectively. Although these reference doses were not routinely used to prescribe treatment, consistent applicator geometry and source selection resulted in a relatively narrow range of delivered doses. The average ratios between the doses at bladder or rectal reference points and Point A were somewhat greater when smaller vaginal applicators were used. Patients received a median of 5600 mgRaEq-h from ICRT. The total mgRaEq-h were correlated with but were not proportional to the dose at Point A. There were no significant correlations between the doses to standard reference points and the rates of central recurrence or major complications. CONCLUSION: When ICRT implants are carefully placed, relatively high paracentral doses can be delivered that yield a high rate of central disease control with an acceptable rate of complications. The narrow range of doses delivered to standard reference points and their inconsistent correlation with the maximum doses delivered to normal tissues probably contributed to a lack of correlation between reference doses and outcome.

Perioperative and postoperative complications of intracavitary radiation for FIGO stage I-III carcinoma of the cervix.

PURPOSE: To evaluate perioperative and postoperative complications of low-dose-rate (LDR) intracavitary radiation therapy in patients with FIGO Stage I-III carcinoma of the uterine cervix. METHODS AND MATERIALS: We retrospectively reviewed the medical and radiotherapy records of all patients treated with radiation between 1960 and 1992 at The University of Texas M. D. Anderson Cancer Center for FIGO I-III carcinomas of the cervix. Patients who had had initial hysterectomy or whose treatment did not include intracavitary irradiation were excluded. The final study included 4043 patients who had undergone 7662 intracavitary procedures. RESULTS: Eleven (0. 3%) patients had documented or suspected cases of thromboembolism resulting in 4 deaths. Of these 11 patients, 8 had clinical or radiographic evidence of tumor involving pelvic nodes or fixed pelvic wall. The risk of postoperative thromboembolism did not decrease significantly with the routine use of mini-dose heparin prophylaxis (p = 0.3). Other life-threatening perioperative complications included myocardial infarction (1 death in 5 patients), cerebrovascular accident (2 patients), congestive heart failure or atrial fibrillation (3 patients), and halothane liver toxicity (2 deaths in 2 patients). Intraoperative complications included uterine perforation (2.8%) and vaginal laceration (0.3%), which occurred more frequently in patients >/= 60 years old (p < 0.01). Fourteen percent of patients had a temperature >/= 101 degrees F during at least one hospital stay. The only correlation between minor intraoperative complications and disease-specific survival was found in patients who had Stage III disease and uterine perforation; survival was significantly (p = 0.01) decreased in these patients. CONCLUSIONS: Fatal or life-threatening complications of intracavitary treatment were very rare. Deep venous thrombosis (DVT) and pulmonary embolism (PE) did not occur in otherwise healthy patients with early disease and were rare even when disease was more advanced. Minor perioperative complications were not correlated with serious late complications or with death from disease.

Figo IIIB squamous cell carcinoma of the cervix: an analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy.

PURPOSE: To define patient, tumor, and treatment factors that influence the outcome of patients with FIGO Stage IIIB squamous cell carcinoma of the intact uterine cervix. METHODS AND MATERIALS: The records of 1,096 patients treated with radiation therapy between 1960 and 1993 for FIGO Stage IIIB squamous cell carcinoma of the intact uterine cervix were reviewed retrospectively. Of these, 983 (90%) were treated with curative intent and 113 were treated only to achieve palliation of symptoms. Of 907 patients who completed the intended curative treatment, 641 (71%) were treated with a combination of external beam irradiation (EBRT) and intracavitary irradiation (ICRT) and 266 (29%) were treated with EBRT only. The median duration of treatment for these 907 patients was 51 days. Between 1966 and 1980, only 52% of patients who completed treatment with curative intent received ICRT, compared with 92% of patients treated during 1981-1993, an increase that reflects an evolution in the philosophy of treatment for advanced tumors. In general, the intensity of ICRT correlated inversely with the dose of EBRT to the,central pelvis. Median follow-up of surviving patients was 134 months. RESULTS: For 983 patients treated with initial curative intent, disease-specific survival (DSS) was significantly worse for those who were < 40 years old, had experienced more than a 10% weight loss, or had a hemoglobin level < 10 g/dl before or during radiation therapy. Tumor factors that correlated with a relatively poor DSS were bilateral pelvic wall involvement, clinical tumor diameter > or = 8 cm, hydronephrosis, lower vaginal involvement, and evidence of lymph node metastases on lymphangiogram (p < 0.01 in all cases). For the 907 patients who completed treatment with curative intent, 641 who had ICRT had a DSS of 45% at 5 years, compared with 24% for those treated with EBRT alone (p < 0.0001). Those who received > 52 Gy of EBRT to the central pelvis had DSS rates of 27-34%, compared with 53% for patients treated with lower doses of EBRT to the central pelvis and more intensive ICRT (p < 0.0001). At 5 years, the actuarial risk of major complications was also greater for patients treated with > 52 Gy of EBRT to the central pelvis (57-68%), compared with those who had 48-52 Gy (28%) and those who had < or = 47 Gy of EBRT to the central pelvis (15%) (p < 0.0001). Outcome was also compared for four time periods during which different treatment policies were in place for patients with Stage IIIB disease. The highest DSS (51%) and lowest actuarial complication rate (17%) were achieved during the most recent period (1981-1993) when modest doses of EBRT were combined with relatively intensive ICRT (p < 0.01 for both comparisons). CONCLUSION: Aggressive use of ICRT, carefully balanced with pelvic EBRT, is necessary to achieve the best ratio between tumor control and complications for patients with FIGO Stage IIIB carcinoma of the cervix. In our experience, the highest DSS rates and the lowest complication rates were achieved with a combination of 40-45 Gy of EBRT combined with ICRT.

Radiation therapy of tumors of the brainstem and midbrain in children: experience of the Joint Center for Radiation Therapy and Children's Hospital Medical Center (1971-1981).

Between 1971 and 1981, 79 previously untreated children with proven or presumed gliomas of the brainstem or midbrain were seen and treated at the Joint Center for Radiation Therapy and Children's Hospital Medical Center in Boston. Twenty-seven patients had tumors of the thalamus and midbrain (Group I) and 52 had lesions of the pons or medulla (Group II). Overall 5- and 10-year survivals were 50% and 41% respectively. Eighty percent of deaths occurred within 2 years of treatment. Eighty-six percent of the children (69/79) had clinical improvement or stabilization of disease after treatment. Group I patients had a 5-year survival of 73% which was significantly greater than that of Group II patients (38%) (p = 0.007). Children who presented with hypothalamic tumors in association with a diencephalic syndrome or other growth abnormality appeared to have had a better prognosis with 6/6 (100%) surviving without evidence of disease. Age at presentation was not correlated with prognosis. Of 10 children less than 3 years of age at presentation and treatment, 6 are alive (60%) at 2, 3, 7, 9, 10, and 12 years after treatment. The functional results in this group have been good--all six are leading apparently normal lives in regular schools with minor or no apparent neurologic deficits. Although these children will require long term follow-up to determine whether cures have actually been achieved, it appears that the majority achieve some benefit, that a significant proportion enjoy long term survival, and that very young children may be treated successfully with minimal radiation-induced neurologic sequela.

Radiation fractionation sensitivity of epiphyseal cartilage in a weanling rat model.

Tibial growth at 100 days of age was measured in Sprague-Dawley rats treated at 21 days to the proximal tibia with various courses of fractionated radiation. In split-dose and multiple-fraction experiments, a minimum interval of 5-6 hr was required to achieve maximal sparing of growth arrest. Total doses required to reduce growth to 80% of untreated controls were computed from dose-response curves for fractionated radiation (dose/fraction 1.0-10 Gy). When fitted to a linear-quadratic model of radiation response the data described an estimated alpha/beta of 4.47 (95% C.I. (3.71, 5.23) Gy). This value suggests that the fractionation sensitivity of the epiphyseal plate is substantially greater than that of most neoplasms, predicting a favorable therapeutic gain with the use of hyperfractionated radiation therapy.

Twice-daily anesthesia in infants receiving hyperfractionated irradiation.

Four children ranging in age from 6-30 months were treated with twice-daily (BID) radiation therapy under general anesthesia with a 5-6 hr treatment interval. Anesthesia was accomplished with sodium thiopental administered intravenously (IV) by bolus injection. This as followed by continuous drip infusion of sodium thiopental in a few instances where more prolonged anesthesia was required. Children received an initial formula feeding 6 hr before their first treatment and were subsequently kept NPO (nothing by mouth) until they recovered from their second anesthesia. Recovery from thiopental was rapid and children were ready for a normal feeding within 1-1 1/2 hr of the second treatment. No parenteral feedings were required in any of these patients. Children maintained their weight during courses of radiation therapy which ranged between 19 and 43 elapsed days. There were no radiation-related treatment breaks. One child experienced two hypotensive episodes during anesthesia which responded rapidly to intravenous atropine. No other anesthetic complications occurred. This experience demonstrates that hyperfractionated radiation therapy can be safely delivered in infants requiring general anesthesia for immobilization. We feel that sodium thiopental is the anesthetic of choice in this setting because of the short duration of action and consequently rapid post-anesthesia recovery which makes it possible to achieve adequate nutrition with oral feedings alone.

The influence of tumor size and morphology on the outcome of patients with FIGO stage IB squamous cell carcinoma of the uterine cervix.

PURPOSE: To define the influence of tumor size and morphology on rates of central tumor control (CTC), pelvic tumor control (PTC), and disease-specific survival (DSS) in patients treated with radiotherapy for squamous cell carcinoma of the intact uterine cervix. METHODS AND MATERIALS: Records of 1526 patients treated with radiotherapy for FIGO Stage IB squamous cell carcinoma of the intact uterine cervix between 1960 and 1989 were retrospectively reviewed. The maximum tumor or cervical diameter was determined from clinical descriptions for 1494 patients. Tumors were divided into nine size categories. Tumors > or = 4 cm were further classified according to the dominant morphology (i.e., exophytic or endocervical). Median follow-up was 12.2 years. Five-year CTC, PTC, and DSS rates were calculated actuarially. RESULTS: CTC, PTC, and DSS rates correlated strongly with tumor diameter (p < 0.0001). Overall, CTC, PTC, and DSS rates for patients with tumors < 5 cm were 99%, 97%, and 88%, respectively. For patients with tumors 5-7.9 cm these rates were 93%, 84%, and 69%, respectively. There were no significant differences in the rates of PTC, CTC, or DSS between subgroups of patients with lesions 5-7.9 cm in diameter. The rates of CTC (97%) and DSS (76%) for patients with 5-7.9 cm exophytic tumors were significantly better than those for patients with endocervical tumors of the same size (91% and 66%, respectively); there was no difference in the PTC rate. CONCLUSION: Although the CTC rates were excellent for all patients with tumors < 8 cm in diameter, these rates for tumors < 5 cm (99%) and for exophytic tumors 5-7.9 cm (97%) make it difficult to justify the use of adjuvant hysterectomy. Although patients with tumors of 5-7.9 cm had consistently poorer PTC and DSS rates than did patients with smaller tumors, the control rates achieved with aggressive radiotherapy were still excellent. The strong correlation between tumor size and outcome suggests that tumor diameter should be assessed when tumors are clinically evaluated and staged and when treatment results are reported for patients with FIGO Stage IB carcinoma of the uterine cervix.

Time course and incidence of late complications in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix.

PURPOSE: To determine the time course and incidence of late complications from radiation therapy in patients treated with radiation for FIGO Stage IB carcinoma of the uterine cervix, and to evaluate patient and tumor factors associated with an increased probability of treatment complications. METHODS AND MATERIALS: The medical records of 1784 patients with FIGO Stage IB cervical carcinoma who were treated with initial radiation therapy between 1960 and 1989 were retrospectively reviewed. Follow-up was obtained from clinic visits and correspondence with patients and their physicians. Treatment complications were graded retrospectively. Complication rates were calculated actuarially; patients who died of disease or intercurrent illness without experiencing a major complication were censored at the time of death. There were 1241, 924, 548, and 274 patients followed for more than 5, 10, 15, and 20 years, respectively. RESULTS: Of patients treated for Stage IB cervical carcinoma, 7.7% and 9.3% had experienced major (> or = Grade 3) complications at 3 and 5 years, respectively. After 5 years, there was a small but continuous risk of approximately 0.34% per year, resulting in an overall actuarial risk of having had major complications of 14.4% at 20 years. The risk of developing major urinary tract complications was approximately 0.7% per year for the first 3 years of follow-up, decreasing to about 0.25% per year for at least 25 years. In contrast, the risk of developing rectal complications was about 1% per year during the first 2 years, with a subsequent sharp decline to about 0.06% per year between Years 2 and 25. The risk of fistula formation was approximately doubled in the 234 patients who underwent adjuvant extrafascial hysterectomy (5.3 vs. 2.6% at 20 years; p = 0.04) and in the 111 patients who had pretreatment laparotomy (5.2 vs. 2.9%; p = 0.007). The risk of developing small bowel obstruction was increased in patients who underwent pretreatment laparotomy (14.5 vs. 3.7% at 10 years; p < 0.0001) and in patients who weighed < 120 pounds (8.2 vs. 3.6%; p = 0.004), but was not increased in patients who underwent adjuvant hysterectomy. A significantly greater risk of gastrointestinal complications was observed in black and non-Hispanic white patients than in Hispanic women (p = 0.01), even though there was no difference in the rate of developing urinary tract complications (p = 1.0). There was no correlation between the actuarial risk of developing major complications and the patients' age at the time of treatment, but the cumulative risk was greater for patients who were treated at a young age because these patients were more likely to survive to be exposed to a very long period of risk. CONCLUSIONS: Using techniques described by Fletcher and Delclos, the risk of major complications from aggressive irradiation for Stage IB carcinoma of the cervix is low and does not warrant compromises in the intensity of treatment that might decrease the high cure rates achieved in such patients. The long time course of some late complications also suggests that continued surveillance of survivors, by physicians experienced in the diagnosis and management of the sequelae of the curative radiation treatment of cervical cancer, is important.

Response of growing bone to irradiation: a proposed late effects scoring system.

The effect of radiation on epiphyseal bone growth is one of the most important dose-limiting factors in the radiotherapeutic management of children with malignant neoplasms. Clinical and laboratory evidence suggest that many factors may influence the severity of radiation-induced growth arrest. However, the absence of a consistent scoring system for late effects has hampered efforts to analyze the influence of various therapeutic maneuvers or to compare and collate results from different reported series. In this review, laboratory and clinical studies of radiation effects on growing bone are summarized, and a late effects scoring system is proposed.

Misonidazole neurotoxicity in mice decreased by administration with pyridoxine.

A series of toxicological and pharmacological experiments was performed to test the hypothesis that alterations of pyridoxine (Vitamin B6) metabolism may play an important role in the development of misonidazole (MISO) neurotoxicity. The formation of a Schiff's base between the final reduction product of MISO, 2-amino MISO (NH2-MISO), and pyridoxal-HCl in ethanol was demonstrated. Mice receiving daily intraperitoneal injections of MISO suffered significantly less toxicity (as determined by survival, weight gain and neurological tests) when large doses of pyridoxine-HCl (PYR) were delivered concomitantly, and consequently were able to tolerate administration of more than twice as many MISO injections. PYR did not alter the pharmacokinetics of MISO, either when given simultaneously or when given by multiple repeated daily injections prior to MISO. The administration of PYR also did not alter the radiosensitization by MISO in an in vivo-in vitro cloning assay with the EMT6 tumor in BALB/c mice. If depletion or altered metabolism of pyridoxine by reduced metabolites is also responsible for the neurotoxic effects of nitroimidazoles in humans, then concomitant administration of pyridoxine (in doses greater than the molar quantity of NH2-MISO formed) should inhibit the development of such symptoms and allow administration of larger doses of MISO than are currently clinically employable.

Treatment of endometrial carcinoma with radiation therapy alone.

PURPOSE: To review the results of treatment with radiotherapy alone in 152 patients with adenocarcinoma of the endometrium who had medical or surgical contraindications to hysterectomy. METHODS AND MATERIALS: We reviewed the records of all patients who were treated with radiotherapy alone for uterine carcinoma at The University of Texas M. D. Anderson Cancer Center between 1960 and 1986. One hundred fifty-two cases were analyzed. Most patients had multiple medical problems. One hundred sixteen patients were treated with intracavitary radiotherapy alone. A combination of external beam and intracavitary radiotherapy was used for 10 patients with Stage I disease who had unusually large cavities, 10 patients with Stage II disease, and 13 of 15 patients with Stage III or IV disease. Histologic material was reviewed in 91 cases. RESULTS: Ten years after treatment, these patients were twice as likely to have died of intercurrent illness as of uterine cancer. The 5-year disease-specific survival rate of patients with Stage I disease was 87%. The disease-specific survival of patients with Stage II disease was 88%, which was not significantly different from that of Stage I patients. Stage III and IV patients had a significantly poorer disease-specific survival rate of 49% at 5 years. Intrauterine recurrence occurred in 14% of the patients with Stage I or II disease. Salvage treatment was attempted in 5 of the 10 patients who had isolated intrauterine recurrences of Stage I disease and was successful in all cases. Extrauterine pelvic recurrence developed in only 3% of Stage I and II patients. Of 82 Stage I and II carcinomas that were available for pathologic review, 17 (21%) were clear-cell or papillary serous variants. The disease-specific survival rate of patients with Stage I or II papillary serous carcinomas was 43%, significantly poorer than that of patients with endometrioid carcinomas. Seven patients experienced acute anesthesia-related complications; none were fatal. Five patients had serious late complications of radiation therapy. CONCLUSION: Radical radiotherapy achieved acceptable DSS and local control rates in patients with medically or surgically inoperable uterine carcinoma. However for patients with localized disease, such treatment is justified only when the operative risk exceeds the 10-15% uterine recurrence rate expected with radiation alone.

The relationship between brachytherapy dose and outcome in patients with bulky endocervical tumors treated with radiation alone.

PURPOSE: To evaluate the relationship between brachytherapy dose and outcome in patients treated with external radiotherapy (40 Gy to the whole pelvis) and intracavitary radium therapy for bulky endocervical tumors. METHODS AND MATERIALS: Between 1962 and 1985, 98 patients with Stage IB-IIB bulky endocervical carcinomas (> or = 6 cm in diameter) treated with radiotherapy alone received 40 Gy to the whole pelvis followed by 2 or more intracavitary treatments. Twenty-five patients received < 6000 mg-hr of intracavitary treatment and 73 received > or = 6000 mg-hr (an average dose to point A of approximately 49 Gy). Brachytherapy exposures ranged from 4800-7885 mg-hrs. RESULTS: Patients who received < 6000 mg-hr tended to have unfavorable (narrow) vaginal anatomy (p < 0.01) and to be treated in the later years of the study (p < 0.01). The high-dose group included a somewhat greater proportion of patients with positive lymphangiograms or poor responses to initial external beam treatment. Despite having somewhat more favorable tumors, patients who received less than 6000 mg-hr had a higher rate of pelvic disease recurrence at 5 years (33%) than those who received higher doses (16%) (p = 0.03). Actuarial survival rates at 5 years were 44% and 60% for the low- and high-dose groups, respectively (p = 0.14). Among those who received more than 6000 mg-hr, there was no significant relationship between brachytherapy dose and pelvic disease control. Calculated actuarially, the rate of major (> or = grade 3) complications at 5 years was 23% in the low-dose group and 10% in the high-dose group (p = 0.1). CONCLUSIONS: The relatively high incidence of pelvic disease recurrence and complications in patients who receive less than 6000 mg-hr reflects the narrow therapeutic window for complication-free pelvic disease control in patients with bulky central disease and unfavorable normal tissue anatomy. The results also demonstrate a high pelvic control rate and acceptable morbidity in patients with favorable anatomy treated with high-dose radiotherapy alone.

Twice-daily fractionation of external irradiation with brachytherapy and chemotherapy in carcinoma of the cervix with positive para-aortic lymph nodes: Phase II study of the Radiation Therapy Oncology Group 92-10.

PURPOSE: The purpose of this study was to evaluate the toxicity and efficacy of twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes. METHODS AND MATERIALS: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and para-aortics at 4- to 6-h intervals, 5 days per week. The total external radiation doses were 24 to 48 Gy to the whole pelvis, 12 to 36 Gy parametrial boost, and 48 Gy to the para-aortics with an additional boost to a total dose of 54 to 58 Gy to the known metastatic para-aortic site. One or two intracavitary applications were performed to deliver a total minimum dose of 85 Gy to point A. Cisplatin (75 mg/m2, days 1 and 22) and 5-FU (1000 mg/m2/24 h x 4 days; days 1 and 22) were given for two or three cycles. RESULTS: Twenty-nine patients with clinical Stages I to IV carcinoma of the cervix with biopsy-proven para-aortic lymph nodes were enrolled in this study. Hyperfractionated external radiotherapy was completed in 86% (25 of 29). Brachytherapy was given in two applications to 48% (14 of 29), 31% (9 of 29) had one intracavitary application, 14% (4 of 29) had no brachytherapy, one had three applications, and one had five HDR applications. Radiotherapy was completed per protocol in 69%. Three courses of chemotherapy were given to 24% (7 of 29), 72% (21 of 29) received two courses, and one patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Radiotherapy toxicity was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. One Grade 5 toxicity occurred and the patient died from a myocardial infarction from chemotherapy and radiotherapy colitis during her course of therapy. The median follow-up time was 18.9 months. The overall survival estimates were 59% at 1 year and 47% at 2 years. The probability of local-regional failure was 38% at 1 year and 49% at 2 years. The probability of disease failure at any site was 45% at 1 year and 59% at 2 years. CONCLUSION: The results suggest that twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (31%, 9 of 29) of Grade 4 nonhematologic toxicity. One patient died from complications of therapy. Radiotherapy was completed per protocol in 69%. The survival estimates appear no better than standard fractionation radiotherapy without chemotherapy. Additional follow-up is necessary for long-term survival estimates.

Twice-daily, split-course abdominopelvic radiation therapy after chemotherapy and positive second-look laparotomy for epithelial ovarian carcinoma.

Between July 1983 and December 1988, 34 patients with ovarian carcinoma received whole abdominal irradiation in an attempt to eliminate residual disease following second-look laparotomy. Three additional patients who had initial complete responses to chemotherapy were treated for a recurrence of their disease. All patients had been treated with chemotherapy that included cisplatin and cyclophosphamide. Three patients had also received doxorubicin with some or all chemotherapy cycles. Thirty Gray of abdominopelvic radiation therapy (APRT) was delivered using a twice-daily, split-course schedule. Eleven patients also had a boost of 9-20 Gy to sites of residual disease. Treatment was well tolerated. Only one patient did not complete therapy and two patients had 1-week prolongations of treatment because of hematologic toxicity. Thirty-two percent of patients had grade 2 neoplasms and 61% had grade 3 disease. Three patients with grade 1 tumors continue to have no evidence of disease 20-50 months after irradiation. Patients with grade 2 and 3 neoplasms who had microscopic residual disease prior to APRT had relapse-free survival rates at 3-years of 10% and 14%, respectively. Twelve patients with gross residual disease had rapid recurrences (median time to relapse, 4.9 months) and all have died of their disease. Although 14 patients (38%) have experienced small bowel obstructions, all of these had known recurrent abdominal disease at the time. Twenty patients (54%) had undergone more than two abdominal surgeries prior to APRT, and several were noted to have extensive adhesions at second-look laparotomy. None of the five patients currently believed to be free of disease has experienced a small bowel obstruction. Radiation is only one of several factors that contributed to bowel obstructions. Although APRT may be able to eliminate residual disease in a small proportion of patients with microscopic residual disease after chemotherapy, the aggressive biology of tumors that respond incompletely to chemotherapy and the compromises in radiation dose and schedule that must be made in these heavily treated patients probably contribute to the disappointing results of this treatment.