Trial Of Adjuvant Radiation Therapy Research Articles

Development and Validation of Consensus Contouring Guidelines for Adjuvant Radiation Therapy for Bladder Cancer After Radical Cystectomy

Todevelop multi-institutional consensus clinical target volumes (CTVs) and organs at risk (OARs) for male and female bladder cancer patients undergoing adjuvant radiation therapy (RT) in clinical trials. We convened a multidisciplinary group of bladder cancer specialists from 15 centers and 5 countries. Six radiation oncologists and 7 urologists participated in the development of the initial contours. The group proposed initial language for the CTVs and OARs, and each radiation oncologist contoured them on computed tomography scans of a male and female cystectomy patient with input from ≥1 urologist. On the basis of the initial contouring, the group updated its CTV and OAR descriptions. The cystectomy bed, the area of greatest controversy, was contoured by another 6 radiation oncologists, and the cystectomy bed contouring language was again updated. To determine whether the revised language produced consistent contours, CTVs and OARs were redrawn by 6 additional radiation oncologists. We evaluated their contours for level of agreement using the Landis-Koch interpretation of the κ statistic. The group proposed that patients at elevated risk for local-regional failure with negative margins should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac, obturator, and presacral), whereas patients with positive margins should be treated to the pelvic nodes and cystectomy bed. Proposed OARs included the rectum, bowel space, bone marrow, and urinary diversion. Consensus language describing the CTVs and OARs was developed and externally validated. The revised instructions were found to produce consistent contours. Consensus descriptions of CTVs and OARs were successfully developed and can be used in clinical trials of adjuvant radiation therapy for bladder cancer.

Validating a Local Failure Risk Stratification for Use in Prospective Studies of Adjuvant Radiation Therapy for Bladder Cancer

To inform prospective trials of adjuvant radiation therapy (adj-RT) for bladder cancer after radical cystectomy, a locoregional failure (LF) risk stratification was proposed. This stratification was developed and validated using surgical databases that may not reflect the outcomes expected in prospective trials. Our purpose was to assess sources of bias that may affect the stratification model's validity or alter the LF risk estimates for each subgroup: time bias due to evolving surgical techniques; trial accrual bias due to inclusion of patients who would be ineligible for adj-RT trials because of early disease progression, death, or loss to follow-up shortly after cystectomy; bias due to different statistical methods to estimate LF; and subgrouping bias due to different definitions of the LF subgroups. The LF risk stratification was developed using a single-institution cohort (n=442, 1990-2008) and the multi-institutional SWOG 8710 cohort (n=264, 1987-1998) treated with radical cystectomy with or without chemotherapy. We evaluated the sensitivity of the stratification to sources of bias using Fine-Gray regression and Kaplan-Meier analyses. Year of radical cystectomy was not associated with LF risk on univariate or multivariate analysis after controlling for risk group. By use of more stringent inclusion criteria, 26 SWOG patients (10%) and 60 patients from the single-institution cohort (14%) were excluded. Analysis of the remaining patients confirmed 3 subgroups with significantly different LF risks with 3-year rates of 7%, 17%, and 36%, respectively (P<.01), nearly identical to the rates without correcting for trial accrual bias. Kaplan-Meier techniques estimated higher subgroup LF rates than competing risk analysis. The subgroup definitions used in the NRG-GU001 adj-RT trial were validated. These sources of bias did not invalidate the LF risk stratification or substantially change the model's LF estimates.

Competing event risk stratification may improve the design and efficiency of clinical trials: Secondary analysis of SWOG 8794

BackgroundComposite endpoints can be problematic in the presence of competing risks when a treatment does not affect events comprising the endpoint equally. MethodsWe conducted secondary analysis of SWOG 8794 trial of adjuvant radiation therapy (RT) for high-risk post-operative prostate cancer. The primary outcome was metastasis-free survival (MFS), defined as time to first occurrence of metastasis or death from any cause (competing mortality (CM)). We developed separate risk scores for time to metastasis and CM using competing risks regression. We estimated treatment effects using Cox models adjusted for risk scores and identified an enriched subgroup of 75 patients at high risk of metastasis and low risk of CM. ResultsThe mean CM risk score was significantly lower in the RT arm vs. control arm (p=0.001). The effect of RT on MFS (HR 0.70; 95% CI, 0.53–0.92; p=0.010) was attenuated when controlling for metastasis and CM risk (HR 0.76; 95% CI, 0.58–1.00; p=0.049), and the effect of RT on overall survival (HR 0.73; 95% CI, 0.55–0.96; p=0.02) was no longer significant when controlling for metastasis and CM risk (HR 0.80; 95% CI, 0.60–1.06; p=0.12). Compared to the whole sample, the enriched subgroup had the same 10-year incidence of MFS (40%; 95% CI, 22–57%), but a higher incidence of metastasis (30% (95% CI, 15–47%) vs. 20% (95% CI, 15–26%)). A randomized trial in the subgroup would have achieved 80% power with 56% less patients (313 vs. 709, respectively). ConclusionStratification on competing event risk may improve the efficiency of clinical trials.

Competing event risk stratification may improve the design and efficiency of clinical trials: Secondary analysis of SWOG 8794.

6121 Background: Efficiency of clinical trials may be improved by stratifying according to competing event risk. We aimed to test whether effect and sample size estimates would be altered when adjusting for competing event risk, using data from the SWOG 8794 trial of adjuvant radiation therapy (RT) for high-risk post-operative prostate cancer. Methods: The primary outcome was metastasis-free survival (MFS), defined as time to first occurrence of metastasis or death from any cause (i.e., competing mortality (CM)). We developed separate risk scores for time to metastasis and CM using backward stepwise competing risks regression. Risk factors for metastasis were PSA, Gleason score, and seminal vesicle invasion, and for CM were age, performance status, and Charlson comorbidity index. Treatment effects were estimated using Cox models adjusted for risk scores. We identified an enriched subgroup of 75 patients at high risk of metastasis and low risk of CM, based on risk score cutoffs. Sample size estimates assumed type I and II error of 0.10 and 0.20, and accrual and follow-up times of 6 and 6 years. Results: The mean CM risk score was significantly lower in the RT vs. control arm (p=0.001). The effect of RT on MFS (HR 0.70; 95% CI, 0.53-0.92; p=0.010) was attenuated when controlling for metastasis and CM risk (HR 0.76; 95% CI, 0.58-1.00; p=0.049). The hazard for CM was reduced by RT (HR 0.82; 95% CI, 0.59-1.14; p=0.24), but this effect was attenuated when controlling for CM risk (HR 0.94; 95% CI, 0.67-1.31; p=0.71). In contrast, there was no difference in the adjusted and unadjusted HRs for metastasis (0.50; 95% CI, 0.31-0.81; p=0.005 and 0.49; 95% CI, 0.30-0.81; p=0.005). Compared to the whole cohort, the enriched subgroup had the same baseline 10-year incidence of MFS (40%; 95% CI 22-57%), but a higher incidence of metastasis (30% (95% CI, 15-47%) vs. 20% (95% CI, 15-26%)). A randomized trial in an enriched population could have achieved 80% power with 44% less patients (313 vs. 709 patients, respectively), due to the differing event composition. Conclusions: Stratification based on competing event risk may improve the design and efficiency of clinical trials. These findings should be externally validated.

Radiation therapy alone or combined with chemotherapy in the treatment of esophageal cancer.

Radiation therapy has been used in the adjuvant setting or as a primary treatment modality for esophageal cancer. Although there are design flaws in all of the trials of adjuvant radiation therapy for esophageal cancer, there is no clear survival advantage when radiation therapy is delivered in the adjuvant setting (preoperatively or postoperatively). Phase II results of preoperative, combined modality therapy are encouraging; however, the approach remains investigational. When radiation therapy is used as a primary modality, the most favorable results are seen when it is combined with adequate doses of systemic chemotherapy. Phase III intergroup trials are in progress which are examining the effectiveness of higher doses of radiation therapy when combined with chemotherapy.

Cardiovascular Mortality in a Randomized Trial of Adjuvant Radiation Therapy versus Surgery Alone in Primary Breast Cancer: International Journal of Radiation Oncology, Biology, and Physics, Vol. 22, No. 5, 1992, pp. 887–896

Cardiovascular Mortality in a Randomized Trial of Adjuvant Radiation Therapy versus Surgery Alone in Primary Breast Cancer: International Journal of Radiation Oncology, Biology, and Physics, Vol. 22, No. 5, 1992, pp. 887–896

Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer

One concern with adjuvant radiation therapy for early breast cancer is the potential risk of increasing intercurrent mortality due to radiation-induced damage of the myocardium. The paper presents an analysis of long-term survival among 960 patients with primary breast cancer included in a randomized trial of pre- or postoperative radiation therapy (45 Gy/5 weeks) versus surgery alone. All patients were treated with a modified radical mastectomy. The mean follow-up was 16 years (range: 13–19 years). During the entire follow-up period there was an overall survival difference in favor of the irradiated patients that was of borderline significance ( p = 0.09). There was no increase in intercurrent mortality due to any cause. However, when the results were analyzed according to estimated doses of radiation to the myocardium, the subset of patients who received the highest doses, that is, those treated with tangential 60Co fields for left-sided tumors, were found to have a significantly increased risk of death due to ischemic heart disease compared to the surgical controls (relative hazard: 3.2, p < 0.05). No such increase was observed among the patients who received less radiation to the myocardium, that is, whose chest wall and internal mammary nodes were treated with electrons or those with right-sided tumors, irrespective of the treatment technique. It is concluded that cardiovascular mortality associated with radiation therapy for early breast cancer is correlated with the biological dose of radiation to the heart and the irradiated volume. All of the following factors are thus important: laterality of the tumor, portal arrangements, radiation energy, fractionation, and total dose. The study illustrates that an increased cardiovascular mortality can be avoided by the use of appropriate techniques and avoidance of excessive treatment.

Randomized trials of adjuvant radiation therapy for rectal carcinoma

An estimated 44,000 cases of rectal carcinoma arise annually in the United States. The traditional management of this disease has been surgery alone, but advances in adjuvant therapy offer potential for improvement of local control, disease-free survival, and survival. In the last two decades, many multicenter randomized trials of adjuvant preoperative and postoperative radiation therapy for rectal carcinoma have been reported. The design and results of these trials are critically reviewed. Results from preoperative trials have been conflicting, reflecting the heterogeneity of the trial designs. Large postoperative adjuvant trials have been reported recently. The combined analysis of local recurrence data from the mature, published trials indicates that radiation therapy results in improved local control (P = 0.02), an important concern in rectal carcinoma as local recurrences present vexing and painful clinical problems often refractory to conventional management. These trials also have shown that radiation therapy can contribute to improved survival in the combined modality setting. Improvements in the clinical outcome of rectal cancer should be possible with appropriate adjuvant therapy. The success of combined modality adjuvant therapy for rectal carcinoma may serve as a model to aid in the design of therapeutic regimens for other solid tumors.

The 5-year results of a randomized trial of adjuvant radiation therapy after chemotherapy in breast cancer patients treated with mastectomy.

The use of adjuvant radiation therapy in breast cancer patients treated with mastectomy and adjuvant chemotherapy has been controversial. In order to assess the necessity and effectiveness of adjuvant radiation therapy in this setting, we reviewed the results in 510 patients with T1-T3 tumors and pathologically positive nodes or tumors larger than 5 cm and negative nodes who were treated with adjuvant chemotherapy. Patients with four or more positive nodes or at least one positive apical node were randomized to receive either five or ten cycles of cyclophosphamide/Adriamycin (Adria Laboratories, Columbus, OH) (CA) and patients with one to three positive nodes or operable tumors larger than 5 cm and pathologically negative nodes were randomized to receive eight cycles of either cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) or methotrexate and 5-FU (MF) chemotherapy. Two hundred six of these patients were subsequently rerandomized to receive either no further treatment or adjuvant radiotherapy. Thirty-five patients withdrew after randomization, including 34 who declined to receive radiotherapy. Radiation therapy consisted of 4,500 cGy in 5 weeks to the chest wall and appropriate draining lymph nodes. Median follow-up from chemotherapy randomization is 45 months for patients in the CA arm and 53 months for those in the CMF/MF arm. The crude rate of local failure (chest wall or draining lymph node areas) as first site of failure for patients randomized to receive chemotherapy only was 14%; for those randomized to receive both chemotherapy and radiotherapy it was 5% (P = .03). For patients in the CMF/MF arm, the rate of local failure as the first site of failure was nearly the same for patients randomized to chemotherapy only as for those randomized to adjuvant radiotherapy as well (5% v 2%). For patients in the CA arm, the crude rate of local failure was 20% for patients randomized to receive chemotherapy only, and 6% for those randomized to both types of adjuvant treatment (P = .03). Among the 43 patients treated with CA who actually received radiotherapy, there was only one local failure, compared with 12 local failures among the 59 patients (20%) who actually did not receive radiotherapy (P = .007). No significant difference was seen in disease-free survival or overall survival in either the CA or the CMF/MF arm between patients randomized to receive radiation therapy and those randomized to no further treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical trials of adjuvant radiation therapy for breast cancer

Years ago, radiation therapists conducted randomized clinical trials which showed that regional irradiation significantly reduces local recurrence of breast cancer but does not often affect life span. No new findings challenge these conclusions. Controlled trials in general have lost some credibility, however, as it has become more widely recognized that they are very vulnerable to fallacious reasoning and to simple human error. There is serious concern that some physicians may be unwisely abandoning well tested treatment methods because of the premature dissemination of early results of some trials. Still, many important questions remain that can only be answered by clinical trials, some including radiation therapy. This paper suggests that randomization schemes be incorporated into "routine" medical practice, although only after the most careful deliberation, in order to hasten fuller understanding of old therapeutic methods as well as new ones.