Showing papers in "International Journal of Radiation Oncology Biology Physics in 1991"

Tolerance of normal tissue to therapeutic irradiation.

Abstract: The importance of knowledge on tolerance of normal tissue organs to irradiation by radiation oncologists cannot be overemphasized. Unfortunately, current knowledge is less than adequate. With the increasing use of 3-D treatment planning and dose delivery, this issue, particularly volumetric information, will become even more critical. As a part of the NCI contract N01 CM-47316, a task force, chaired by the primary author, was formed and an extensive literature search was carried out to address this issue. In this issue. In this manuscript we present the updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, with a special emphasis on partial volume effects. Due to a lack of precise and comprehensive data base, opinions and experience of the clinicians from four universities involved in the contract have also been contributory. Obviously, this is not and cannot be a comprehensive work, which is beyond the scope of this contract.

Fitting of normal tissue tolerance data to an analytic function

Abstract: During external beam radiotherapy, normal tissues are irradiated along with the tumor. Radiation therapists try to minimize the dose of normal tissues while delivering a high dose to the target volume. Often this is difficult and complications arise due to irradiation of normal tissues. These complications depend not only on the dose but also on volume of the organ irradiated. Lyman has suggested a four-parameter empirical model which can be used to represent normal tissue response under conditions of uniform irradiation to whole and partial volumes as a function of the dose and volume irradiated. In this paper, Lyman's model has been applied to a compilation of clinical tolerance data developed by Emami et al. The four parameters to characterize the tissue response have been determined and graphical representations of the derived probability distributions are presented. The model may, therefore, be used to interpolate clinical data to provide estimated normal tissue complication probabilities for any combination of dose and irradiated volume for the normal tissues and end points considered.

Histogram reduction method for calculating complication probabilities for three-dimensional treatment planning evaluations.

Abstract: New tools are needed to help in evaluating 3-D treatment plans because of the large volume of data. One technique which may prove useful is the application of complication probability calculations. A method of calculating complication probabilities for inhomogeneously irradiated normal tissues is presented in this paper. The method uses clinical estimates of tolerance doses for a few discreet conditions of uniform partial organ irradiation, an empirical fit of a continuous function to these data, and a technique (the effective volume method) for transforming nonuniform dose-volume histograms into equivalent uniform histograms. The behavior of the effective volume histogram reduction method for various boundary conditions is reviewed. The use of complication probabilities in evaluating treatment plans is presented, using examples from an NCI 3-D treatment planning contract.

The effect of local control on metastatic dissemination in carcinoma of the prostate: Long-term results in patients treated with 1251 implantation

Abstract: The study evaluates the effect of the locally recurring tumor on the incidence of metastatic disease in early stage carcinoma of the prostate. The probability of distant metastases was studied in 679 patients with Stage B-C/NO carcinoma of the prostate treated at MSKCC between 1970 and 1985 (median follow-up of 97 months). Patients were staged with pelvic lymph node dissection and treated with retropubic 125I implantation. The actuarial distant metastases free survival (DMFS) for patients at risk at 15 years after initial therapy was 37%. Cox proportional hazard regression analysis of covariates affecting the metastatic outcome showed that local failure, used in the model as a time dependent variable, was the most significant covariate, although stage, grade, and implant volume were also found to be independent variables. The relative risk of metastatic spread subsequent to local failure was 4-fold increased compared to the risk without evidence of local relapse. The 15-year actuarial DMFS in 351 patients with local control was 77% compared to 24% in 328 patients who developed local relapses (p < 0.00001). The relation of distant spread to the local outcome was observed regardless of stage, grade, or implant dose. Even stage BI/NO-Grade I patient with local control showed a 15-year actuarial DMFS of 82%, compared to 22% in patients with local relapse; p < 0.00001). The median local relapse-free survival (LRFS) in the 268 patients with local recurrences who did not receive hormonal therapy before distant metastases were detected was 51 months, compared to a median of 71 months for DMFS in the same patients (p < 0.001), consistent with the possibility that distant dissemination may develop secondary to local failure. Furthermore, distant metastases in patients with local control, apparently already existing as micrometastases before treatment, were detected earlier (median DMFS of 37 months) than in patients with local relapse (median DMFS of 54 months; p = 0.009). These data suggest that the existence and re-growth of local residual disease in localized prostatic carcinoma promotes an enhanced spread of metastatic disease, and that early and complete eradication of the primary tumor is required if a long term cure is to be achieved, although the clinical expression of secondary metastases may not become apparent for 6.5 years or more in one-half of the patients.

Epidermoid anal cancer: Treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C

Abstract: One hundred ninety-two patients with primary epidermoid cancer of the anal canal were treated by a series of prospectively designed, sequential non-randomized protocols of radiation alone (RT), radiation with concurrent 5-Fluorouracil and Mitomycin C (FUMIR), or radiation with concurrent 5-Fluorouracil only (FUR). The 5-year cause-specific survival rates were 69% overall, 68% RT, 76% FUMIR, 64% FUR. The primary tumor was controlled by radiation with or without chemotherapy in 68% (130/191) overall, 56% (32/57) by RT, 86% (59/69) by FUMIR, 60% (39/65) by FUR. The results with FUMIR were significantly better than with either RT alone or FUR, and except in tumors up to 2 cm in size, this superiority was found in all T stages. Regional lymph node metastases were controlled in 33 of 38 (87%) overall. The finding of clinically detectable regional lymph node metastases at presentation did not affect survival significantly in any treatment group. Anorectal function was preserved in 88% of the patients in whom the primary tumor was controlled, and in 64% overall. The delivery of 5FU and MMC concurrently with uninterrupted radical irradiation, 50 Gy in 20 fractions in 4 weeks, produced severe acute and late normal tissue morbidity. Split course treatment, and reduction of the daily fractional dose to 2 Gy, diminished the severity of normal tissue damage. Omission of Mitomycin C reduced acute hematological toxicity, but was associated with a decreased primary tumor control rate. The most effective treatment protocols as measured by survival rates, primary anal tumor control rates, and the likelihood of conservation of anorectal function included the administration of both Mitomycin C and 5-Fluorouracil concurrently with radiation therapy.

Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy

Abstract: The likelihood of radiation pneumonitis and factors associated with its development in breast cancer patients treated with conservative surgery and radiation therapy have not been well established. To assess these, we retrospectively reviewed 1624 patients treated between 1968 and 1985. Median follow-up for patients without local or distant failure was 77 months. Patients were treated with either tangential fields alone ( n = 508) or tangents with a third field to the supraclavicular (SC) or SC-axillary (AX) region ( n = 1116). Lung volume treated in the tangential fields was generally limited by keeping the perpendicular distance (demagnified) at the isocenter from the deep field edges to the posterior chest wall (CLD) to 3 cm or less. Seventeen patients with radiation pneumonitis were identified (1.0%). Radiation pneumonitis was diagnosed when patients presented with cough (1517, 88%), fever (917,53%), and/or dyspnea (617,35%) and radiographic changes (1717) following completion of RT. Radiographic infiltrates corresponded to treatment portals in all patients, and in 12 of the 17 patients, returned to baseline within 1–12 months. Five patients had permanent scarring on chest X ray. No patient had late or persistent pulmonary symptoms. The incidence of radiation pneumonitis was correlated with the combined use of chemotherapy (CT) and a third field. Three percent (11/328) of patients treated with a 3-field technique who received chemotherapy developed radiation pneumonitis compared to 0.5% (6 of 1296) for all other patients ( p = 0.0001). When patients treated with a 3-field technique received chemotherapy concurrently with radiation therapy, the incidence of radiation pneumonitis was 8.8% (892) compared with 1.3% (3236) for those who received sequential chemotherapy and radiation therapy ( p = 0.002). A casexontrol analysis was performed to determine if the volume of lung irradiated (as determined using central lung distance [CLD]) was related to the risk of developing radiation pneumonitis. Three control patients were matched to each case of radiation pneumonitis based on age, side of lesion, chemotherapy (including sequencing), use of a third field, and year treated. Lung volumes were similar in the radiation pneumonitis cases and controls. We conclude that radiation pneumonitis following conservative surgery and radiation therapy for breast cancer is a rare complication, and that it is more likely to occur in patients treated with both a 3-field technique and chemotherapy (particularly given concurrently with radiation therapy). Over the limited range of volumes treated, lung volume was not associated with an increased risk of radiation pneumonitis.

Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706

Abstract: Significant late intestinal and urinary morbidity from external beam irradiation for adenocarcinoma of the prostate has been a constant concern of both the urologist and the radiation oncologist. We analyzed two large Radiation Therapy Oncology Group trials (7506 and 7706) using primary irradiation in the treatment of local or locoregional adenocarcinoma of the prostate to assess morbidity via the Radiation Therapy Oncology Group scoring scheme (grade 1–5). One thousand twenty patients were treated in total with a minimum follow-up of 7 years in the surviving patients. There was a 3.3% incidence of intestinal complications defined as grade 3 toxicity or more with .6% of patients experiencing bowel obstruction or perforation. Urinary complications defined as grade 3 toxicity or more were found in 7.7% of patients with only 0.5% experiencing morbidity that would require a major surgical intervention such as laparotomy, cystectomy, or prolonged hospitalization. Intestinal and urinary complications were evaluated in reference to several parameters that might have an impact on their incidence (i.e., previous laparotomy, stage of disease, hypertension, positive lymph nodes, previous transurethral resection, total dose, and energy of accelerator used). Only total dose (70 Gray) was found to have a significant impact on the incidence of the urinary complications. None of these factors had a significant impact on the incidence of intestinal complications. These data from two large multi-institutional trials represent a fair estimate of the actual incidence of major intestinal and urinary complications from external beam irradiation in the management of local and locoregional adenocarcinoma of the prostate. Since the incidence of these major complications remains very low, we believe that external beam irradiation remains an excellent alternative to radical prostatectomy in the management of these patients.

Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: Report of intergroup study 0034

Abstract: To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region, a randomized clinical trial was conducted under the auspices of the Head and Neck Intergroup (Radiation Therapy Oncology Group, Southwest Oncology Group, Eastern Oncology Group, Cancer and Leukemia Group B, Northern California Oncology Group, and Southeast Group). Eligible patients had completely resected tumors of the oral cavity, oropharynx, hypopharynx, or larynx. They were then randomized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy (CT/RT) or postoperative radiotherapy alone (RT). Patients were categorized as having either "low-risk" or "high-risk" treatment volumes depending on whether the surgical margin was greater than or equal to 5 mm, there was extracapsular nodal extension, and/or there was carcinoma-in-situ at the surgical margins. Radiation doses of 50-54 Gy were given to "low-risk" volumes and 60 Gy were given to "high-risk" volumes. A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis. The 4-year actuarial survival rate was 44% on the RT arm and 48% on the CT/RT arm (p = n.s.). Disease-free survival at 4 years was 38% on the RT arm compared to 46% on the CT/RT arm (p = n.s.). At 4 years the local/regional failure rate was 29% vs. 26% for the RT and CT/RT arms, respectively (p = n.s.). The incidence of first failure in the neck nodes was 10% on the RT arm compared to 5% on the CT/RT arm (p = 0.03 without adjusting for multiple testing) and the overall incidence of distant metastases was 23% on the RT arm compared to 15% on the CT/RT arm (p = 0.03). Treatment related toxicity is discussed in detail, but, in general, the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy. Implications for future clinical trials are discussed.

Pretreatment and treatment factors associated with improved outcome in squamous cell carcinoma of the uterine cervix: a final report of the 1973 and 1978 patterns of care studies.

Abstract: The Patterns of Care Study (PCS) conducted two national surveys of patients treated in 1973 and 1978 for squamous cell cancer of the uterine cervix. In addition, a survey of patients treated in 1973 from selected large facilities was conducted to establish outcome with “optimal” radiotherapy. The large facility survey consistently reported improved outcome compared to both national average surveys when analyzed by stage and other significant pretreatment factors. That improved outcome was associated with the paracentral (PCS point A) dose and the use of intracavitary irradiation. In this study, we report the pretreatment and treatment factors associated with improved outcome in squamous cell carcinoma of the uterine cervix by analysis of the 1973 and 1978 PCS data. Pretreatment factors associated with improved pelvic control in multivariate analysis include higher Karnofsky Performance Status (KPS) (Stage I and II), older age (Stage I and II), unilateral parametrial involvement (Stage IIB), and unilateral sidewall involvement (Stage III). The only treatment factor associated with improved pelvic control in multivariate analysis is the use of intracavitary irradiation. However, a dose response for infield pelvic control was demonstrated only in Stage III cervix cancer with the highest rate of pelvic control with paracentral (PCS point A) dose > 8500 cGy. Multivariate analysis revealed that unilateral parametrial involvement for Stage IIB and unilateral sidewall involvement for Stage III are significant positive prognostic factors with respect to survival after treatment with radiotherapy. No FIGO substage significantly affected survival after radiotherapy. Although FIGO staging is the single most important pretreatment prognostic factor with respect to survival and infield pelvic failure, FIGO substaging deserves reappraisal and further refinement. Major complications were seen in only 9.5% of patients treated with radiotherapy and were stage but not survey related. There is a significant relationship between PCS point A dose and complications with the highest rate of complications for PCS point A dose > 8500 cGy. A significant relationship between lateral (external iliac lymph nodes or PCS point P) dose and major complications is also found, and doses > 5000 cGy are associated with a significant increase in complications. The PCS has established two sequential national benchmarks of treatment outcome for squamous cell carcinoma of the uterine cervix treated with radiotherapy with respect to survival, infield pelvic control, and complications. Through this study, several pretreatment and treatment prognostic factors have been established and a national goal of dose intensification through the use of intracavitary radiation identified to improve the results of radiotherapy for cervical cancer. A concommitant increase in complications can be expected and new strategies need to be developed to improve the therapeutic ratio.

Dose-volume histograms

Abstract: A plot of a cumulative dose-volume frequency distribution, commonly known as a dose-volume histogram (DVH), graphically summarizes the simulated radiation distribution within a volume of interest of a patient which would result from a proposed radiation treatment plan. DVHs show promise as tools for comparing rival treatment plans for a specific patient by clearly presenting the uniformity of dose in the target volume and any hot spots in adjacent normal organs or tissues. However, because of the loss of positional information in the volume(s) under consideration, it should not be the sole criterion for plan evaluation. DVHs can also be used as input data to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). The sensitivity of TCP and NTCP calculations to small changes in the DVH shape points to the need for an accurate method for computing DVHs. We present a discussion of the methodology for generating and plotting the DVHs, some caveats, limitations on their use and the general experience of four hospitals using DVHs.

Treatment planning issues related to prostate movement in response to differential filling of the rectum and bladder.

Abstract: Conventional simulation for patients with localized prostatic carcinoma often includes opacification of the dose limiting adjacent normal tissues. However, CT-based treatment planning is performed with the bladder and the rectum naturally filled or emptied. These latter conditions more closely approximate those in place at treatment. Comparison of these CT-based treatment plans to simulator films taken with the rectum and bladder opacified yielded indirect evidence of movement of the prostate gland by 0.5 cm or more in 31 of 50 consecutive patients. The range of motion was 0 to 2 cm with an average of 0.5 cm (1.0 cm in the 31 patients). Six additional patients (five with local recurrence following I-125 seed implantation) were analyzed separately using CT scans. Registered CT images (3 mm slices) taken with the rectum and bladder full and/or empty provided direct evidence of prostate movement in 3 of the 6 patients. The dosimetric consequences of this movement are demonstrated using 3-dimensional dose distributions.

The use of 3-D dose volume analysis to predict radiation hepatitis.

Abstract: Although it is well known that the tolerance of the liver to external beam irradiation depends on the volume of liver irradiated, few data exist which quantify this dependence Therefore, a review was carried out of our clinical trial for the treatment of intrahepatic malignancies in which the dose of radiation delivered depended on the volume of normal liver treated Three dimensional treatment planning using dose-volume histogram analysis of the normal liver was used for all patients Nine of the 79 patients treated developed clinical radiation hepatitis None of the patient related variables assessed were associated with radiation hepatitis All patients who developed radiation hepatitis received whole liver irradiation, as all or part of their treatment, which produced a mean dose greater than or equal to 37 Gy Dose volume histograms were used to calculate normal tissue complication probabilities based on parameters derived from the literature The risk of complication was greatly overestimated among patients receiving a high dose of radiation to part of the liver without whole liver treatment An estimation of model parameters based on the clinical results indicated a larger magnitude for the "volume effect parameter" than the literature estimate (n = 069 +/- 005 vs 032; p less than 0001) Computation of the normal tissue complication probabilities using the larger value of n produced a good description of the observed risk of radiation hepatitis These findings suggest that dose volume histogram analysis can be used to quantify the tolerance of the liver to radiation The predictive value of this parameterization of the normal tissue complication probability model will need to be tested with liver tolerance and dose volume histogram data from an independent clinical trial

Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy.

Abstract: Low dose rate interstitial brachytherapy is extremely useful for those tumors that are accessible for an implant, while the introduction of remote afterloaders has eliminated exposure to nursing personnel. Currently, such machines require an inventory of many sources which are loaded into catheters implanted in the tumor and kept in place during treatment. A significant simplification of such machines would be possible in a pulsed mode, with a single source moving under computer control through the catheters. Assuming that the treatment time and average dose rate are kept unchanged, the question addressed is to find those combinations of radiation pulse widths and frequencies that would be functionally equivalent to a continuous irradiation. The linear-quadratic formalism was used to reanalyze published low dose-rate studies on cells of human origin to obtain 36 parameter sets [alpha, beta, T1/2], where T1/2 is the half time for sublethal damage repair. These data are consistent with those for human tumors. For each parameter set, those combinations of pulse width and frequency were calculated that would yield a functionally equivalent cell survival. For a regimen of 30 Gy in 60 hr, a pulse width of 10 min with a period between pulses of 1 hr would be appropriate for all the cell lines considered. Similar results were found for other possible time/dose combinations. For late effects, a 1-hr period between 10-min pulses might produce up to a 2% increase in late-effect probability, which is probably acceptable for the small volumes irradiated in interstitial brachytherapy.

Astro plenary: Effect of chemotherapy on locally advanced non-small cell lung carcinoma: A randomized study of 353 patients

Abstract: Most patients with locally advanced non small cell lung carcinoma are treated with external thoracic radiotherapy. Because of the high incidence of distant metastasis the addition of chemotherapy has been proposed. The present randomized study was conducted from June 1983 to February 1989 and included 353 patients. The trial compared arm A, thoracic megavoltage radiotherapy alone at a total dose of 65 Gy in 26 fractions and 45 days, to arm B that comprised the same radiotherapy preceded and followed by 3 monthly cycles of VCPC (vindesine 1.5 mg/m2 d 1-2, cyclophosphamide 200 mg/m2 d 2-4, cisplatinum 100 mg/m2 d 2 and lomustine 75 mg/m2 d 3). Disease was deemed unresectable but non-metastatic after bronchoscopic, radiologic, CAT, and nuclear scans and physical examinations. Only patients in clinical, radiological, endoscopic, and histological complete remission were considered as locally controlled; these patients were monitored by fiberoptic bronchoscopy and systematic biopsies to the primary site. One hundred seventy-seven patients received thoracic radiotherapy alone and 176 received the combined modality. Twenty-seven percent of arm B patients had an objective response after 2 VCPC cycles. At the time of final assessment, performed 3 months after the end of thoracic radiotherapy in both arms, there were 20% of complete responders in arm A versus 16% in arm B. The two-year survival rate was 14% in arm A versus 21% in arm B (p = 0.08, logrank test). The distant metastasis rate was 67% in arm A versus 45% in arm B (p less than 0.001). Local control at 1 year was poor in both groups (17% and 15%, respectively). The striking effect of VCPC chemotherapy on the incidence of distant metastasis did not have a significant impact on overall survival. We conclude that thoracic tumor control remains a significant problem in unresectable non small cell lung cancer.

Long-term results of infusional 5-FU, mitomycin-C, and radiation as primary management of esophageal carcinoma

Abstract: An analysis of the results of 90 patients with esophageal cancer treated prospectively with combined chemotherapy and radiation without surgery and with a median follow-up of 45 months is presented. Fifty-seven patients with Stage I or II disease received definitive treatment consisting of 6,000 cGy in 6 to 7 weeks and 5-FU (1,000 mg/m 2 /24 hr) as a continuous intravenous (IV) infusion for 96 hours, starting on days 2 and 29. Mitomycin C (10 mg/m 2 ) was administered as a bolus injection on day 2. Thirty-three patients received palliative treatment (5,000 cGy plus above chemotherapy) for Stage III, IV, or otherwise advanced disease (extraesophageal spread, distant metastases, multiple primary tumors). Follow-up ranged from 1 month to 96 months. Overall median survival of Stage I and II patients was 18 months with 3- and 5-year actuarial survival of 29% and 18%, respectively, while the median disease specific survival was 20 months with an actuarial disease specific survival of 41% and 30% at 3 and 5 years, respectively. A multivariate analysis of sex, histology, tumor location, and tumor size on survival revealed that the effect of stage was highly significant (Stage I versus 11, 73% versus 33% at 3 years, p = .01), whereas the effect of sex approached significance (females versus males, 57% versus 34% at 3 years, p = p = p = .07). The pattern of failure may be altered with this treatment regimen from local failure to one dominated by distant metastases. Of 29 patients who have failed, 14 (48%) had any component of local failure, whereas 21 (72%) had a distant failure as a component of failure. The median survival of patients with Stage III or IV disease was 9 months and 7 months, respectively. Palliation in this group of patients with advanced disease was good as 77% were rendered free of dysphagia post-treatment, and 60% were without dysphagia until death with a median dysphagia-free duration of 5 months. Severe toxicities were uncommon and nearly all were transient. Eleven of 90 patients (12.2%) had severe acute toxicities, whereas only 3 patients (33%) developed significant late treatment-related complications requiring hospitalization for management.

Ten year results of conservative surgery and irradiation for stage I and II breast cancer

Abstract: Between 1977 and 1985, 697 women with clinical Stage I or II invasive breast cancer underwent excisional biopsy, axillary dissection, and definitive irradiation. Reexcision of the primary was performed in 330 and residual tumor was identified in 57% of these patients. Margins of resection were assessed in 50% and 257 had final margins of resection that were negative. Four hundred eighty patients had negative axillary dissections and 217 had histologically positive axillary nodes. Median follow-up was 58 months. The 10-year actuarial survival for the entire group was 83% with an NED survival of 73%. The 10-year actuarial survival was 87% for clinical Stage I and 77% for clinical Stage II patients with an NED survival of 79% and 67%, respectively. Patients with histologically negative axillary nodes had a 10-year overall survival of 86% (NED 78%) compared to 74% (NED 66%) for patients with positive nodes. Sixty-one patients developed a recurrence in the treated breast and in seven of these it was associated with simultaneous distant metastases. The cumulative probability of an isolated breast recurrence was 6% at 5 years and 16% at 10 years. The overall breast recurrence rate (+/- distant metastasis) was 8% at 5 years and 18% at 10 years. Breast recurrence was unrelated to T size, clinical stage, or histologic nodal status. The addition of adjuvant chemotherapy significantly decreased the risk of an isolated breast recurrence both at 5 and 10 years; however, there was no significant impact on the overall risk of a breast recurrence. Complications of treatment included moderate arm edema (5%), symptomatic pneumonitis (less than 1%), rib fraction (1%), pericarditis (0%), and brachial plexopathy (less than 1%). Cosmesis was judged to be good to excellent in 93% of patients in 10 years. These results have been achieved in a series of patients who for the most part have been treated by contemporary standards, that is, pathologic assessment of the axilla in all patients, reexcision in 47%, and adjuvant chemotherapy in 77% of node positive patients. Assessment of resection margins, however, was not performed in all patients (50%) and further follow-up in the group of patients with margin assessment will provide long term information on breast recurrence rate in this group of patients.

Relocatable frame for stereotactic external beam radiotherapy.

Abstract: A non-invasive head fixation system is described which is accurately relocatable and enables the transfer of stereotactic positions between a variety of radiodiagnostic images and therapeutic procedures. The system can be simply and repeatedly applied for planning stereotactic radiation therapy from one or more diagnostic images and for repeated treatment with a conventional linear accelerator. In addition, the long-term effects of therapy can be objectively monitored by relocating the frame and repeating images in an identical way, months or years later.

Fraction size in external beam radiation therapy in the treatment of melanoma

Abstract: RTOG 83-05 was a prospective randomized trial evaluating the effectiveness of high dose per fraction irradiation in the treatment of melanoma. Retrospective analysis suggested a dose response curve of melanoma to external beam irradiation as the dose per fraction is increased. RTOG 83-05 randomized patients with measureable lesions to 4 x 8.0 Gy in 21 days once weekly to 20 x 2.5 Gy in 26-28 days, 5 days a week. One hundred thirty-seven patients were randomized and 126 patients were evaluable: 62 patients in the 4 x 8.0 Gy arm and 64 patients in 200 x 2.5 Gy arm. Patient characteristics were essentially identical. Stratification was performed on lesions less than 5 cm or greater than or equal to 5 cm. The study was closed on May 31, 1988 when interim statistical analysis suggested that further accrual would not reveal a difference between arms. Response rate overall was complete remission 23.8%, partial remission 34.9%. The 4 x 8.0 Gy arm exhibited a complete remission of 24.2% and partial remission of 35.5%. The 20 x 2.5 Gy arm exhibited a complete remission of 23.4% and partial remission of 34.4%. There was no difference between arms.

Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma : long-term follow-up of RTOG study 73-03

Abstract: This is a report of a 10-year median follow-up of a randomized, prospective study investigating the optimal sequencing of radiation therapy (RT) in relation to surgery for operable advanced head and neck cancer. In May 1973, the Radiation Therapy Oncology Group (RTOG) began a Phase III study of preoperative radiation therapy (50.0 Gy) versus postoperative radiation therapy (60.0 Gy) for supraglottic larynx and hypopharynx primaries. Of 277 evaluable patients, duration of follow-up is 9-15 years, with 7.6% patients lost to follow-up before 7 years. Loco-regional control was significantly better for 141 postoperative radiation therapy patients than for 136 preoperative radiation therapy patients (p = 0.04), but absolute survival was not affected (p = 0.15). When the analysis was restricted to supraglottic larynx primaries (60 postoperative radiation therapy patients versus 58 preoperative radiation therapy patients), the difference for loco-regional control was highly significant (p = .007), but not for survival (p = 0.18). In considering only supraglottic larynx, 78% of loco-regional failures occurred in the first 2 years. Thirty-one percent (18/58) of preoperative patients failed locally within 2 years versus 18% (11/60) of postoperative patients. After 2 years, distant metastases and second primaries became the predominant failure pattern, especially in postoperative radiation therapy patients. This shift in the late failure pattern along with the increased number of unrelated deaths negated any advantage in absolute survival for postoperative radiation therapy patients. The rates of severe surgical and radiation therapy complications were similar between the two arms. Because of an increased incidence of late distant metastases and secondary primaries, additional therapeutic intervention is required beyond surgery and postoperative irradiation to impact significantly upon survival.

A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG-7916).

Abstract: From 1979 through July 1983, 859 patients were enrolled in a Phase III RTOG Protocol (7916) evaluating the role of Misonidazole combined with radiation in the treatment of brain metastasis. Patients were randomized to one of four treatment arms 3.0 Gy × 10 fractions with or without 1 g/m 2 of Misonidazole [total 10 g/m2] versus 5.0 Gy × 6 fractions with or without 2 g/m 2 of Misonidazole) [total 12 g/m 2 ]. Among the 779 analyzable cases, 63% had a lung primary and 12% had breast. Of the histologic types, 43% were adenocarcinoma and 24% were squamous cell. Seventy-eight percent had a Karnofsky of greater than 70. Of the 779 cases, 773 are dead (99%). Median survival is 3.9 months, with 60% alive at 3 months, 35% at 6 months, and 15% at 1 year. Survival was evaluated by treatment arm, Misonidazole status, and fractionation scheme; none showed any statistical significance. Favorable prognostic factors were assessed (age less than 60, Karnofsky of 70–100, controlled primary and brain metastasis only) in each treatment arm and no difference was found. Brain metastasis was cause of death in 13, and 19–33% of patients were retreated. Because up to 13 of the patients in this study died secondary to uncontrolled brain metastasis, improvement in local control remains an important goal. Until proven otherwise, the treatment of choice for the majority of patients still remains a conventional palliative course of 3.0 Gy × 10 fractions.

The effect of local-regional control on distant metastatic dissemination in carcinoma of the head and neck: Results of an analysis from the RTOG head and neck database

Abstract: A retrospective analysis of the effect of local control on the development of distant metastases was performed in 2648 patients with carcinoma of the head and neck selected from the RTOG database. The 5-year time-adjusted incidence of distant metastases was 21% for patients who were in local-regional control at 6 months after the start of treatment, compared to 38% for local-regional failure patients (p less than 0.001). The incidence of distant metastases detected between the interval of 6 months to 2.5 years after treatment was significantly increased in patients with tumors of the oral cavity, oropharynx, supraglottic larynx, and glottis who developed local-regional failure within this time period, compared to those who remained locally controlled (19% distant metastases for local-regional failure vs 7% for local-regional control (p less than 0.001)). In contrast, there as no difference in the incidence of distant metastases in patients with carcinoma of the nasopharynx or hypopharynx regardless of the local-regional disease status. A Cox proportional hazards regression analysis demonstrated that local-regional control was the most significant variable affecting the development of distant metastases, followed by tumor site, N-stage, and T-stage. For all tumor sites, except for the hypopharynx and nasopharynx, improvements in local-regional control are likely to improve survival. Tumors of the hypopharynx and nasopharynx have a higher probability of micro-metastatic dissemination at the time of initial diagnosis, and until effective methods to treat disseminated disease are developed, the effect of local control on survival will not be readily discerned.

Distant metastases after irradiation alone in carcinoma of the uterine cervix.

Abstract: This is a retrospective analysis of 1211 patients with invasive carcinoma of the uterine cervix treated with irradiation alone from 1959 through 1986, of whom 322 developed distant metastases during the course of the disease. The 10-year actuarial incidence of distant metastases was 3% in Stage IA (34 patients), 16% in Stage IB (384 patients), 31% in Stage IIA (128 patients), 26% in Stage IIB (353 patients), 39% in Stage III (292 patients), and 75% in Stage IVA (20 patients). A multivariate analysis of factors influencing the incidence of distant metastases showed clinical stage, endometrial extension noted by dilatation and cureage (DC histology, volume of disease, and age of patient were not significant. The frequency of metastases in all stages except IVA was greater when endometrial tumor extension was detected by D & C before to definitive irradiation (Stage IB, 28%; Stage IIA, 48%; Stage IIB, 42%; Stage III, 72%; and Stage IVA, 75%). In contrast, with normal D & C findings, the incidence of distant metastases was 15% in Stage IB, 29% in Stage IIA, 25% in Stage IIB, 45% in Stage III, and 84% in Stage IVA. The incidence of metastases in patients with pelvic tumor control was 11% in Stage IB, 22% in Stage IIA, 21% in Stage IIB, 34% in Stage III, and 50% in Stage IVA; in contrast, the corresponding incidence in patients failing in the pelvis was 76% in Stage IB, 88% in Stage IIA, 62% in Stage IIB, 87% in Stage III, and 74% in Stage IVA. The frequency of metastases per histology was comparable in squamous cell carcinoma and other histologic types. The incidence of metastases to other organs was 56%: Most frequent sites were lung, abdominal cavity, liver, and gastrointestinal tract. The incidence of clinically apparent lymph node involvement was 22%, predominately to paraaortic, supraclavicular, and inguinal nodes. Bone metastases occurred in 16% of the patients, most commonly to the lumbar and thoracic spine. Despite aggressive local therapy with excellent local control, the incidence of distant metastases in patients with invasive carcinoma of the uterine cervix is high. The management of these patients and their response to salvage therapy are discussed. The need for effective adjuvant systemic therapy in the management of patients with invasive carcinoma of the cervix is also discussed.

Primary breast irradiation in large-breasted or heavy women: analysis of cosmetic outcome.

Abstract: Treatment of early stage breast cancer with lumpectomy, axillary dissection, and radiation therapy is considered by many to be relatively contraindicated in heavy women or women with large or pendulous breasts. To quantitatively analyze this, we reviewed the cosmetic outcome in 257 patients. These patients were divided into "large" (89) and "average" (168) groups by one or more of the following criteria: weight greater than or equal to 80 kg, bra size greater than or equal to 40 in., cup size greater than or equal to D, and tangent separation greater than or equal to 23 cm. All patients were given cosmetic scores on a 1-10 scale by an independent observer for each of 8 cosmetic indices. These scores were analyzed at 1, 3, and 5 years follow-up (median 3 years). The average group scored higher than the large group on overall cosmesis (8.01 vs 7.34, p = 0.0004) and on 5 of 7 subindices (p = 0.0001 to 0.05) at 1 year. At 3 and 5 year follow-up only symmetry and retraction remained significantly different, favoring the average group. The largest difference noted at any point between the groups was 1.27 (retraction at 5 years, 8.54 vs 7.27, p = 0.0148). Therefore, although an inferior cosmetic result has been documented in the large group, we do not feel the magnitude of the difference mandates a change in our policy of offering all of these women breast-conserving therapy.

The significance of the pathology margins of the tumor excision on the outcome of patients treated with definitive irradiation for early stage breast cancer.

Abstract: To evaluate the significance of the pathology margins of the tumor excision on the outcome of treatment, an analysis was performed of 697 consecutive women with clinical Stage I or II invasive carcinoma of the breast treated with breast-conserving surgery and definitive irradiation. Complete gross excision of the primary tumor was performed in all cases, and an axillary staging procedure was performed to determine pathologic axillary lymph node status. The 697 patients were divided into four groups based on the final pathology margin from the primary tumor excision or from the re-excision if performed. These four groups were: (a) 257 patients with a negative margin (>2 mm), (b) 57 patients with a positive margin, (c) 37 patients with a close margin (⪯2 mm), and (d) 346 patients with an unknown margin. The patients with positive final pathology margins were focally positive on microscopic examination. Patients with grossly positive margins or with diffusely positive microscopic margins were treated with conversion to mastectomy. There was a significant difference in the total radiation dose for the four groups (median dose of 6000 vs 6500 vs 6400 vs 6240 cGy, respectively; p p = .19), no evidence of disease (NED) survival ( p = .95), or relapsefree survival ( p = .80). There was no significant difference among the four groups for five year actuarial local or regional control (all p ≥ .29). Subset analyses did not identify any poor outcome subgroups. These results have demonstrated that selected patients with focally positive or close microscopic pathology margins can be adequately treated with definitive breast irradiation. Patient selection and the technical delivery of radiation treatment including a boost may have been important contributing factors to the good outcome in these patients.

Comparison of high and low dose rate remote afterloading for cervix cancer and the importance of fractionation.

Abstract: Analysis of the data obtained from a survey of 56 institutions treating a total of over 17,000 cervix cancer patients with high dose rate (HDR) remote afterloading, shows that the average fractionation regimen is about 5 fractions of 7.5 Gy each to Point A, regardless of stage of disease. Comparison with historical controls treated by the same clinicians at low dose rate (LDR), showed that 5-year survival was statistically significantly better for HDR versus LDR for Stage III patients (47.2% compared to 42.6%, P = 0.005) and for all patients pooled together (60.8% vs. 59.0% P = 0.045). Morbidity rates were considerably lower for HDR versus LDR for both severe (2.23% vs. 5.34%, P less than 0.001) and moderate plus severe complications (9.05% vs. 20.66%, P less than 0.001). There is an apparent geometrical advantage of HDR intracavitary therapy in that there is a reduction in the "hot-spot" rectal and bladder doses relative to Point A of, on average, (13 +/- 4)% for the HDR compared to the LDR treatments. Fractionation of the HDR treatments significantly influenced toxicity: morbidity rates were highly significantly lower for Point A doses/fraction less than or equal to 7 Gy compared with greater than 7 Gy for both severe injuries (1.28% vs. 3.44%, P less than 0.001) and moderate plus severe (7.58% vs. 10.51%, P less than 0.001). The effect of dose/fraction on cure rates was equivocal. Finally, the data showed that for conversion from LDR to HDR the total dose to Point A was reduced on average by a factor 0.54 +/- 0.06.

Acute and long-term effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma.

Abstract: A retrospective review is presented on 145 patients who underwent limb-sparing surgery and radiation therapy (with or without adjuvant chemotherapy) for their primary soft tissue sarcomas of the extremities on protocol between 1975 and 1986. The focus on our analysis was the acute and long term toxicity of treatment on limb function. The most common acute complication was skin reaction, occurring in 52 patients (36%). Long term (occurring after more than 1 year following all treatment) treatment complications in the extremity were as follows: bone fracture = 6%; contracture = 20%; pain requiring narcotics = 7%; edema greater than 2+ = 19%; moderate to severe decrease in range of motion = 32%; moderate to severe decrease in manual muscle strength = 20%; orthotic device required = 9%; cane or crutch required = 7%; chronic infection = 9%; and tissue induration = 57%. Three amputations for treatment complications were required. Inclusion of more than 50% of the joint in the radiation portal was associated with a higher frequency of contracture. High nominal standard dose (greater than 1760 rets, greater than 63 Gy at 1.8 Gy per fraction) resulted in more painful limbs as well as limbs with increased edema, decreased manual muscle strength, decreased range of motion, and skin telangiectasias. Edema was more often noted in patients with a longer radiation portal (greater than 35 cm), as was tissue induration. Chronic ulcer or infection was more frequently seen in patients with lower extremity tumors and when more than 75% of the extremity diameter was irradiated. Although chemotherapy given concurrent with radiation therapy was associated with a higher number of acute skin reactions, this did not appear to translate into increased long term morbidity. The percentage of patients ambulating without assistive devices and with mild or no pain was 84%. Careful attention to the techniques of radiation therapy may have a significant impact on minimizing acute and long term complications of limb sparing treatment for extremity soft tissue sarcoma.

Adjuvant therapy of resected adenocarcinoma of the pancreas.

Abstract: Seventy-two patients underwent resections of pancreatic carcinomas between 1981 and 1989 at the Hospital of the University of Pennsylvania and were evaluable for follow-up. There were three treatment groups as treatment policies evolved. Initially, patients were observed after surgery without adjuvant treatment (Group 1–33 patients). Beginning in 1984, patients were offered adjuvant radiation therapy postoperatively (Group 2–19 patients) and eight of these patients also received 5-FU as an IV bolus on the first 3 days of the first and fifth weeks of treatment. Twenty patients were treated with chemosensitized radiation therapy following surgery using 96-hour 5-FU infusions during the first and fifth weeks of treatment. There were four postoperative deaths, which are excluded from the analysis, and sites of failure could not be determined for five other patients. Among evaluable patients, local recurrences occurred in 85% of the patients in group 1, 55% of the patients in group 2, and 25% of the patients in group 3. The 2-year survival was 35% in group 1, 30% in group 2, and 43% in group 3. Patients with involved surgical margins had a poor survival; only 2 of these 16 patients survived longer than 18 months. Among patients with negative margins, the 2-year survival is 41% in group 1, 33% in group 2, and 59% in group 3. Although the number of patients is smaller, the 3-year survival is 22% in group 1, 11% in group 2, and 47% in group 3. Chemosensitized irradiation is well tolerated in these patients. The major challenge in this group of patients is nutritional maintenance. There was no other significant toxicity. The trend in these observations suggests that survival following pancreatic resection is substantially improved with the addition of adjuvant chemosensitized radiation therapy.

External irradiation followed by an interstitial high activity iodine-125 implant “boost” in the initial treatment of malignant gliomas: NCOG study 6G-82-2 gliomas: NCOG study 6H-82-2

Abstract: Between January 1982 and January 1990, 107 patients with unifocal, circumscribed malignant gliomas participated in a non-randomized trial testing brachytherapy in their initial treatment. Focal external irradiation (6000 cGy) was combined with an implant of high-activity iodine-125 (5000-6000 cGy) and six courses of procarbazine, lomustine, and vincristine. Of the 101 evaluable patients, 63 received implants. Of these, 29 had non-glioblastoma anaplastic gliomas, and 34 had glioblastoma multiforme. The other 38 did not receive implants, in most cases because radiation therapy failed to reduce the size of the tumor. The median survival was 165 weeks for all evaluable patients with non-glioblastoma anaplastic gliomas, 157 weeks for those with implants, 67 weeks for all evaluable glioblastoma patients, and 88 weeks for those with implants. Of the glioblastoma patients with implants, nine were alive after 2 years, and three were alive after 3 years. In each of the groups, nearly half the patients underwent reoperation for clinical deterioration, increasing steroid dependency, and increasing mass effect at the implantation site after 46.1 weeks (median) for glioblastoma multiforme and 41.3 weeks for non-glioblastoma patients. Karnofsky Performance Scores showed only a small decline in performance after brachytherapy. Patients receiving implants for non-glioblastoma anaplastic gliomas had a mean Karnofsky Performance Score of 91% (range 90-100%) after 1 month and 78% (range 60-100%) 30 months after brachytherapy. Those treated for glioblastoma multiforme had a mean Karnofsky Performance Score of 86% (range 60-100%) at 1 month and 75% (range 60-100%) at 24 months. The quality of life of treated patients appears to be satisfactory. On the basis of comparisons with previous studies, we conclude that a brachytherapy "boost" after external irradiation may be valuable for some patients with glioblastoma multiforme but not for those with non-glioblastoma anaplastic gliomas.

Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: a comparative study.

Abstract: In head and neck carcinoma, the finding of extracapsular lymph node extension and/or positive resection margins pootends poor locoregional control and survival. The effectiveness of postoperative radiotherapy in these patients has been controversial due to insufficient studies comparing resected patients with those also receiving radiation. Between 1982 and 1988, 441 radical head and neck resections were performed at the Medical College of Virginia. Pathologic review of these cases identified 125 with extracapsular lymph node extension and/or positive resection margins. Of these, 43 had extracapsular lymph node extension only, 24 had both positive resection margins and extracapsular lymph node extension, and 58 demonstrated positive resection margins only. Surgery alone was performed in 71 of these patients while 54 cases received surgery and postoperative radiotherapy, (combined modality treatment) CMT. Radiotherapy doses ranged from 50 to 70 Gy. The surgery alone and combined modality treatment groups were comparable with respect to the distribution of positive resection margins and extracapsular lymph node extension. Slightly more CMT patients had clinical T4 disease compared with the surgery alone group (22% vs 14%). Slightly fewer combined modality treatment patients had clinical NO necks than the surgery alone group (20% vs 29%). Multivariate analysis was performed with the variables T, N stages, radiotherapy, margin status, primary tumor sites, microscopic and macroscopic extracapsular lymph node extension, number of positive lymph nodes, number of nodes with extracapsular lymph node extension. Locoregional control was maintained at 5 years in 59% of the combined modality treatment group and 31% of the surgery alone group (p.0001). Subgroup analysis likewise reveals significant differences favoring the combined modality treatment group for positive resection margins only (49% vs 41%; p = .04), extracapsular lymph node extension only (66% vs 31%; p = .03) and extracapsular lymph node extension + positive resection margins (68% vs 0%; p = .001). Adjusted survival also shows a significant benefit of combined modality treatment vs surgery alone for the entire group (72% vs 41%; p = .001). Multivariate analysis revealed that the use of radiotherapy is a strongly favorable variable for local control and adjusted survival. Macroscopic extracapsular lymph node penetration and positive resection margins are unfavorable independent variables for local control. T-stage is the only variable predicting local control in the combined modality group. Extracapsular extension remains an important negative prognostic variable for survival in both treatment groups. In conclusion, this study demonstrates a locoregional control and survival benefit for postoperative radiotherapy in patients with the high risk pathologic findings of extracapsular lymph node extension and positive resection margins.

The results of radiation therapy for isolated local regional recurrence after mastectomy.

Abstract: Between 1967 and 1988 128 patients with isolated local-regional recurrence of breast cancer after mastectomy were treated with definitive radiation therapy. Recurrence was confined to a single site in 108 patients and multiple sites in 20. The chest wall was the most common location (86) and the supraclavicular region was the second most common (20). Surgical treatment for recurrence prior to irradiation consisted of excision of all gross disease in 78 patients and incisional biopsy in 49 patients. Irradiation was directed to the entire chest wall in 19% of patients with isolated chest wall recurrences and to the chest wall and regional nodes in 81%. In patients with isolated nodal failures, treatment was directed to the nodal site and chest wall in 87% and to the regional site alone in 13%. Patients with multiple sites received treatment to the chest wall and regional nodes in all cases. Electively treated sites usually received 4500–5000 cGy. Following excision of chest wall disease, the median dose was 6000 cGy. Gross disease on the chest wall received a median dose of 6100 cGy. Gross disease in nodal sites received a median dose of 5600 cGy; 66 patients received systemic therapy at recurrence. The 5-year actuarial local-regional control was 43%. In a multivariate analysis only the estrogen receptor status of the recurrence remained significant ( p = .002). The 5-year actuarial survival was 49% with a relapse-free survival of 24%. In a multivariate analysis for survival, the disease-free interval (p = .007 local regional control ( p = .006), and excisional biopsy for recurrence ( p = .03) remained significant. In a multivariate analysis for relapse-free survival, the disease-free interval ( p = .03), excisional biopsy ( p = .0001 and the extent of axillary nodal involvement ( p = .007) remained significant. In the subgroup of patients with a disease-free interval ≥ 24 months, excisional biopsy, and local regional control, the 5-year survival was 61% with a relapse-free survival of 59%. This subgroup represents 18% of the entire group and has a relatively good prognosis after recurrence.