The role of radiotherapy in the management of operable locally advanced breast carcinoma: results of a randomized trial by the Eastern Cooperative Oncology Group.

BACKGROUND: The purpose of this study was to test the role of radiotherapy following total mastectomy, axillary dissection, and adjuvant systemic therapy in the management of operable locally advanced breast carcinoma. METHODS: After undergoing mastectomy and axillary dissection, 426 patients with locally advanced breast carcinoma were registered on study and stratified by patient characteristics and risk factors. All patients were then treated with six courses of chemohormonotherapy. After being restaged, the 332 patients remaining without recurrence were randomized to receive prophylactic radiotherapy or to undergo observation and receive radiotherapy only if and when there was locoregional recurrence. RESULTS: Three hundred twelve of 332 randomized patients were deemed eligible and analyzed for both time to relapse and survival. The median follow-up period was 9.1 years. There were no significant differences in time to relapse and overall survival between the two treatment arms. Of those assigned to radiation, 60% relapsed, with a median time to relapse of 4.7 years, and 46% were alive at last follow-up, with a median survival of 8.3 years. Of those assigned to observation, 56% relapsed, with a median time to relapse of 5.2 years, and 47% were alive at last follow-up, with a median survival of 8.1 years. The two treatment arms had significantly different patterns of sites of first recurrence. There were 9% fewer locoregional first recurrences among those assigned to radiation than among those assigned to observation (15% vs. 24%), whereas there were 15% more first relapses at distant sites (50% vs. 35%) among those assigned to radiation (P = 0.003). CONCLUSIONS: Radiotherapy for locally advanced breast carcinoma, following mastectomy, axillary dissection, and adjuvant systemic therapy, results in fewer locoregional but more distant recurrences at first relapse. No significant advantage was seen for consolidation radiotherapy over observation in terms of either time to relapse or survival, both of which were virtually identical in the two treatment arms. [See editorial counterpoint on pages 1061-6 and reply to counterpoint on pages 1067-8, this issue.]

Bilateral synchronous testicular germ cell cancer.

Bilateral synchronous testicular cancer is a rare occurrence usually associated with similar histologic findings in each testicle. We describe eight patients with bilateral synchronous testicular germ cell cancer, of whom four had dissimilar histologic findings. Contralateral disease in three patients was identified only by testicular ultrasonography or intraoperative exploration of the contralateral testicle, and in two cases by palpation 6 months after identification of the primary cancer. Treatment was determined by conventional staging and five of eight patients have remained free of recurrent disease.

Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council.

PURPOSE: To compare the efficacy of fast neutron radiotherapy versus conventional photon and/or electron radiotherapy for unresectable, malignant salivary gland tumors a randomized clinical trial comparing was sponsored by the Radiation Therapy Oncology Group in the United States and the Medical Research Council in Great Britain. METHODS AND MATERIALS: Eligibility criteria included either inoperable primary or recurrent major or minor salivary gland tumors. Patients were stratified by surgical status (primary vs. recurrent), tumor size (less than or greater than 5 cm), and histology (squamous or malignant mixed versus other). After a total of 32 patients were entered onto this study, it appeared that the group receiving fast neutron radiotherapy had a significantly improved local/regional control rate and also a borderline improvement in survival and the study was stopped earlier than planned for ethical reasons. Twenty-five patients were study-eligible and analyzable. RESULTS: Ten-year follow-up data for this study is presented. On an actuarial basis, there continues to be a statistically-significant p = 0.009) but there is no improvement in overall survival (15% vs. 25%, p = n.s.). Patterns of failure are analyzed and it is shown that distant metastases account for the majority of failures on the neutron arm and local/regional failures account for the majority of failures on the photon arm. Long-term, treatment-related morbidity is analyzed and while the incidence of morbidity graded "severe" was greater on the neutron arm, there was no significant difference in "life-threatening" complications. This work is placed in the context of other series of malignant salivary gland tumors treated with definitive radiotherapy. CONCLUSIONS: Fast neutron radiotherapy appears to be the treatment-of-choice for patients with inoperable primary of recurrent malignant salivary gland tumors.

Primitive neuroectodermal tumor of the chest wall in a patient with Jeune's syndrome and renal transplant.

Jeune's syndrome is a rare autosomal disorder characterized by osseous dysplasia, fetal respiratory distress, and renal failure in later life. We describe a 27-year-old man with Jeune's syndrome who underwent renal transplantation and 6 years later developed a sarcoma (primitive neuroectodermal tumor [PNET]) in the soft tissue of the chest wall, a principal site of dysplasia in this disorder.

Immobilization and stabilization of testicular clamshell shields in seminoma patients.

It is standard practice when treating the pelvic and para-aortic lymph nodes of seminoma patients, to use a method to reduce the dose to the testicles due to scattered radiation. A common method is the use of lead testicular shields (clamshells). We have developed a method of immobilizing the patient while at the same time providing a stable and reproducible position for the testicular shield.

High energy (42-66 MeV reactions) fast neutron dose optimization studies in the head and neck, thorax, upper abdomen, pelvis and extremities.

Five hundred and fifty patients were entered into a set of dose-searching studies designed to determine normal tissue tolerance to high energy (42-66 MeV reactions) fast neutrons delivered in 12 equal fractions over 4 weeks. Participating institutions included: The Fermilab (66 MeV p+----Be), The University of Washington (50 MeVp+----Be), U.C.L.A. (45 MeVH-----Be), M.D. Anderson Hospital (42 MeVH-----Be), and The Cleveland Clinic (42 MeVp+----Be). Patients were stratified by treatment facility and then randomized to receive 16, 18 or 20 Gy for tumors located in the upper abdomen or pelvis, and 18, 20 or 22 Gy for tumors located in the head and neck, thorax or extremities. Following completion of the randomized protocols, additional patients were studied at the 20.4 Gy level in the head and neck, thorax and pelvis. Normal tissue effect scoring was accomplished using the RTOG-EORTC acute and late normal tissue effect scales. Acute Grade 3 + toxicity rates in the head and neck were 19% for 20/20.4 Gy and 20% for 22 Gy. Time adjusted late toxicity rates in the head and neck at 12 months were 15% for 20/20.4 Gy and 0% for 22 Gy. The 18 Gy treatment arm of the head and neck protocol was dropped early in the study after only two patients were accrued. For cases treated in the thorax, acute Grade 3 + toxicity rates were 6% for 18 Gy, 15% for 20/20.4 Gy and 7% for 22 Gy. Late toxicity rates at 12 months were 0% for 18 Gy, 11% for 20/20.4 Gy and 18% for 22 Gy. Acute Grade 3+ toxicity rates in the upper abdomen were 0% for 16 Gy, 8% for 18 Gy and 12% for 20 Gy. There were no Grade 3 + late toxicities in the upper abdomen. In the pelvis, acute Grade 3 + toxicity rates were 0% for 16 Gy, 3% for 18 Gy and 3% for 20/20.4 Gy. Late Grade 3 + toxicities at 24 months were 20% for 16 Gy, 5% for 18 Gy and 24% for 20/20.4 Gy. In extremities, acute Grade 3 + toxicity rates were 7% for 20 Gy and 21% for 22 Gy while at 12 months, late Grade 3 + toxicity rates were 14 and 35%, respectively. The 18 Gy treatment arm of the extremities protocol was dropped early in the study after only two patients were accrued. Factors associated with normal tissue effects in addition to treatment dose are discussed.

The effect of oral nutritional supplements on head and neck cancer.

Fifty ambulatory patients with head and neck cancer treated by definitive radiation therapy at the Fox Chase Cancer Center were prospectively studied to determine the effect of oral nutritional supplements on both nutritional status and treatment response. Nutritional supplements maintained serum albumin during and post treatment. Nutritional supplements were shown to increase total protein and total calorie intake rather than displace these nutrients in usual food intake. Equal weight loss occurred in both the supplemented and non-supplemented groups during the observation period of 6 months, with the same or greater amount of weight loss registered 10 weeks after the start of treatment. Food supplements did not affect treatment response or complications, nor did they offer any survival advantage.

Neutron vs photon irradiation of inoperable salivary gland tumors: results of an RTOG-MRC Cooperative Randomized Study.

A total of 32 patients with inoperable, recurrent or unresectable malignant salivary gland tumors were entered on a randomized RTOG/MRC study comparing fast neutron radiotherapy with conventional photon radiotherapy. Twenty-five patients were entered from the United States and 7 patients were entered from Scotland. Seventeen patients were randomized to receive neutrons and 15 patients were randomized to receive photons. Sixty-one percent of the neutron-treated patients and 75% of the photon-treated patients presented with inoperable or unresectable tumors, while 39% of the neutron-treated and 25% of the photon-treated patients had recurrent disease. Twenty-five patients were study-eligible and analyzable. The minimum follow-up time is 2 years. The complete tumor clearance rates at the primary site were 85% (11/13) for neutrons and 33% (4/12) for photons following protocol treatment (p = 0.01). The complete tumor clearance rates in the cervical lymph nodes were 86% (6/7) for neutrons and 25% (1/4) for photons. The overall loco/regional complete tumor response rates were 85% and 33% for neutrons and photons respectively. The loco/regional control rates at 2 years for the 2 groups are 67% for neutrons and 17% for photons (p less than 0.005). The 2-year survival rates are 62% and 25% for neutrons and photons respectively (p = 0.10). These findings are consistent with previously published uncontrolled series.

Quantitative lung scans for prediction of post-radiotherapy pulmonary function.

Quantitative perfusion scans were used to predict the proportion of pulmonary function lost by inclusion of lung in radiotherapy fields. Nineteen patients receiving radiotherapy for carcinoma of the lung had pulmonary function evaluated by forced expiratory volume at 1 second (FEV1) prior to and following radiotherapy. FEV1 measurement followed initiation of radiotherapy from two to 18 months (mean: seven months). Prior to radiotherapy quantitative lung scans were performed with Tc-99m macroaggregated albumin. On images acquired by computer, the radiotherapy field was drawn as a region of interest (ROI) and the proportion of count within this ROI relative to total lung count was determined. The total FEV1 was apportioned by the ROI ratio of count excluded from radiation ROI to total count in lungs to predict the FEV1 expected to be remaining after radiotherapy. In only two cases was the measured post-therapy FEV1 less than predicted (and then, by only 2% and 5%, respectively). The data indicate that quantitative perfusion lung scans can be used to predict conservatively the pulmonary function that may be expected to remain post-radiotherapy. Therapy fields may be adjusted in patients with underlying compromised pulmonary function to conserve a pre-selected FEV1.

Prospective prediction of post-radiation therapy lung function using quantitative lung scans and pulmonary function testing.

Surgeons have made use of quantitative perfusion lung scanning (QS) and forced expiratory volume in one second (FEV1) to predict a patient's ability to tolerate lung resection. In this study QS and FEV1 were used to predict prospectively pulmonary function following lung irradiation (XRT). Twenty-two patients have had QS and FEV1 determined before XRT and at planned intervals post-XRT. Serial determination of lung function post-XRT allows comment on the temporal nature of the XRT effect on lung function. Seventeen patients had QS and FEV1 determined at an interval of 2-6 months post-irradiation with a drop in the groups mean FEV1 from 1.91 to 1.87L. or 2% during that interval. In the interval from 6-12 months post-XRT, 13 patients had studies with the groups mean FEV1 dropping from 1.79 to 1.58L or 12% of the original. In the interval from 12-18 months, 6 patients had a decline in mean FEV1 from 1.73 to 1.56L. or 10% of the original. In 22 patients a predicted final FEV1 was compared with a measured value at an interval from XRT. Fourteen of these determinations were at intervals greater than 6 months from the start of XRT and 6 at intervals of greater than 1 year. FEV1 was seen to drop during the follow-up intervals toward the predicted value. In only 2 patients did the final FEV1 drop below the predicted FEV1 and never by more than 0.12L. (6%). In summary, a method for predicting post-XRT pulmonary function using QS and FEV1 is described. Serial follow-up revealed a latent period followed by a late phase where FEV1 fell toward, but not significantly below, the predicted value. Such a determination can be of value in formulating a treatment plan for patients with significantly diminished pulmonary function.

Practice of 3-dimensional treatment planning at the Fox Chase Cancer Center, University of Pennsylvania.

The use of 3-dimensional (3-D) dose distributions and dose-volume histograms in radiation therapy treatment planning is illustrated on a patient with a head and neck tumor. The patient was immobilized in a rectangular tissue compensation bolus box. The treatment was planned with a 14 MeV D-T derived fast neutron therapy beam. The isodose distributions and the dose-volume histograms at multiple adjacent levels are used to evaluate the adequacy of coverage of target volumes and the doses to the normal tissues. Such dose-volume histograms are useful and practical in summarizing the dose distribution throughout the irradiated volume, assessing the degree of uniformity of the dose distribution within the target volume, quantifying the amount of normal tissue irradiated, and evaluating rival treatment plans for both particle and nonparticle beams.

A prospective study of treatment techniques to minimize the volume of pelvic small bowel with reduction of acute and late effects associated with pelvic irradiation.

The volume, distribution, and mobility of opacified pelvic small bowel (PSB) were determined by fluoroscopy and orthogonal radiographs in 150 consecutive patients undergoing pelvic irradiation. Various techniques including uteropexy, omental transposition, bladder distention, inclining the patient, and anterior abdominal wall compression in the supine and prone treatment position were studied for their effect on the volume and location of small bowel within the pelvis. Abdominal wall compression in the prone position combined with bladder distention was selected for further investigation because of its simplicity, reproducibility, patient comfort, and ability to displace the small bowel. Factors correlating with the volume of pelvic small bowel (PSB) included prior pelvic surgery, pelvic irradiation (XRT), and body mass index. After pelvic surgery, especially following abdominoperineal resection (APR), there was a greater volume of PSB which was also less mobile. The severity of acute gastrointestinal effects positively correlated with the volume of irradiated small bowel. Overall, 67% of patients experienced little or no diarrhea, 30% developed mild diarrhea, and no patient required treatment interruption. Late gastrointestinal effects correlated with the prior pelvic surgery and with the volume of small bowel receiving greater than 45 Gy. Small bowel obstruction was not observed in 75 patients who had no previous pelvic surgery. However, following pelvic surgery excluding APR, 2/50 patients and following APR, 3/25 patients developed small bowel obstruction.

Oxygen tension in human tumors: in vivo mapping using CT-guided probes.

The role of oxygen in tumor response to therapy has been studied for several decades. We describe a technique that allows in vivo measurement of oxygen in tumors using computed tomography to guide probes. In the evaluation of 16 tumors, oxygen tensions were found to be substantially lower than surrounding tissue and varied nonrandomly. This technique has allowed construction of detailed tumor oxygen level maps.

The postoperative irradiation of transitional cell carcinoma of the renal pelvis and ureter.

The role of adjuvant irradiation in the treatment of transitional cell carcinoma of the renal pelvis and ureter was reviewed. Between June 1966 and March 1981, 41 patients underwent curative resections. A poor risk group was identified, with 23 patients demonstrating disease greater than grade 2 or stage B. Postoperative irradiation was administered to 11 of 23 patients. Median patient followup was 40 months. Two-thirds of all failures occurred within the first 12 months and no failure was seen beyond 35 months. Patients with poor prognostic features had a 60 per cent failure rate compared to 11.8 per cent of the patients with good risk factors (p equals 0.023). The median survival of the 2 groups was 28 and 99 months, respectively (p less than 0.001). Outcome of the poor risk patients was analyzed whether or not the patient received postoperative irradiation. None of the irradiated patients failed with local disease only, while there was 1 patient with local and distant recurrence. In contrast, the nonirradiated group had 5 local failures and twice the number of failures over-all. Median survival of the irradiated and nonirradiated patients was 35 and 26 months, respectively. The number of patients treated is too small to permit valid statistical conclusions and indicates the need for a multi-institutional study to determine if these suggestive findings of improved local control will be corroborated and translate into an improved survival rate.

A pilot study of combined radiotherapy and chemotherapy for esophageal carcinoma.

Between 9/80 and 9/83, 20 patients with esophageal carcinoma were treated with combined radiotherapy and chemotherapy (5-FU and mitomycin). Thirteen patients with Stages I or II disease received definitive treatment consisting of 6000 rad in 6-7 weeks and 5-FU (1000 mg/m2/24 hours) as a continuous I.V. infusion for 96 hours starting on days 2 and 28. Mitomycin (10 mg/m2) was administered as a bolus injection on day 2. Palliative treatment (5000 rad plus above chemotherapy) was delivered to six patients with Stage III disease (two with extra-esophageal spread, four with distant metastases) and to one patient with an anastomotic recurrence following resection. Two of 13 definitively treated patients were not evaluable due to early death from intercurrent disease. Ten of 11 evaluable patients treated definitively are alive from 4-32 months; the median survival has not been reached at 17 months. Four of 11 evaluable patients treated definitively have relapsed, with only one relapsing within the irradiated field. Among the palliative and definitively treated patients, relief of dysphagia was seen in 16/17, and continued until the time of last follow-up or until death in 13/17. The treatment was well tolerated and no significant hematologic problems were incurred. This combination of radiation therapy with infusional 5-FU and mitomycin appears to be an effective and well-tolerated regimen in the treatment of esophageal carcinoma and is worthy of further study.

Current status of high linear energy transfer irradiation.

Based on laboratory investigations, high linear energy transfer (LET) particle irradiation is capable of more efficient cell kill than that associated with conventional or low LET irradiation. The advantages of high LET irradiation include: (1) a greater ability to damage hypoxic cells; (2) a lesser ability for repair of sublethal and potentially lethal radiation-induced damage; (3) less variation in radiation sensitivity relative to the cell cycle; and (4) a greater ability to deposit the radiation dose in the region of the tumor as opposed to the normal surrounding tissue (neutrons do not have this advantage compared to other particle therapy). Despite these laboratory advantages, it has been difficult to demonstrate any advantage of high LET irradiation in the clinic. A number of new developments have occurred to test the role of high LET: (1) sophisticated technology to enable treatment delivery with higher dose rate and improved depth dose; (2) the construction of hospital-based facilities; and (3) the development of randomized studies involving diseases in which the risk of early metastasis is minimized. It is hoped that careful study in the clinic over the next decade will elucidate the role of high LET particle therapy.

CT-guided biopsy for the detection and staging of tumors of the head and neck.

Twenty patients underwent computed tomography (CT)-guided thin-needle biopsy of tumors of the had and neck without complication. This technique was found to have wide application in confirming the presence and extent of primary disease as well as documenting nodal and bony metastases not apparent clinically.

Research in cancer patient education and compliance.

A study design has been presented which has the advantage of combining the research questions of education program evaluation and patient compliance. While it would be possible to evaluate education programs in other ways (e.g., using a sample of all program participants rather than a sample of all patients for whom a regimen was recommended), such an alternative design would not assess the potentially significant proportion of noncompliance which might occur when the regimen recommendation is made. It is the specification of inception cohorts as the study population that allows the accrual of more complete compliance data for the regimen as well as evaluation data for the education program. Given the recognized need for data on the compliance of cancer patients, the added cost of specifying inception cohorts for education program evaluations seems small. The proposed research design has the potential to contribute to cancer control programs: 1. a careful evaluation of new education programs for patients; 2. modifications of education programs based on feedback from professionals and patients during the initial implementation; 3. needed data on cancer patient compliance with extended detection and treatment regimens; and 4. increased understanding of the process of patient compliance, including identification of key variables in the health belief model which account for compliance among cancer patients.