Colin Poulter

Single-dose half-body irradiation for palliation of multiple bone metastases from solid tumors: Final radiation therapy oncology group report

This is the final analysis of Protocol #78–10 which explored increasing single‐doses of half‐body irradiation (HBI) in patients with multiple (symptomatic) osseous metastases. When given as palliation, HBI was found to relieve pain in 73% of the patients. In 20% of the patients the pain relief was complete; over two thirds of all patients achieved better than 50% pain relief. The HBI pain relief was dramatic with nearly 50% of all responding patients doing so within 48 hours and 80% within one week from HBI treatment. Furthermore, the pain relief was long‐lasting and continued without need of retreatment for at least 50% of the remaining patients life. These results compare favorably with those obtained by the Radiation Therapy Oncology Group (RTOG) using several conventional daily fractionated schemes on similar patients in a prior study (RTOG #74–02). HBI achieves pain relief sooner and with less evidence of pain recurrence in the irradiated area than conventionally treated patients. The most effective and safest of the HBI doses tested were 600 rad for the upper HBI and 800 rad for the lower or mid‐HBI. Increasing doses beyond these levels did not increase pain relief, duration of relief, or achieved a faster response; however, the increase in dose was associated with a definite increase in toxicity. Single‐dose HBI was well tolerated with no fatalities seen among 168 treated patients. A comprehensive premedication program has proven to decrease the acute radiation syndrome to very acceptable levels. There were excellent responses found in practically all tumors treated, but especially breast and prostate among which over 80% of all patients experienced pain relief, 30% in a complete fashion. Single‐dose HBI emerges as one of the safest, fastest, and more effective palliative tools for intractable cancer pain in modern radiation oncology. Cancer 58:29–39, 1986.

A report of RTOG 8206: A phase III study of whether the addition of single dose hemibody irradiation to standard fractionated local field irradiation is more effective than local field irradiation alone in the treatment of symptomatic osseous metastases

Hemibody irradiation (HBI) in a single exposure is an effective and safe technique for palliation of symptoms due to widespread bony metastases (RTOG 78-10). The present study (82-06) sought to explore the possibility that HBI added to local-field irradiation might delay the onset of metastases in the hemibody effected, as assessed by bone scans and X rays, and decrease the frequency of further treatment. The results of this clinical trial establish that 800 cGy of HBI is indeed causes micro-metastases to regress, perhaps completely. A total of 499 patients were randomized to receive either HBI or no further treatment following completion of standard palliative local field irradiation (300 cGy x 10) to the symptomatic site. Improvement was seen in time-to-disease progression at one year, 35% for local + HBI versus 46% on the local-only control arm. Time-to-new disease in the targeted hemibody was also improved. At one year, 50% of patients on the local + HBI arm showed new disease compared to 68% on the local-only arm. Furthermore, the median time-to-new disease within the targeted HBI area was 12.6 months for the local + HBI arm versus 6.3 months for patients in the local-only arm. Time-to-new treatment within the hemibody segment was also delayed. At one year, 76% of the local only group had been retreated versus 60% in the local + HBI arm. There were no fatalities and no radiation pneumonitis was seen in the local + HBI arm. Overall, the incidence of toxicities was low (5-15%). The occurrence of severe hematopoetic toxicities were significantly different in the local + HBI arm, but they were transitory. One life-threatening thrombocytopenia occurred, for a limited time, indicating excellent tolerance to HBI. This clinical trial demonstrates that HBI has the potential to be used to treat systemic and occult metastases, particularly if both halves of the body can be treated.

Randomized trial comparing single dose versus fractionated irradiation for prevention of heterotopic bone: A preliminary report

Radiation therapy has been shown to prevent heterotopic bone formation in high risk patients undergoing total hip replacement. A number of doses have been used without a randomized trial comparing one dose regimen against another. A prospective randomized trial was undertaken comparing 10 Gy in 5 fractions versus 8 Gy in 1 fraction. Forty-seven patients have been randomized at the time of this evaluation with 37 patients eligible for analysis. The pre-operative, immediate post-operative and 2 month post-operative radiographs were graded. At the time of this analysis, 17 patients were randomized to the 8 Gy arm with 20 patients in the 10 Gy arm. Patients were treated with limited fields so as to only cover the area at risk for development of heterotopic bone to prevent adverse effects on biologic fixation of uncemented implants. When comparing the pre-operative, operative, and 2 month post-operative radiographs, only four patients (1 patient in the 8 Gy arm and 3 patients in the 10 Gy arm), had an increase in the score. No patient had an increase in score to a clinically significant level, usually grade 3 or 4. These preliminary results appear to show that 8 Gy in a single fraction can be as effective as 10 Gy in 5 fractions in preventing heterotopic bone in susceptible individuals. Further follow-up of the remaining patients may confirm this.

Complications of irradiation related to apparent drug potentiation by adriamycin

Abstract Clinical observations were made on 18 patients who were treated with combined irradiation and chemotherapy. A total of 21 irradiation reactions were noted, remarkable for their severity and persistence. Adriamycin (ADM) was the one drug common to all chemotherapeutic regimens. The reactions involved skin, esophagus, heart, lung and oral mucosa. No consistent pattern was established between the type or severity of reaction and the dose of drug or irradiation, nor of the temporal relationship of one to the other. It appears that ADM toxicity may potentiate irradiation reactions and that a “standard” total dose may be equivalent to a dose of irradiation on the order of 1000 rad. Since ADM persists in body tissues for prolonged periods of time, irradiation reactions may occur unexpectedly. All reactions improved, but eventual long-term effects cannot be determined at this time. A plea is made for controlled observations to determine safe schedules for the combination of these agents.

Tumor persistence as a predictor of outcome after radiation therapy of head and neck cancers

Abstract Tumor clearance or persistence was assessed at different time intervals during, at the completion of, and after radiation therapy in order to predict local control of failure in 144 cases of head and neck cancer. The rate of tumor clearance (TC) during treatment is less important than is complete tumor clearance in predicting for local control (LC). If tumor clearance occurred within one to three months following completion of treatment, local control could be predicted in cancers of the oral cavity, oropharynx and hypopharynx with approximately 80, 70 and 50% reliability, respectively. However, tumor persistence (TP) (evidenced by induration and surface irregularity) was a highly accurate predictor of failure (90–100%) at this assessment interval. Persistence of induration at the completion of treatment is inaccurate in the assessment of eventual local failure (LF), since local control eventually is achieved in 25–35% of the cases.

Absence of prognostic significance, peritoneal dissemination and treatment advantage in endometrial cancer patients with positive peritoneal cytology

Peritoneal cytology has been shown to be one of the prognostic factors in endometrial cancer. A series of 134 patients was seen between January 1977 and March 1985 with clinical Stage I (or treated as a clinical Stage I) endometrial adenocarcinoma at the University of Rochester Cancer Center. The majority of patients underwent extrafascial hysterectomy with the majority of washings obtained at the time of surgery. Fourteen percent (19/134) of the patients were found to have positive cytology. Eleven patients with positive cytology (11/19) were treated with local-regional pelvic treatment; the other eight patients received whole abdominal therapy. The recurrence rates were less with the local treatment than with the whole abdominal treatment groups (9.1% vs. 25%) in those patients having positive cytology. There was no statistical difference in recurrence rates between the pathologic Stage I patients with positive cytology (10%) versus those patients having negative cytology (5%), nor was there statistical difference in survival between pathologic Stage I positive or negative cytology patients. It is suggestive from this non-randomized study that positive cytology in endometrial cancer is not an independent prognostic factor and that whole abdominal irradiation did not influence outcome.

Effect of rest interval on tumor and normal tissue response—A report of phase III study of accelerated split course palliative radiation for advanced pelvic malignancies (RTOG-8502)☆

From August 1985 through September 1989, 284 patients with advanced pelvic malignancies were entered into a trial (RTOG 8502) of palliative split course radiation (4440 cGy in three courses of 1480 cGy/2 days/4 fractions with a rest of 2-4 weeks between courses). The initial 148 patients were part of a Phase II acceptable response rate and minimal acute or late toxicity (IJRBP 17:659-662, 1989). The present analysis is a report of the subsequent 136 patients randomized between rest intervals of 2 weeks versus 4 weeks to determine if length of rest would influence tumor response or patient toxicity. The patients were stratified for performance status (Karnofsky Performance Status) and histology. The patients were evenly matched for age and sex. There was a trend toward increased acute toxicity incidence in patients with shorter rest interval (5/68 versus 0/68; p = .07). Late toxicity was not significantly different between the two groups. Decreasing the interval between courses did not result in a significant improvement in tumor response (CR+PR = 34% vs. 26%, p = n.s.). More patients in the 2 week groups completed all three courses (72% vs. 63%). Not surprisingly, patients completing cell three courses had a significantly higher overall response rate than for patients completing less than three courses (42% vs. 5%) and higher complete response rate (17% vs. 1%). A multivariate analysis indicated performance status as the significant predictor for number of courses completed. For Karnofsky Performance Status greater than or equal to 80, the survival at 12 months was 40% for the 2 week interval and 25% for the 4 week interval. Performance status and histology were the only significant variables in a multivariate analysis of survival.

Single-dose half-body irradiation for the palliation of multiple bone metastases from solid tumors: A preliminary report

Abstract The on-going protocol of the Radiation Therapy Oncology group RTOG #78-10, which tests escalating single doses of half-body irradiation (HBI) for the palliation of multiple!,bone metastases, has accrued 108 patients as of August 1980. Of these, 91 patients are evaluable at this time. Low r half-body irradiation (LHBI) was given to 52 patients and another 12 patients received mid-body irradiation (MBI) both LHBI and MBI were targeted to receive escalating doses of 800 rod (27 patients), 900 rod (25 patients), and 1000 rod (12 patients). The latter test dose still required another 13 patients for completion. The remaining 27 patients received upper half-body irradiation (UHBI) with single doses of 600 rod (24 patients), 700 rod (3 patients) and 800 rod (no patients). The 700 rod test dose just opened for accrual and patients will not enter the 800 rodtegory until the lower dose closes with approximately 25 patients. Of the 91 evaluable patients, 36 96 bad breast,596 prostate, and 18% lung primary tumors. Seventy patients (77 96) bad pain relief after HBI, 21% actually had complete subjective responses. Of all relieved patients, 50% achieved pain relief within two days after HBI and aft r a week, almost 80% bad achieved relief. The duration of pain relief was substantial and persisted for 70% of the patients remaining life. The technique has been well tolerated with mininal toxicity and no treatment-related fatalities were reported in the doses employed. Increasing the dose from 600 rod to 800 rod was beneficial, but 800 rad on (to 900 red or 1000 rod) has not produced better symptomatic responses and may result in increased toxicity. HBI appears to be highly effective in achieving results similar to conventional (2–3 week) radiation with localized fields

Late effect of multiple daily fraction palliation schedule for advanced pelvic malignancies (RTOG 8502)

PURPOSE Determine late complication incidence for pelvic palliation using accelerated multiple daily fraction radiation [Radiation Therapy Oncology Group (RTOG) 8502]. METHODS AND MATERIALS Prospective evaluation of a palliative radiation schedule for advanced pelvic malignancies was conducted from 1985 to 1989 by RTOG 8502. The dose was 44.40 Gy in 12 fractions (3.7 Gy BID) with a rest after 14.80 Gy and 29.60 Gy. The pilot part of the study allowed for a variable rest interval of 3-6 weeks. The rest interval was then randomized between 2 and 4 weeks to determine effect on tumor control. No difference in tumor control was identified (p = 0.59). The pilot segment accrued 151 patients and the randomized segment accrued 144 patients. A total of 290 cases were analyzable (four ineligible or canceled) for late effects. To minimize actuarial bias, only patients surviving 90 days (193) were analyzed for late effect risk. The primary site consisted of gynecologic (40%), colorectal (28%), genitourinary (25%), and miscellaneous (7%). The extent of tumor consisted of pelvis only (62%) and additional tumor outside the pelvis (38%). Most of the patients were elderly (76% > 60 years, 47% > 70 years). Karnofsky performance status (KPS) was > or = 80 in 60% of patients and < 80 in 40%. RESULTS None of the patients with < 30 Gy (less than three courses) developed late toxicity. A total of 11/193 (6%) developed Grade 3+ late toxicity (nine Grade 3, one Grade 4, one Grade 5). Actuarial analysis of complication rate by survival time for Grades 3, 4, and 5 shows a cumulative incidence for complications after 6 months that plateaus at 6.9% by 18 months. The cumulative incidence for Grades 4 and 5 is 2.0% by 12 months. The difference in late effect for the 2-week rest vs. 4-week rest was not statistically different (p = .47). Patient factors evaluated for increased risk of late complications included prior surgeries, age, sex, KPS and primary. None were found to have significant statistical correlations with late effects. CONCLUSION The crude late complications rate is 6%. Actuarial analysis using cumulative incidence shows 6.9% by 18 months. This represents a significant decrease in late complications from 49% seen with higher dose per fraction (10 Gy x 3) piloted by Radiation Therapy Oncology Group (7905) for a similar group of patients. Long-term analysis of late complication indicates this schedule can be used in the pelvis with relatively low incidence of complication. This schedule has significant logistic benefits and has been shown to produce good tumor regression and excellent palliation of symptoms.

Phase II study of multiple daily fractionations in the palliation of advanced pelvic malignancies: Preliminary report of RTOG 8502

This Phase II protocol was designed around the format of a previously reported study for the palliation of advanced pelvic malignancies (RTOG 7905). The large dose per fraction (1000 cGy) of the first study unexpectedly demonstrated frequent late gastrointestinal toxicity and was replaced in the present study by 2 days of twice daily fractionation (370 cGy/fraction totaling 1480 cGy/course) based on linear quadratic consideration of acute and late toxicities. The interval between courses of 4 weeks was retained and the total dose for three courses was 4440 cGy. A total of 152 patients were entered of which 142 have sufficient follow-up information for analysis. Fifty-nine percent of the patients completed all three courses, 20% completed two courses, and 20% received only one course. The primary sites were: gynecological (39.4%); colorectal (32.4%); genitourinary (24.7%); and other (2.8%). The best overall response was: complete remission (10%); partial remission (22%); no change (24%); progression (10%); and unknown (27%). For the patients completing all three courses, the response was: complete remission (14%); partial remission (31%); no change (40%); progression (7%); and unknown (8%). Median survival was 4.5 months and the actuarial survival at 12 months is 19%. In RTOG 7905, 90% of the late toxicities appeared by 12 months. For RTOG 8502, there were 32 patients alive at 9 months and 19 patients alive at 12 months available for evaluation of late toxicity. There has been one late grade 3 GI toxicity reported and only one acute grade 3 gastrointestinal toxicity. Even if the true rate of late toxicity for 8502 were 20%, the chance of seeing none or one toxicity would be 0.007. This toxicity report represents a marked reduction of the grade 3 and 4 late toxicity seen in RTOG 7905 (37% at 9 months and 45% at 12 months) without lowering the tumor response rate. The interval between courses in both protocols allows for potential tumor proliferation. To test for the effect of tumor proliferation, RTOG 8502 is continuing as a Phase III randomization between 4 weeks and 2 weeks separation.