1. JOURNAL CRITICAL APPRAISAL Michael Angelo L. Suñaz, M.D. August 2007

2. Adjuvant Radiotherapy and Chemotherapy in Node-Positive Premenopausal Women with Breast Cancer Ragaz J, Jackson SM, Le N, Plenderlieth IH, Spinelli JJ, Basco VE, Wilson KS, Knowling MA, Coppin M, Paradis M, Coldman AJ, Olivotto IA. N Engl J Med 337:956-962, 1997

3. PUBLISHED ABSTRACT BACKGROUND –Radiotherapy after mastectomy to treat early breast cancer has been known since the 1940s to reduce the rates of local relapse. –However, the routine use of post-operative radiotherapy began to decline in the 1980s because it failed to improve overall survival. –We prospectively tested the efficacy of combining radiotherapy with chemotherapy.

4. PUBLISHED ABSTRACT METHODS –From 1978 through 1986, 318 premenopausal women were randomly assigned after modified radical mastectomy, to receive chemotherapy plus radiotherapy or chemotherapy alone. –Radiotherapy was given to the chest wall and locoregional nodes between the fourth and fifth cycles of cyclophosphamide, methotrexate and fluorouracil.

5. PUBLISHED ABSTRACT RESULTS –Chemotherapy + radiotherapy 33% reduction in the rate of recurrence (relative risk, 0.67; 95% confidence interval, 0.50 to 0.90) 29% reduction in mortality (relative risk, 0.71; 95% confidence interval, 0.51 to 0.99)

6. PUBLISHED ABSTRACT CONCLUSION –Radiotherapy combined with chemotherapy after modified radical mastectomy decreases rates of locoregional and systemic relapse and reduces mortality from breast cancer

7. APPRAISAL ARE THE RESULTS VALID? –Was the assignment of patients to treatments randomized? YES As stated in the methodology, after written informed consent was obtained, the patients were randomly assigned to one of two groups: those receiving adjuvant chemotherapy plus locoregional radiotherapy in 5 fields (164 patients) ant those receiving chemotherapy alone (154 patients)

8. APPRAISAL ARE THE RESULTS VALID? –Were all the patients who entered the trial properly accounted for and attributed at its conclusion? YES 318 patients were randomized and analyzed according to the intention-to-treat principle. In the table for the main analysis, the sum of patients in each group totalled 318, the number who were randomized.

9. APPRAISAL ARE THE RESULTS VALID? –Were the patients, health workers, and study personnel blind to the treatment? NO

10. APPRAISAL ARE THE RESULTS VALID? –Were the groups similar at the start of the treatment? YES The characteristics of the patients were evenly balanced.

13. APPRAISAL ARE THE RESULTS VALID? –Aside from the experimental intervention, were the groups treated equally? NO As Part of a second randomization, 68 patients with estrogen-positive tumors were treated with radiation induced ovarian ablationthat included Gy over a period of 5 days plus prednisone (7.5 mg per day) for 2 years. Among the 68 patients, 33 were assigned to chemotherapy and 35 were assigned to chemotherapy and radiotherapy.

14. APPRAISAL WHAT ARE THE RESULTS? –How large was the treatment effect? (refer to the next slide)

17. APPRAISAL WHAT ARE THE RESULTS? –How precise was the estimate of the treatment effect? Measurements of treatment outcomes in terms of disease-free survival, survival free of systemic disease, survival free of locoregional disease, and breast cancer-specific survival were precise. –95% CI for these were all <1.

18. APPRAISAL WHAT ARE THE RESULTS? –How precise was the estimate of the treatment effect? However, measurement of outcome in terms of overall survival was slightly imprecise –95% CI was 0.53 to 1.02

21. FURTHER INSIGHTS Validity of the study is questionable. Blinding of data collectors should at least have been done. –Although blinding of patients from receiving radiotherapy is impracticable. Hormone receptor-positive cases should have been excluded in order to avoid any co-interventions that may affect the measurement of outcomes

22. THANK YOU