Ned B. Hornback

Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: a preliminary report.

A total of 304 patients with limited small-cell carcinoma of the lung were treated with a combination of cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, Ohio), and vincristine (CAV) and elective brain irradiation (3,600 rad TD in 14 fractions). The patients were randomized to either receive or not receive thoracic irradiation (4,000 rad TD, split course). Of the 304 patients, 291 were eligible for the study. Two hundred eighteen (75%) were completely evaluable. In each group, 81% of the patients had a Karnofsky index of 80% or higher and 14% had supraclavicular or scalene lymph nodes. Patients treated with CAV and no thoracic irradiation had a complete response (CR) of 48%, in contrast to 63% for those receiving chest irradiation (P = .05). In the first group, the complete and partial response rate was 70%; in the second, 80%. The median survival for the eligible patients treated with CAV and brain radiation therapy was 49 weeks; for those treated with the same regimen plus thoracic irradiation, the median survival was 60 weeks. The actuarial two-year tumor-free survival is 19% in the first group and 28% in the second group. The median survival for the responders in the CAV plus brain irradiation group was 57 weeks and for those receiving thoracic irradiation, 78 weeks (P = .12). Thoracic failure was 52% in patients not treated with thoracic radiation therapy v 36% in those receiving it (P = .06). The distant metastases incidence was 23% in patients not treated with thoracic radiation and 35% in patients treated with thoracic radiation. Hematologic toxicity was comparable in both groups; 30% of the patients had moderate to severe granulocytopenia and 6%, low homoglobin. Two toxicity-related deaths occurred (one in each group). Moderate gastrointestinal toxicity was noted in 41% and severe in 16% of the patients receiving CAV and brain irradiation without thoracic radiotherapy v 44% and 20% in those irradiated in the thorax. Disease-free survival is enhanced in the patients receiving thoracic irradiation. More effective chemotherapy is critically needed to significantly improve overall survival. These preliminary results suggest that thoracic irradiation should be a primary component in the therapy of these patients, although this combined therapy is moderately toxic.(ABSTRACT TRUNCATED AT 400 WORDS)

Doxorubicin as an adjuvant following surgery and radiation therapy in patients with high-risk endometrial carcinoma, stage I and occult stage II: A Gynecologic Oncology Group study

The Gynecologic Oncology Group studied the use of adjuvant doxorubicin after surgery and radiation therapy for endometrial carcinoma in a randomized, prospective manner. The study population consisted of patients clinically stage I or II (occult) who, after surgical-pathologic evaluation, had one or more risk factors for recurrence: greater than 50% myometrial invasion, pelvic or aortic node metastasis, cervical involvement, or adnexal metastases. All patients without aortic node metastasis received 5000 rads to the whole pelvis at 160-180 rads per day. If aortic node metastasis was documented, aortic field radiation to the top of T12 was offered. The aortic target dose was 4500 rads at 150 rads per day. After completion of radiation therapy, the patients were randomized to receive doxorubicin bolus therapy (60 mg/m2 starting dose) to a maximum cumulative dose of 500 mg/m2. Between November 1977 and July 1986, 92 patients were entered into the doxorubicin (DOX) treatment arm, and 89 patients entered the no-DOX arm. There was no statistically significant difference in survival or progression-free interval of the two arms. The 5-year survival rates for patients with deep myometrial invasion, cervical involvement, and pelvic node metastases were similar (63-70%), whereas the rate for patients with aortic node metastases was 26%. There was no significant difference in the recurrence pattern between the two treatment arms. There were no cases of grade 3 or 4 cardiac toxicity. Twelve patients (6.9%) developed small bowel obstruction after radiation therapy. There were three treatment-related deaths in the DOX arm and two in the radiation therapy-only arm. We conclude that, because of protocol violations, small sample size, and the number of patients lost to follow-up, this study was unable to determine what effect use of doxorubicin as adjuvant therapy had on recurrence, progression, and survival of the endometrial cancer study population. The combination of surgical staging and postoperative radiation as used in this study appears to increase the risk of bowel complications.

Enhanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer

In a recently completed study, combination chemotherapy consisting of bleomycin, adriamycin, cyclophosphamide, and vincristine was given to 29 patients with oat cell lung cancer. There were no cases of pulmonary fibrosis in these 29 patients. Although several of these patients had prior radiotherapy, none had concomitant radiotherapy and chemotherapy. This same four‐drug chemotherapy regimen was combined with concomitant radiotherapy in 13 patients with oat cell lung cancer. There were three cases of fatal pulmonary fibrosis and two other cases of clinically significant pulmonary fibrosis. All five cases of pulmonary fibrosis occurred several weeks after completion of a six‐week course of bleomycin (total dosage 90 units). It is concluded that bleomycin cannot be safely administered while patients are receiving radiotherapy to the lung.

Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group.

A total of 307 patients with superficial measurable tumors were registered on a Radiation Therapy Oncology Group (RTOG) protocol involving fractionated radiation therapy, either alone or followed immediately by hyperthermia (42.5°C, 45–60 min). Overall complete response (CR) was observed in 30% of the lesions treated with radiotherapy (RT) and 32% of those receiving RT and heat. Response was found to be significantly related to both maximum tumor diameter (<3 or >3 cm) and site/histology (breast/adenocarcinoma, head and neck/squamous, or other site/histologies). In tumors < 3 cm in diameter in the breast, trunk, and extremities, a better CR rate was noted with irradiation and heat (62 and 67%) than with irradiation alone (40 and 0%). However, in the head and neck there was only minimal difference in CR with irradiation alone or combined with hyperthermia (50 vs 38%). In lesions < 3 cm treated with irradiation and heat, there was improved local control. In lesions > 3 cm, there was no difference in local control between the two treatment arms. The higher response rate in patients with smaller lesions (<3 cm) may be explained by the fact that these tumors are easier to heat. Problems in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to map the temperature distribution in a tumor. Acute and late toxicities in both treatment arms were comparable, except for an overall 30% incidence of thermal blisters in the heated tumors.

Carcinoma of major salivary glands

Ninety‐four patients with carcinoma of the major salivary glands seen at Indiana University Hospitals from 1960–1977 were studied. Eighty‐four patients completed their planned course of therapy, and 49 of 84 patients remain alive with no evidence of disease 2–17 years following treatment. Comparison has been made for three modalities: surgery alone, radiation therapy alone, and a combined approach. Surgery alone was used for treatment of early lesions, and 22 of 38 patients (58%) remain free of disease. Radiation therapy alone was used for advanced cases and palliation, and 6 of 16 patients (37.5%) remain free of disease. In the combination treatment, 21 of 30 patients (70%) are alive and free of disease from 2–17 years after treatment. Ten patients did not complete treatment and all of these patients died of disease. Cancer 45:693‐697, 1980.

Observations on the use of adjuvant radiation therapy in patients with stage I and II uterine sarcoma

From November 1973 through July 1982, 225 women with Stage I or II uterine sarcoma were entered on a protocol which evaluated the use of doxorubicin in the adjuvant setting. Of these, 157 patients had a minimum follow-up of 2 years. Following complete surgical removal of all known clinical disease, consenting patients were randomized to receive either 60 mg/m2 of doxorubicin every 3 weeks for eight courses or no further therapy. The use of radiation therapy in this protocol was optional, and a review of protocol cases was undertaken to determine progression-free interval, survival rates, and site of first recurrence in the radiation therapy and no radiation therapy groups. In patients with Stage I or II leiomyosarcoma of the uterus, there was no difference in the progression-free interval, absolute two-year survival rate, or site of first recurrence in the two groups. There was no difference in the progression-free interval or absolute survival rates for cases with Stage I and II uterine mixed mesodermal sarcomas in the two treatment groups. However, those who received radiation therapy to the pelvis experienced a statistically significant reduction of recurrences within the radiation treatment field.

Prophylactic irradiation of the para-aortic lymph node chain in stage iib and bulky stage ib carcinoma of the cervix, initial treatment results of RTOG 7920

From November 1979 to October 1986, 367 patients were entered onto RTOG 7920 and randomized to receive either pelvic irradiation alone or pelvic plus para-aortic radiation. Patients with Stage IIB cervical carcinoma who had not undergone curative surgery and patients with Stages IB and IIA cervical carcinoma who were determined by digital exam to have primary tumors measuring 4 cm or greater in lateral dimension were eligible for this study. Clinically apparent or surgically involved para-aortic nodes were reason for exclusion from the study. Pelvic irradiation consisted of 1.6-1.8 Gy per day for 5 days per week to a total of 40-50 Gy. Para-aortic irradiation delivered 44 to 45 Gy in 1.6-1.8 Gy per day, 5 days per week. Pelvic irradiation was to be completed in 4 1/2 to 6 1/2 weeks and para-aortic irradiation in 4 1/2 to 5 1/2 weeks. Intracavitary brachytherapy delivered a total of 4000-5000 mg hr of radium-equivalents or 30-40 Gy to point A. Patients were stratified prior to random treatment assignment by histology, para-aortic nodal status (negative vs. unevaluated), and FIGO stage. As of June 1, 1989, 30 cases were excluded, including five patients who were inevaluable. Two patients who refused the assigned treatment were also excluded. Therefore, a total of 330 cases were analyzable. At 5 years the estimates of survival, the primary endpoint, for the pelvic only and pelvic plus para-aortic irradiation arms are 55% and 65%, respectively (p = 0.043). Several secondary endpoints were also analyzed. Estimates for loco-regional control at 5 years are, for pelvic irradiation only, 66%, and for pelvic plus para-aortic irradiation, 75% (p = 0.21). Distant metastases are estimated in 32% of pelvic irradiation only patients and 25% of pelvic plus para-aortic irradiation patients at 5 years (p = 0.17). When the first disease failure patterns are examined, more patients fail distally when treated only with pelvic radiation than when using pelvic plus para-aortic fields (p = .04). In analysis of patients with grade 3 (severe), grade 4 (life-threatening), and grade 5 (fatal complications), 8% of the patients in both groups had grade 3 severe complications. In the pelvic plus para-aortic group, 11 patients had grade 4 and 2 had grade 5 complications, whereas 6 had grade 4 and none had grade 5 in the pelvic only treatment group.(ABSTRACT TRUNCATED AT 400 WORDS)

Preliminary clinical results of combined 433 megahertz microwave therapy and radiation therapy on patients with advanced cancer

Seventy patients with far‐advanced histologically proven malignancies were treated with a combination of microwave irradiation (433.92 MHz) and ionizing radiation. Of the twenty‐one patients who completed the planned course of treatments and are eligible for a minimum of nine‐month follow‐up, 90% experienced complete relief of symptoms and 10% received partial relief of symptoms. Complete regression of all localized tumor occurred in sixteen of the twenty patients (80%), and nine of the complete responders remain free of disease from nine to fourteen months. It was the opinion of the clinicians involved in this study that the heat administered by the microwave unit potentiated the effects of ionizing radiation over those which would have been seen if radiation were used alone. In view of the fact that all patients in this study had cancers which were previously considered to be refractory to further medical treatment, the marked relief of symptoms and tumor response to combined therapy were encouraging. This preliminary study confirms the impression that the effects of radiation are enhanced by heat and forms the basis for a randomized series involving far‐advanced but previously untreated head and neck and gynecological malignancies. Cancer 40:2854‐2863, 1977.

RADIOTHERAPY WITH OR WITHOUT MISONIDAZOLE FOR PATIENTS WITH STAGE IIIB OR STAGE IVA SQUAMOUS CELL CARCINOMA OF THE UTERINE CERVIX: PRELIMINARY REPORT OF A RADIATION THERAPY ONCOLOGY GROUP RANDOMIZED TRIAL

Between August 1980 and November 1984, 119 patients with FIGO Stage IIIB or IVA squamous cell carcinoma of the uterine cervix were randomized to receive radiation therapy (4600 cGy pelvis plus 1000 cGy parametrial boost) followed by intracavitary or external boost to the primary with or without misonidazole (MISO) (400 mg/m2 daily 2 to 4 hours prior to radiation therapy). Patients in the two treatment groups were evenly distributed with respect to stratification variables including stage, Karnofsky Performance score, and positivity of para-aortic nodes. Eighty-nine percent of patients had Stage IIIB disease and 88% had a Karnofsky score of 80 or better. Seventy-five percent of patients treated with radiation therapy alone and 79% of patients treated with radiation therapy plus MISO received a boost via intracavitary application. Life threatening (Grade 4) complications occurred in 5 patients receiving radiation therapy alone and one patient receiving radiation therapy plus MISO. MISO toxicity (Grade 3) was limited to severe nausea and vomiting in two patients. With 119 evaluable patients and a median follow-up of 33 months, 64% of patients receiving radiation therapy alone are alive at 18 months compared with 54% for patients assigned to radiation therapy plus MISO. The median survival for patients treated with radiation therapy alone and radiation therapy plus MISO was 1.9 years and 1.6 respectively. At this point in the study the difference in survival is inconsistent with the hypothesis of an improvement associated with MISO. There have been 23 deaths among the 49 patients treated with radiation therapy plus MISO who have been followed for at least 18 months compared with 17 deaths in 48 patients treated with radiation therapy alone. The chance of observing this number of deaths with radiation therapy plus MISO if the addition of MISO improves survival by 10 to 20% is 0.003 and less than 0.001, respectively. The addition of MISO to radiation failed to improve survival for these patients. The results cannot be explained by an uncharacteristically high survival on the radiation therapy alone arm or by an imbalance in the distribution of prognostic factors. Local-regional control remains a problem in the management of patients with advanced cervical carcinoma. More effective and less toxic radiosensitizing agents are needed.

Influence of elevated temperature on natural killer cell activity, lymphokine-activated killer cell activity and lectin-dependent cytotoxicity of human umbilical cord blood and adult blood cells

PURPOSE To determine whether hyperthermia is to the benefit or detriment of host immune function, the effect of hyperthermia was evaluated on various functions of T-lymphocytes from human umbilical cord blood and compared to that of adult blood. METHODS AND MATERIALS Nonadherent mononuclear cells from cord blood or adult blood were used as the effector cells. To generate lymphokine activated killer (LAK) cells, effector cells were kept in culture for 5 days in complete medium containing recombinant human interleukin-2. To activate effector cells to become cytotoxic, cells were kept in culture in complete medium containing Con A. Cytotoxicity was determined in a standard 4-h chromium release assay using K-562 human erythroleukemic cells (in the natural killer cell activity assay) or Daudi cells (in the LAK cell activity or Lectin dependent cytotoxicity assay) as targets. For heat effects, cells in complete medium were heated at the desired temperature in a water bath for 1 h. RESULTS Lymphokine-activated killer cell activity, lectin-dependent cytotoxicity and T-cell proliferative capacity were not deficient in human cord blood. Cytotoxic activities of T-cells from adult blood as well as from cord blood can be enhanced at febrile range (< or = 40 degrees C), and were significantly decreased by exposure to 1 h at 42 degrees C. CONCLUSION The febrile responses (< or = 40 degrees C) to infection, in the course of malignant disease and with biological response modifiers treatment, may all be related to host defense mechanisms. Based on these observations, whole body hyperthermia (< or = 40 degrees C), in combination with the appropriate cytokines, may have therapeutic potential in the treatment of neonatal infections and malignancies under certain circumstances. Hyperthermia in febrile range may, therefore, confer an important immunoregulatory advantage to the host. In contrast, tumor killing therapeutic temperature (> 42 degrees C) which inhibits host immunocompetence should probably be used only for local hyperthermia.