A Scandinavian study has the potential to determine whether endocrine therapy combined with radiotherapy is more effective than endocrine therapy alone in treating locally advanced prostate cancer. Scientifically, its quite an important trial, Anders Widmark, MD, of the Department of Oncology at Umea University in Sweden, told participants at the First Sonoma Conference on Prostate Cancer. Dr. Widmark is coordinating the study for the Scandinavian Prostatic Cancer Group and the Swedish Society for Urological Oncology.
The study builds on a number of ongoing studies to compare the efficacy of neoadjuvant or adjuvant endocrine therapy in combination with radiotherapy, to radiotherapy alone.
These include studies by the Radiation Therapy Oncology Group in the United States and the European Organization for Research and Treatment of Cancer.
Some of these studies have indicated that the combination treatment of radiotherapy and endocrine treatment should be of value, according to a summary report of the Scandinavian study. The mechanism of action of this potentiation of radiotherapy is unknown, but modification of different growth factors could be of importance. If these data are confirmed, deprivation of testosterone would be the optimal form of radiation sensitization since the major effect is on the target organ, the prostate.
Primary End Point Is Survival
The primary end point for the study is survival, with secondary end points being: prostate-specific antigen (PSA) progression, clinical progression (local/distant), and quality of life issues (evaluated by periodic questionnaires) with special focus on sexual function, urinary, and gastrointestinal morbidity.
To detect a significant increase in 7-year survival from 65% to 75%, 330 patients need to be recruited into each arm of the study.
Patients must be younger than 76 years of age with a life expectancy of more than 10 years. Of the first 100 patients enrolled in the study, most are between 66 and 70 years of age, Dr. Widmark reported, with about 25% above age 70.
Most in Study Have T3 Disease
Known as SPCG-7/SFUO-3, the Scandinavian study focuses on patients with locally advanced prostatic carcinoma. The target population is T3 G1-G3 patients, with T1b-T2, G2-G3 as optional patients.
Of the first 100 patients enrolled in the study, 75% are T3 (Table 1). Its the population that we actually were aiming for, Dr. Widmark said.
About 40% of the Swedish prostate cancer population is diagnosed at the T3 stage and 25% of newly diagnosed prostate cancer patients without distant metastases present with locally advanced clinical stage.
Because these patients have more symptoms, I think theres more need for treatment, Dr. Widmark explained.
Patients must have histologically/cytologically verified prostate cancer without metastases. Patients with a PSA less than 10 are considered to be lymph node negative. Staging operations are performed on patients with PSA levels between 11 and 70. (Among the first 100 patients enrolled, 79% have a PSA of 30 or less.) Patients with a PSA greater than 70 or with positive lymph nodes are excluded. Since were focusing on aggressive local treatment, we think its important to restrict the study to node-negative patients, Dr. Widmark said.
Treatment and Follow-Up
All patients receive neoadjuvant total androgen blockade (Procren Depot [Lupron]) plus flutamide (Eulexin) for 3 months and then continue with the antiandrogen alone (flutamide). One arm of the study also receives minimal dose radiotherapy70 Gy to the prostate and up to 50 Gy to the seminal vesicles. (Age and treatment arms for the first 100 patients are summarized in Table 2.)
Clinical and laboratory follow-up are performed every 3 months for the first year and every 6 months thereafter. Progression of disease is counted from the start of the hormonal treatment to the day when progression is first suspected.
Progression is evaluated according to the Scandinavian tradition of sequential evaluation of progression, Dr. Widmark explained. Youre allowed to follow the patients for about 2, 3, or 6 monthswhatever it takesuntil you have sufficient information to say that it is a real PSA or clinical progression. Then you can go back and set the date when you saw the first PSA rise or clinical progress, to define the time point for progression.
Dr. Widmark noted that there is a parallel study being done in Canada. That study uses total androgen blockade in both arms and radiotherapy in one arm, Dr. Widmark said. But ours utilizes 3 months of neoadjuvant total androgen blockade and then we switch to an antiandrogen alone. So I think its good the two studies are going on simultaneously, Dr. Widmark commented, so that we can compare the results.
Neoadjuvant Therapy and Surgery
Another Swedish Study (known as the POPCORN study) looked at whether neoadjuvant therapy prior to radical prostatectomy would facilitate or optimize surgery in some patients, Dr. Widmark reported. They didnt find any improvement regarding facilitation of surgery, Dr. Widmark said, but did find neoadjuvant therapy decreased the number of positive margins.
For that study, 122 patients with T1b-T3a were randomized between immediate radical retropubic prostatectomy or 3 months neoadjuvant total androgen blockade (triptorelin and cyproterone acetate) followed by radical prostatectomy.
No differences were found in blood loss or operation time, but patients who had neoadjuvant treatment had a significantly lower frequency of positive margins (41% vs 23%). The authors conclude that neoadjuvant treatment does not facilitate radical prostatectomy, but may improve the chances of local cure. Long-term follow-up of these randomized patients is needed.