JOURNAL CRITICAL APPRAISAL

Michael Angelo L. Suñaz, M.D.

August 2007

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

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.

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.

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)

PUBLISHED ABSTRACT

• CONCLUSION– Radiotherapy combined with chemotherapy

after modified radical mastectomy decreases rates of locoregional and systemic relapse and reduces mortality from breast cancer

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)

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.

APPRAISAL

• ARE THE RESULTS VALID?– Were the patients, health workers, and

study personnel blind to the treatment?• NO

APPRAISAL

• ARE THE RESULTS VALID?– Were the groups similar at the start of the

treatment?• YES• The characteristics of the patients were evenly

balanced.

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.

APPRAISAL

• WHAT ARE THE RESULTS?– How large was the treatment effect?

(refer to the next slide)

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.

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

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

THANK YOU