Here’s a question that comes up over and over again from newly diagnosed patients: “My doctor is suggesting I get hormones in combination with radiation therapy. How long am I likely to be on hormone therapy?”
We have just come across the results of a randomized, Phase III trial we were not previously aware of, conducted in Canada between 1995 and 2001. The results of this trial were published by Crook et al. in 2004.
The primary objective of this trial was to compare the value of 3 months of hormone therapy vs. 8 months of hormone therapy given before initiation of conventional dose external beam radiotherapy (EBRT) on disease-free survival, using PSA levels and biopsy results as end points for treatment of 378 patients with clinically localized prostate cancer. The 378 patients were randomized to receive either 3 or 8 months of flutamide and goserelin prior to EBRT with a total of 66 Gy at four participating centers.
The results of the trial were as follows:
- The median patient age was 72 years (range, 50-84 years).
- The stage distribution was 17 percent T1c, 35 percent T2a, 34 percent T2b-T2c, 13 percent T3-T4.
- Gleason scores were ≤ 6 in 51 percent , 7 in 38 percent, and 8-10 in 11 percent of patients.
- The median baseline PSA level was 9.7 ng/ml (range, 1.3-189 ng/ml).
- Of the 378 men, 26 percent were low risk (clinical stage T1c-T2a, GS ≤ 6, PSA <10 ng/ml), 43 percent were intermediate risk (clinical stage T2b or GS 7 or PSA 10-20 ng/ml), and 31 percent were high risk (clinical stage T3 or GS 8-10 or PSA >20 ng/ml).
- The numbers of patients in the two arms of the trial were balanced in terms of age, Gleason score, T stage, risk group, and presenting PSA level.
- The median follow-up was 44 months (range, 10-84 months), and 361 patients were available for evaluation.
- Patients in the 8-month arm achieved a lower PSA level before starting EBRT (0.37 vs. 0.74 ng/ml, p ≤ 0.001) and had greater downsizing of the prostate (mean volume 26.6 cm3 vs. 30.5 cm3, p ≤ 0.001).
- The actuarial rates of freedom from biochemical failure (using the original American Society for Therapeutic Radiology and Oncology definition, local or distant) for the 3-month vs. the 8-month arms were 66 vs. 68 percent at 3 years and 61 vs. 62 percent at 5 years, respectively (p = 0.36).
- No statistically significant difference was noted in the types of failure between the two arms (crude final status): biochemical failure, 22.2%vs. 22.3 percent; local failure, 10.2 vs. 6.5 percent; and distant failure, 3.4 vs. 4.4 percent (p = 0.61).
- Post-EBRT biopsies were carried out 2 years after completion of radiotherapy in 57 percent of the patients (n = 205).
- Negative biopsies were obtained in 68 percent of the 3-month and 77 percent of the 8-month patients
- Indeterminate biopsy results were obtained in 18 and 14 percent of patients in the 3-month and 8-months groups
- Positive biopsies indicating residual cancer were noted in 14 and 9 percent in the two arms, respectively.
- The median PSA level for non-failing patients was 0.50 ng/ml in both the 3-month and the 8-month arms.
- A suggestion of improvement was found in the 8-month arm for disease-free survival at 5 years for high-risk patients (39 vs. 52 patients) but did not achieve statistical significance.
What do we learn from this randomized trial?
- First, there appears to be no evidence that a longer period of neoadjuvant hormonal therapy prior to standard-dose EBRT confers any meaningful benefit in terms of disease-free survival.
- Second, although early failure was delayed by the use of 8 months of hormone therapy as compared to 3 months, this short-term benefit has disappeared for most patients by 5 years of follow-up.
- Third, there was some suggestion of greater benefit from a longer period of hormonal therapy for high-risk patients.
Now, in another paper based on this study, just published in the past week, Crook et al. have also shown that post-EBRT prostate biopsies conducted between 2 and 3 years after completion of EBRT were strongly predictive of subsequent biochemical disease-free survival. Specifically, they have shown that:
- The median follow-up for the patients who remained alive was 6.6 years (range, 1.6-10.1 years).
- Of 361 evaluable patients, 290 patients remained alive.
- Two-year post-treatment biopsy status was a strong predictor of 5-year biochemical disease-free survival rate (82 and 83 percent for negative and indeterminate biopsies, respectively, vs 27 percent for positive biopsies; P < 0.0001).
- Biopsy status at 2 years of follow-up and Gleason score at time of the original biopsy were the strongest determinates of biochemical disease-free survival.
In understanding these results, we should be clear that the authors classified biopsies that had residual tumor with severe treatment effect as “indeterminate,” and biopsies that had minimal or no treatment effect as “positive.”
What does this mean for patients? The “New” Prostate Cancer InfoLink would suggest that the implications are as follows:
- For any patient who is determined to need neoadjuvant (or possibly adjuvant) hormonal therapy in conjunction with EBRT for treatment of localized prostate cancer, a limited period of hormone therapy is necessary (possibly as little as 3-4 months).
- For patients at high risk for progression who are determined to need neoadjuvant (or possibly adjuvant) hormonal therapy in conjunction with EBRT for treatment of localized prostate cancer a longer period of hormone therapy may be advisable (perhaps of the order of 6-12 months)
- Long-term hormone therapy of 3 years duration has been proven to extend disease-free and overall survival in combination with EBRT among men receiving treatment for T2b-T3 disease, but there is no evidence yet that shorter term hormone treatment may not achieve similar outcomes.
- A follow-up biopsy at 2 years post EBRT, in combination with regular PSA testing, can provide accurate prognostic information about 5-year biochemical disease-free survival
The bottom line: Some hormone therapy may be wise, but exactly how long an individual patient may need to stay on hormones is a matter for discussion between that patient and his doctor. And if you have a follow-up biopsy at 2 years, you can get a pretty accurate assessment of your probability of continuing disease-free survival up to 5 years.
Filed under: Management, Treatment, Uncategorized Tagged: | hormone therapy, neoadjuvant, outcomes, radiotherapy
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A study in which prostate cancer was treated with only 66 Gy of radiation is the equivalent to a study of surgery performed with a Bowie knife.
Back in the day such lower doses of radiation were used because targeting them was much less precise. Now they can inject targeting markers directly into the prostate itself and can use a much higher radiation dose and as a result are achieving much higher success rates with much less damage to the surrounding tissues.
Many studies have been conducted and published showing that doing about 6 months of hormone deprivation therapy in connection with doing external beam radiation at higher doses gives better results than doing less or more. When I did my external beam radiation in the fall of 2006 I did one 3-month Lupron shot in July and another one in early October, and then had my 45 days of daily radiation treatments from mid-October through mid-December.
When I went in to see my urologist in January he had a needle all ready to give me a third Lupron shot. But by then we (my wife and I) had found a half dozen studies on-line that showed that while two are beneficial, a third one not only isn’t helpful, but may actually be unhelpful in some ways. So we challenged him to show us a single study that showed that getting the third one was beneficial. He couldn’t. So we skipped it, and I was later very glad that I did, because I was still under the influence of my early October “3-month” shot on into the next June!
John Arnold, 33 months into this adventure.
Dear Mr. Arnold:
If you are aware of any other large, randomized clinical trials comparing different time courses of hormone therapy in association with radiation, we would be interested in knowing of these.
We are aware of other small studies, but either not randomized or not sufficiently powered to give statistically meaningful results.
You are of course correct about the fact that current total radiotherapy doses are now much more likely to be in in the 72-75 Gy range than 66 Gy. This study was initiated in 2001. However, we can only report the data that are available. As far as we are aware there has never been a similar trial in which men received higher-dose, better targeted radiotherapy.