Hyperfractionated radiation therapy plus chemotherapy in locally advanced cervical cancer: results of two phase I dose-escalation Gynecologic Oncology Group trials.

OBJECTIVE: The aims of this study were to assess the early and late toxicities of multiple-daily-fraction whole pelvic radiation plus concurrent chemotherapy with either hydroxyurea or 5-fluorouracil (5-FU)/cisplatin and to determine the maximum tolerated external radiation dose in conjunction with brachytherapy, when given with either of these drug regimens, as treatment for locally advanced carcinoma of the cervix. METHODS: The first study (GOG 8801) of 38 patients utilized hydroxyurea as a single oral dose of 80 mg/kg to a maximum of 6 g at least 2 h prior to a radiation treatment twice every week. In the second study (GOG 8901) of 30 patients, cisplatin and 5-FU were used concomitantly with radiotherapy. Fifty milligrams per square meter of cisplatin was administered on days 1 and 17 of external radiation. 5-FU was given by continuous intravenous infusion at a dose of 1000 mg/m(2)/day for 4 consecutive days on days 2, 3, 4, 5, and 18, 19, 20, and 21 of external radiation therapy. Both studies utilized external radiation given by an accelerated hyperfractionated regimen of 1.2 Gy per fraction, two fractions per day. All patients were treated 5 days per week with a minimum of 4 h between fractions. RESULTS: Acute toxicity was manageable on both protocols but nausea, vomiting, and myelosuppression were more severe with hydroxyurea. Chronic toxicity was primarily enteric and appeared to be dose-related. There was no obvious correlation seen between pelvic failure rates and the radiation dose or between the chemotherapy regimens used. CONCLUSIONS: The defined maximal tolerated dose of whole pelvic radiation was 57.6 Gy in 48 fractions which could be delivered in a hyperfractionated setting with concomitant chemotherapy, followed by brachytherapy. Follow-up is now sufficient that further adverse events should be rare.

A phase I/II study of intraoperative radiotherapy in advanced unresectable or recurrent carcinoma of the rectum: a Radiation Therapy Oncology Group (RTOG) study.

The Radiation Therapy Oncology Group (RTOG) initiated a phase I/II study of intraoperative radiotherapy (IORT) in advanced or recurrent rectal cancer to assess therapeutic efficacy, toxicity, and establish quality control guidelines prior to beginning a phase III trial. From October 1985 through December 1989, 87 patients with histologically proven adenocarcinoma of the rectum or rectosigmoid with recurrent/persistent disease after surgery or those primarily inoperable were entered by 14 institutions. Of 86 evaluable patients, 42 patients received IORT either alone (n = 15) or in combination with external beam (n = 27). Local control was dependent on the amount of residual disease prior to IORT, with 2-year actuarial local control of 77% if no gross residual disease remained vs. 10% with gross residual disease (P = 0.001). For the recurrent/residual group (n = 33), this observation was also significant with a 2-year actuarial local control rate of 64% if no gross residual remained vs. 10% with gross residual disease (P = 0.004). Local control translated into an improved survival for all patients and the recurrent/residual group with 2-year actuarial survival of 88% and 89% if no gross residual disease remained vs. 48% and 45% with gross residual disease, respectively (P = .0005, 0.006). Six patients (14.6%) experienced four grade 3 and three grade 4 complications as a possible result of IORT during follow-up with a 2-year actuarial risk of major complications of 16%. We conclude that IORT is feasible within a cooperative group and can be performed with acceptable complication rates. A phase III trial to demonstrate a therapeutic advantage for IORT over external beam alone is currently in progress.

Whole-abdominal irradiation for the management of gastrointestinal and abdominal manifestations of agnogenic myeloid metaplasia.

A patient with a long-standing history of agnogenic myeloid metaplasia developed weight loss and ascites secondary to gastric/small bowel infiltration and peritoneal implants of myeloid tissue. Moderate doses of radiation were very effective in controlling her gastrointestinal symptoms. In contrast to previous reports, clinical improvement after irradiation was a slow, gradual process, requiring 5 months for complete resolution of the patient's ascites. Hematologic suppression may be profound and careful attention to the rate of change in leukocyte and platelet counts is necessary to avoid severe toxicity.

Delayed split whole abdominal irradiation in the combined modality treatment of ovarian cancer.

Fifty-eight patients with ovarian malignancies have been treated using a delayed split whole abdominal irradiation technique (DSA) allowing the entire tumor volume to be irradiated with tumoricidal fractional doses without undue toxicity. The lower hemiabdomen was irradiated with 2 Gy per fraction to a total dose of 40 Gy. A 2-6 hour delay was used between the irradiation of each half of the abdomen to avoid excessive acute gastrointestinal toxicity. The upper hemiabdomen was irradiated with 1.5 Gy per fraction to a total dose of 30 Gy. The acute toxicity was acceptable, with 53 of 58 patients able to complete the prescribed course of treatment. Three patients (5%) experienced grade 3 or greater acute gastrointestinal toxicity. Fourteen of 60 patients (24%) required treatment breaks because of thrombocytopenia. Nadir platelet counts were lower in patients who had received previous chemotherapy than in previously untreated patients (80,000 vs 118,000; p = .02). However, only 4 out of 60 patients were unable to complete DSA because of prolonged thrombocytopenia. In addition to DSA, patients were also treated with intraperitoneal 32P (52 patients), intraperitoneal human ovarian antitumor serum (14 patients), and prior (14 patients) or subsequent (32 patients) chemotherapy. Granulocytopenia was more severe among patients who had received prior chemotherapy (mean nadir 900 vs 2200). Seven patients (11.5%) developed delayed bowel obstruction in the absence of recurrence. There was one death caused by hepatitis, presumably related to colloidal 32P and DSA. Twenty-five percent of Stage III optimally cytoreduced patients were disease-free at 5 years; these patients had a median survival of 45 months. DSA irradiation is an acceptable technique for delivering a high fractional dose of radiation to the entire peritoneal cavity. Shielding of the iliac crests spares bone marrow allowing DSA irradiation to be integrated into an aggressive combined modality treatment plan.

The sonographic appearance of the irradiated breast.

A dedicated supine breast ultrasound scanner was used to perform 48 bilateral breast sonograms on 21 patients who had undergone segmental resection and radiation therapy for breast cancer. Skin thickening was seen in 13 of 21 patients (62%). There was an increased echogenicity of the fat in 13 patients (62%) and poor definition of Cooper's ligaments in nine patients (43%). Fifteen patients (71%) had decreased compressibility and 8 (38%) had decreased penetration of the sound beam into the breast. The radiation changes were seen as early as one month after the completion of radiotherapy and improved by one year in the majority of patients studied with sequential sonograms.

A comparison of findings at second-look laparotomy with preoperative computed tomography in patients with ovarian cancer.

Prior to undergoing second-look laparotomy, 57 patients with ovarian cancer were evaluated with computed axial tomography (CT). All patients were clinically free of disease following chemotherapy. At laparotomy, 25 patients had visible evidence of disease, 9 had microscopic disease only, and 23 were free of cancer. Tumor was correctly identified on CT in 9 of the 25 patients (36%) with macroscopic disease. Tumors smaller than 2 cm in size were not detected by CT. CT suggested disease in 8 of the 32 patients (25%) who were free of macroscopic disease. CT provides useful information when it is abnormal. Fine needle aspiration of suspicious areas can spare some patients laparotomy. However, CT has a significant false-negative rate due to its inability to detect small volume disease. Patients with negative CT will continue to require reexploration and tissue confirmation to assess the need for further therapy.

Pitfalls in interpretation of computed tomography prior to second-look laparotomy in patients with ovarian cancer.

Fifty-seven patients with ovarian cancer were assessed with computed tomography (CT) prior to undergoing second-look laparotomy. All patients were clinically free of disease following chemotherapy. Patients were scanned from the top of the liver to the symphysis pubis using oral, rectal and intravenous contrast medium. Tumour was correctly identified on CT scan in nine of 25 patients who had visible evidence of cancer at laparotomy. However, in the remaining 16 patients peritoneal studding was present and was not detected. Tumours smaller than 1.5 cm in size were not found by CT scanning. Computed tomography showed abnormality in eight of 32 patients subsequently found to be free of disease. Fine-needle aspiration cytology, bolus contrast injection and repeat scanning with additional oral contrast medium could have assisted in these circumstances. As persistent disease is by definition, a contraindication to second-look laparotomy, aggressive pre-operative assessment will spare some patients unnecessary surgery. However, CT cannot detect the small nodules often present in ovarian cancer, and thus, normal scans cannot replace surgical restaging.

Impact of myelography on the radiotherapeutic management of malignant spinal cord compression.

From December 1981 through August 1984, 24 patients with spinal cord compression syndrome due to epidural neoplasms were evaluated for radiotherapy with clinical examination, radiographs of the spine, and myelography. All plain films were reviewed, and mock radiotherapy fields designed using specific criteria for margins. The same patients were reviewed a second time considering the additional information provided by myelography. The initial treatment fields were found to be inadequate in 69% of the patients. Even in patients with discrete bony lesions, the results of myelography affected the treatment 45% of the time. A history of previous spinal irradiation significantly influenced port design in only 1 of the 7 patients who had received previous radiotherapy. Although invasive, myelography is essential in planning the treatment of spinal cord compression.

Adenocarcinoma corpus et colli: analysis of diagnostic variables.

Between January 1973 and December 1983, 469 patients with carcinoma of the endometrium were seen at this institution. Eighty-one patients were identified with adenocarcinoma involving both the uterine body and the cervix. Patients were divided into three groups for evaluation. Group A (n = 58) had a positive cervical biopsy or endocervical curettage, but a normal-appearing cervix at clinical examination. Group B (n = 18) had gross tumor involving the cervix which was confirmed by biopsy. Group C (n = 5) had unsuspected cervical involvement revealed at hysterectomy. Fourteen Group A patients received preoperative radiation therapy. Thirty of the 44 Group A patients (68.2%) who did not receive preoperative radiation, had no involvement of the cervix by tumor in the hysterectomy specimen. Seventy-six patients were eligible for follow-up of at least 18 months. There were 24 recurrences among these 76 patients. Recurrence was more common with advancing grade and with increasing myometrial invasion. Pelvic failures occurred with comparable frequency in both Groups A and B. Only 4 of 11 patients who were found to have extrauterine disease at surgery are still alive. In this study, we found that endocervical curettage has a significant false-positive rate, both histologic grade and volume of cervical involvement should be considered in treatment planning, primary operation should be considered in the management of selected patients with Stage II endometrial carcinoma, and extrauterine disease is a grave prognostic factor.