Theodore L. Phillips

Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials

PURPOSE Promising results from new approaches such as radiosurgery or stereotactic surgery of brain metastases have recently been reported. Are these results due to the therapy alone or can the results be attributed in part to patient selection? An analysis of tumor/patient characteristics and treatment variables in previous Radiation Therapy Oncology Group (RTOG) brain metastases studies was considered necessary to fully evaluate the benefit of these new interventions. METHODS AND MATERIALS The database included 1200 patients from three consecutive RTOG trials conducted between 1979 and 1993, which tested several different dose fractionation schemes and radiation sensitizers. Using recursive partitioning analysis (RPA), a statistical methodology which creates a regression tree according to prognostic significance, eighteen pretreatment characteristics and three treatment-related variables were analyzed. RESULTS According to the RPA tree the best survival (median: 7.1 months) was observed in patients < 65 years of age with a Karnofsky Performance Status (KPS) of at least 70, and a controlled primary tumor with the brain the only site of metastases. The worst survival (median: 2.3 months) was seen in patients with a KPS less than 70. All other patients had relatively minor differences in observed survival, with a median of 4.2 months. CONCLUSIONS Based on this analysis, we suggest the following three classes: Class 1: patients with KPS > or = 70, < 65 years of age with controlled primary and no extracranial metastases; Class 3: KPS < 70; Class 2- all others. Using these classes or stages, new treatment techniques can be tested on homogeneous patient groups.

A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003

Abstract Purpose: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation. Methods and Materials: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1.2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. Results: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control ( p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival ( p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. Conclusions: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.

Radiosurgery for brain metastases: is whole brain radiotherapy necessary?

PURPOSE Because whole brain radiotherapy (WBRT) may cause dementia in long-term survivors, selected patients with brain metastases may benefit from initial treatment with radiosurgery (RS) alone reserving WBRT for salvage as needed. We reviewed results of RS +/- WBRT in patients with newly diagnosed brain metastasis to provide background for a prospective trial. METHODS AND MATERIALS Patients with single or multiple brain metastases managed initially with RS alone vs. RS + WBRT (62 vs. 43 patients) from 1991 through February 1997 were retrospectively reviewed. The use of upfront WBRT depended on physician preference and referral patterns. Survival, freedom from progression (FFP) endpoints, and brain control allowing for successful salvage therapy were measured from the date of diagnosis of brain metastases. Actuarial curves were estimated using the Kaplan-Meier method. Analyses to adjust for known prognostic factors were performed using the Cox proportional hazards model (CPHM) stratified by primary site. RESULTS Survival and local FFP were the same for RS alone vs. RS + WBRT (median survival 11.3 vs. 11.1 months and 1-year local FFP by patient 71% vs. 79%, respectively). Brain FFP (scoring new metastases and/or local failure) was significantly worse for RS alone vs. RS + WBRT (28% vs. 69% at 1 year; CPHM adjustedp = 0.03 and hazard ratio = 0.476). However, brain control allowing for successful salvage of a first failure was not significantly different for RS alone vs. RS + WBRT (62% vs. 73% at 1 year; CPHM adjusted p = 0.56). CONCLUSIONS The omission of WBRT in the initial management of patients treated with RS for up to 4 brain metastases does not appear to compromise survival or intracranial control allowing for salvage therapy as indicated. A randomized trial of RS vs. RS + WBRT is needed to assess survival, quality of life, and cost in good-prognosis patients with newly diagnosed brain metastases.

Injury to the lung from cancer therapy: Clinical syndromes, measurable endpoints, and potential scoring systems

Toxicity of the respiratory system is a common side effect and complication of anticancer therapy that can result in significant morbidity. The range of respiratory compromise can extend from acute lethal events to degrees of chronic pulmonary decompensation, manifesting years after the initial cancer therapy. This review examines the anatomic-histologic background of the lung and the normal functional anatomic unit. The pathophysiology of radiation and chemotherapy induced lung injury is discussed as well as the associated clinical syndromes. Radiation tolerance doses and volumes are assessed in addition to chemotherapy tolerance and risk factors and radiation-chemotherapy interactions. There are a variety of measurable endpoints for detection and screening. Because of the wide range of available quantitative tests, it would seem that the measurement of impaired lung function is possible. The development of staging systems for acute and late toxicity is discussed and a new staging system for Late Effects in Normal Tissues (LENT) is proposed.

Radiation tolerance of the spinal cord

A series of nine cases of radiation myelopathy seen at the University of California, San Francisco (UCSF) is reviewed, and their treatment data converted into nominal single doses (NSD) and equivalent single doses (ED). The 1% incidence level of myelopathy in the thoracic cord is 1015 rets (ED), and the 50% incidence level is 1476 rets (ED). Caution should be used when utilizing a rapid fractionation schedule; it appears that 2000 rads in 5 fractions and 3000 rads in 10 fractions is a safe regimen for the thoracic spinal cord.

Modification of radiation injury to normal tissues by chemotherapeutic agents

The effects of several cancer chemotherapeutic agents on radiation damage to normal intestine, esophagus, and lung tissue were evaluated in LAF1 mice using quantitive endpoints. In all tissues tested, actinomycin D increased injury and BCNU did not. In the intestine, adriamycin enhanced radiation damage more than any other agent. Bleomycin increased damage in the esophagus but not in the lung or intestine. Cyclophosphamide increased injury only in the lung, where vincristine caused minimal injury, and hydroxyurea, none. Only prednisolone caused significant radioprotection when given at the time of irradiation or at the time of expected death from pulmonary injury.

Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors.

PURPOSE To identify factors associated with radiation pneumonitis (RP) resulting from combined modality therapy (CMT) for lung cancer. MATERIALS AND METHODS Series published before 1994 that used CMT for the treatment of lung cancer and explicitly reported the incidence of RP are the basis for this analysis. Factors evaluated included the radiation dose per fraction (Fx), total radiation dose, fractionation scheme (split v continuous), type of chemotherapy and intended dose-intensity, overall treatment time, histology (small-cell lung cancer [SCLC] v non-small-cell lung cancer [NSCLC]), and treatment schedule (concurrent v induction, sequential, or alternating CMT). RESULTS Twenty-four series, including 27 treatment groups and 1,911 assessable patients, met our criteria for inclusion in this analysis. The median total dose of radiation used in the trials analyzed was 50 Gy (range, 25 to 63 Gy). The median daily Fx used was 2.0 Gy (range, 1.5 to 4.0 Gy). Nineteen series included 22 treatment groups and 1,745 patients treated with single daily fractions. Among these patients, 136 received a daily Fx greater than 2.67 Gy. Five series used twice-daily radiotherapy and included 166 patients (Fx, 1.5 to 1.7 Gy). The incidence of RP was 7.8%. In a multivariate analysis, only daily Fx, number of daily fractions, and total dose were associated with the risk of RP (P < .0001, P < .018, and P < .003, respectively). CONCLUSION In this analysis, the use of Fx greater than 2.67 Gy was the most significant factor associated with an increased risk of RP. High total dose also appears to be associated with an increased risk, but twice-daily irradiation seems to reduce the risk expected if the same total daily dose is given as a single fraction. High-Fx radiotherapy should be avoided in patients who receive CMT with curative intent.

Overview: Late effects of normal tissues (LENT) scoring system

The purpose of the Late Effects of Normal Tissues (LENT) Conference was to analyze the current scoring system for acute and late effects and develop a system that embodies simplicity of design and will result in accuracy of detail. The conference has concerned itself specifically with the development of scoring systems to be used in all anatomical sites and to recommend methods to validate them. These methods and the questions outlined for research will need to be conducted through the resources of the national and regional cooperative groups. The conference participants have the responsibility of implementing these recommendations and methods into the appropriate cooperative group with which each may be affiliated. While the development of studies for interventions to ameliorate acute and prevent late effects is the desired end, this will be a future development. Two acronyms introduce the new scoring system for late effects toxicity and the key elements forming the scales:

Quantification of combined radiation therapy and chemotherapy effects on critical normal tissues

In order to determine the modification of radiation effect on critical normal tissues which occurs with combinations of radiation and cancer chemotherapy, a review of laboratory and clinical data has been carried out. Information on 10 different normal tissues is available. It is clear that the antibiotic cancer chemotherapeutic agents are the most likely to enhance radiation injury, with increased levels reported in all tissues except the central nervous system. The second most common type of injury with combination therapy appears to occur with drugs causing injury to the normal tissue on their own, such as adriamycin in the heart and methotrexate in the central nervous system. Quantification of the dose‐effect factor is only available on a limited number of tissues and, primarily, in experimental animals. From these limited data, it is clear that dose‐effect factors between 1.1 and 1.8 are seen, indicating that radiation doses must be reduced by 10–80% for the same level of injury when combined with chemotherapy. The augmentation of radiation damage by cancer chemotherapeutic agents is a serious problem in a wide range of tissues, but a problem which can be dealt with by accurate knowledge as to the dose‐effect factor and appropriate modification of the radiation treatment.

Radiation pneumonitis: A new approach to the derivation of time‐dose factors

A series of 51 patients treated with 92 separate lung fields for metastatic pulmonary disease between 1958 and 1971 is reviewed. The treatment data are converted into nominal single doses (NSD) and a newly derived formula for estimated single doses (ED). The 5% incidence level of pneumonitis without dactinomycin is 770 rets (NSD) and 510 rets (ED) and with dactinomycin, 520 rets (NSD) and 450 rets (ED). A safe treatment regimen for avoiding radiation pneumonitis is 1500 rads in 10 fractions with dactinomycin and 2500 rads in 20 fractions without dactinomycin.