JOURNAL CRITICAL APPRAISAL

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