Frank J. Thomas

Randomized neutron dose searching study for malignant gliomas of the brain: Results of an RTOG study

From September 1980 through January 1985, the Radiation Therapy Oncology Group (RTOG) conducted a randomized, dose-searching study testing the efficacy of a concomitant neutron boost along with whole brain photon irradiation in the treatment of malignant gliomas of the brain. Patients had to have biopsy-proven, supratentorial, anaplastic astrocytoma or glioblastoma multiforme (Nelson schema) to be eligible for the study. The whole brain photon irradiation was given at 1.5 Gy per treatment, 5 days-a-week to a total dose of 45 Gy. Two days-a-week the patients were to receive neutron boost irradiation to the tumor volume as determined on CT scans. The neutron irradiation was to be given prior to and within 3 hours of the photon irradiation on that day. The rationale for this particular treatment regime is discussed. A total of 190 evaluable patients were randomized among 6 different neutron dose levels: 3.6, 4.2, 4.8, 5.2, 5.6 and 6.0 Gyn gamma. There was no difference in overall survival among the 6 different dose levels, but for patients having less aggressive tumor histology (anaplastic astrocytoma), there was a suggestion that patients on the higher dose levels had poorer overall survival than patients on the lower dose levels and also did worse than historical photon controls. Important prognostic factors were identified using a Cox stepwise regression analysis. Tumor histology, Karnofsky performance status, and patient age were found to be related to survival while extent of surgery and neutron dose had no significant impact. Autopsies were performed on 35 patients and the results correlated with the actual neutron dose as determined by central-axis isodose calculations. At all dose levels there were some patients with both radiation damage to normal brain tissue and evidence of viable tumor. No evidence was found for a therapeutic window using this particular treatment regimen.

Response of a non-Hodgkin lymphoma to 60Co therapy monitored by 31P MRS in situ☆

High quality 31P MR spectra (signal to noise ratio (S/N) approximately 18, 15 min acquisition for each spectrum) were consistently obtained with surface coils over a period of 6-week RT. Both transient and steady state alterations in metabolites in response to RT were found in this case. The transient changes occurred during the first 3 hr immediately after the 3rd fractionated RT, these changes include the transient elevation of the PCr resonance, a decrease in PDE and an increase in intracellular pH. The monitoring showed that the metabolites approached steady state approximately 2 hr after the fractionated radiation intervention, suggesting that in vivo MRS can be useful for studying the dynamics of tumor response to RT such as repair of potential lethal damage, growth delay, and reoxygenation etc. The steady-state MR spectra showed the net response to each intervention and can clinically be useful for predicting and measuring the result of the fractionated RT. In this case study, the PDE peak which contains the phospholipid metabolites GPC and GPE, is the most sensitive resonance in response to RT. After the 3rd RT, prior to tumor size reduction, the PDE to ATP ratio decreased 33% and intracellular pH increased to 7.34 +/- 0.05 from 7.27 +/- 0.05. In the subsequent RT interventions, both the tumor size and PDE/ATP ratio continually decreased whereas the pH values remained alkaline and fluctuated around 7.34 to 7.65. The data suggest that the phospholipid metabolite PDE may signal important alterations in membrane metabolism that eventually lead to cell death.

Neutron Therapy in Cervical-cancer - Results of a Phase-iii Rtog Study

Between October 1976 and May 1984, 156 patients with locally advanced cervical cancer were entered into a Phase III trial with the participation of five institutions. Patients were randomly assigned to receive photons only (50 Gy in 25 fractions over 5 weeks plus intracavitary applications or external-beam boost) or mixed-beam radiotherapy (2 fractions a week of neutrons, 3 fractions a week of photons to a total RBE-adjusted dose of 50 Gy over 5 weeks plus intracavitary applications or external mixed-beam boost). Only patients with squamous carcinoma of FIGO Stages IIB, III, or IVA with negative para-aortic nodes on lymphangiogram were eligible. Ten patients were excluded from the analysis because of ineligibility or cancellation. Of the 146 patients analyzed, 80 were treated with mixed-beam radiotherapy and 66 with photons. Patients were grouped by stage and institution. The percentage of patients undergoing intracavitary applications was 50% on mixed beam and 75% on photons (p less than 0.01). Tumor clearance was 52% and 72% for mixed beam and photons, respectively (p less than 0.03). Local control at 2 years was 45% for mixed beam and 52% for photons. Median survivals were 1.9 years on mixed beam and 2.3 years on photons. Severe complications occurred in 19% and 11% in mixed beam and photons respectively (p less than 0.13). The inferior outcome with neutron therapy in this study may have resulted from the use of horizontal neutron beams of varying energy and penetration. A new randomized trial using high-energy hospital-based cyclotrons with gantry-mounted beam-delivery systems has recently been activated to evaluate more rigorously the role of fast-neutron therapy for advanced cervical cancer.

Evaluation of neutron irradiation of pancreatic cancer: results of a randomized radiation therapy oncology group clinical trial

Between 1980–84, the Radiation Therapy Oncology Group conducted a trial in patients with untreated, unresectable localized carcinomas of the pancreas. Patients were randomly chosen to receive either 6,400 cGy with photons, the equivalent dose with a combination of photons and neutrons (mixed-beam irradiation), or neutrons alone. A total of 49 cases were evaluable, of which 23 were treated with photons, 11 with mixed-beam therapy, and 15 with neutrons alone. The median survival time was 5.6 months with neutrons, 7.8 months with mixed-beam radiation, and 8.3 months with photons. The median local control time was 6.7 months with neutrons, 6.5 months with mixed-beam radiation, and 2.6 months with photons. These differences are not statistically significant. Evidence of moderate-to-life-threatening gastrointestinal or hepatic injury was present in three patients treated with neutrons and one patient treated with photons. The causes of this apparent difference are discussed. This study demonstrates there is no evidence to suggest that neutron irradiation, either alone or in combination with photon irradiation, produces better local control or survival rates than photon irradiation.

Fast neutron and mixed beam radiotherapy for inoperable non-small cell carcinoma of the lung. Results of an RTOG randomized study.

From July 1979 through March 1984 the Radiation Therapy Oncology Group conducted a randomized study comparing fast neutron radiotherapy versus mixed beam (neutron/photon) radiotherapy versus conventional radiotherapy for patients with non-small cell carcinoma of the lung. Patients were either medically or technically inoperable. One hundred two evaluable patients were placed on the study. The radiation doses were approximately 60 Gy-equivalent on each arm. Patients were stratified according to size of primary, histology, Karnofsky performance status, and age distribution. Overall local response rates as measured by serial radiographs were the same on the three arms, and an actuarial analysis showed no significant differences in either median or long-term survival. However, for the subgroup of patients exhibiting a complete or partial tumor response at 6 months there was a suggestion of improved 3-year survival on the two experimental arms (mixed beam, 37%; neutrons, 25%; photons, 12%). The p value for the difference between the mixed beam and photon curves is 0.14 (two-sided test). The incidence of major complications was higher on the neutron and mixed beam arms. These complications included four cases of myelitis which are analyzed in detail. The results are placed in the context of other published work on the use of neutrons in the treatment of lung cancer.

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.

Evaluation of a neutron boost in head and neck cancer. Results of the randomized RTOG trial 78-08

Patients with untreated squamous cell cancer of the head and neck region were randomized to receive either a boost of 25–30 Gy using photon-beam irradiation (photons) or an equivalent boost using neutron-beam irradiation (neutrons). All patients received an initial 45–50 Gy of wide-field photon irradiation. A total of 57 patients was evaluable on the neutron arm and 58 were evaluable on the photon arm. The proportion of patients with complete responses was 60 and 64% on the neutron and photon arms, respectively. The locally disease-free proportion at 2 years was estimated to be 20 and 31%, and the 2-year survival was estimated to be 32 and 41%, respectively. These differences are not statistically significant. There was a higher rate of severe complications on the neutron arm, 16 versus 7%. Thus, there was no evidence that a neutron boost produces better initial tumor clearance, local tumor control, or survival than a photon boost, and it may produce more complications.

Application of thermal dilution measurements for thermal treatment planning

The use of thermal dilution measurements is demonstrated in quantifying effective thermal conductivity distributions through tumours. For focused acoustic sources these data are applied in the solution of the heat diffusion equation to estimate steady-state temperature distributions. The advantages and disadvantages of this approach are presented. The effective conductivity measurements are found to be useful in predicting the circumstances under which this simple model can be applied and in aiding the selection of the most appropriate heating modality.