Adjuvant Hormonal Therapy Benefits Prostate Cancer Patients Treated With Radiotherapy

ABSTRACT: To investigate the potential use of adjuvant hormonal therapy, a randomized, prospective trial was conducted among patients with locally advanced prostate cancer, comparing irradiation alone, with irradiation plus hormonal treatment with goserelin, an agonist anologue of gonadotropin-releasing hormone that reduces testosterone secretion. A total of 415 men under 80 years old with locally advanced disease and no previous treatment for prostate cancer were initially recruited, with data available for analysis on 401 of these patients. Preliminary results at 33-months’ follow-up suggested that goserelin started at the onset of external irradiation improved both local control and 5-year survival. Updated results at 45 months confirm these data. The overall 5-year survival rate for those treated with goserelin in addition to radiotherapy was 79%, compared to 62% in the radiotherapy only group. The localized control rate was 97% in the combined treatment group compared to 77% in the radiotherapy only group. [Oncol News Int 6(Suppl 3):21-22, 1997]

Introduction

Adjuvant hormonal treatment with goserelin, when started simultaneously with external irradiation, improves both local control and survival in patients with locally advanced prostate cancer. These and other results of a European Organization for Research and Treatment of Cancer (EORTC) study of the potential use of adjuvant hormonal therapy were reported at the First Sonoma Conference on Prostate Cancer by Michel Bolla, MD, of the Radiotherapy Department at University Hospital in Grenoble, France.

For the study, more than 400 patients were randomized to receive pelvic radiotherapy alone, or radiotherapy plus immediate treatment with goserelin. An agonist analogue of gonadotropin-releasing hormone that reduces the secretion of testosterone, goserelin (Zoladex) was administered subcutaneously in 3.6 mg doses every 4 weeks, starting on the first day of irradiation and continuing for 3 years.

To inhibit the transient rise of testosterone caused by goserelin, 150 mg of a steroidal antiandrogen, cyproterone acetate (Androcur), was given orally for 1 month starting the week before the first dose of goserelin.

Goserelin Helped

Both groups of patients received equal amounts of radiation: 50 Gy delivered to the pelvis over 5 weeks, 5 days per week, plus 20 Gy in 2 weeks as a prostatic boost.

Dr. Bolla shared his preliminary results at the Sonoma Conference suggesting that at a median follow-up of 33 months, patients who received goserelin at the onset of external irradiation had improved local control and survival. Subsequent publication in the New England Journal of Medicine (Vol. 337, No. 5) shows that these improvements were borne out at 45-months’ follow-up:

• The overall 5-year survival rate among those treated with goserelin in addition to radiotherapy (combined therapy) was 79%, compared to an overall 5-year survival rate of 62% for those treated with radiotherapy alone.
  
  
• Among those who did survive for 5 years, 85% of patients receiving combined therapy were disease-free, compared to 48% of those receiving radiotherapy alone.
  
  
• The 5-year local control rate was 97% in the combined treatment group, compared to 77% in the radiotherapy alone group. “Local control was clinically defined, which is not sufficient,” Dr. Bolla admitted. “But we were reluctant to ask patients to receive a second biopsy because we have to take into account the [effect on] quality of life.”
  
  
• The time until the first treatment failure after a biologic response averaged 6.6 years for the combined treatment group, compared to 4.4 years for the radiotherapy only group.
  
  
• The 5-year failure-free rate after biologic response was 81% for the combined treatment group, compared to 43% for the radiotherapy only group.
  
  
• There were 35 deaths in the combined treatment group (6 attributed to prostate cancer) and 58 in the radiotherapy only group (26 attributed to prostate cancer).
  
  
• In the combined treatment group, 20 patients showed disease progression, compared to 78 in the radiotherapy group. For 56 of those individuals (72%) in the radiotherapy only group, treatment given after disease progression included goserelin.

Patient Characteristics and Evaluation

To be eligible, a patient had to have no previous treatment for prostate cancer and be under 80 years of age. A total of 415 patients were originally enrolled in the study, ranging in age from 51 to 80, with a median age of 71. Data on 401 patents were available for analysis. Those accepted had histologically proven adenocarcinoma of the prostate that was:

• intracapsular or confined to the gland (T1 or T2), with no detectable involvement of regional lymph nodes (NO-X), and a World Health Organization (WHO) histologic grade of 3;
• and/or prostate cancer of any histologic grade that extended beyond the capsule (T3) or infiltrated surrounding structures (T4) without involving regional lymph nodes.

The clinical evaluation included bone scans, chest radiography, and ultrasound or CT scan of the liver, evaluation of the lymph nodes, complete blood counts, and measurements of creatinine, serum prostatic acid phosphatase, and serum testosterone. PSA was measured by radio-immunometric or immunoenzyme assays.

The Downside of Goserelin

 Among those patients receiving goserelin, 62% had hot flashes, with 34% having more than 3 per day. At 45-months’ follow-up, patients in the combined treatment group were more likely to report late grade 1-3 incontinence: 29%, compared to 16% in the radiotherapy only group. There were no significant differences in other side effects among the two groups of patients.

Rationale Based on Studies of Hormone Therapy for Breast Cancer

The rationale for giving goserelin for an extended period of time was based, Dr. Bolla told the conference participants, on studies showing that administering tamoxifen to breast cancer patients for at least 2 years, and preferably 5, had an impact on survival. “It was the reason why I have proposed three years of a luteinizing hormone-releasing hormone (LHRH) analogue,” Dr. Bolla explained.

“The hypothesis was to reduce, with chemical castration, the occurrence of metastases outside the pelvis,” Dr. Bolla continued, “and the hope was to improve the results of radiation treatment within the pelvis. And my hypothesis was that we could potentiate the results of radiation treatment.”

Dr. Bolla’s study showed that adjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer.