A new article in Lancet Oncology has reported that a mere 6 months of neoadjuvant hormone therapy, when combined with radiation therapy, cuts the risk of dying from locally advanced prostate cancer by 50 percent compared to radiation alone at 10 years of follow-up.
Between June 1996 and February 2000, the Trans-Tasman Radiation Oncology Group (TROG) enrolled 818 men into the TROG 96.01 study to assess whether short-term neoadjuvant androgen deprivation therapy (NADT) could decrease clinical progression and mortality after radiotherapy for locally advanced prostate cancer.
All 818 patients had to be initially diagnosed with locally advanced prostate cancer (i.e., clinical stages T2bN0M0, T2cN0M0, T3N0M0, or T4N0M0). The patients were then randomly assigned to one of three arms of the study:
- Arm A: radiotherapy alone
- Arm B: 3 months of NADT + radiotherapy
- Arm C: 6 months of NADT + radiotherapy
Because this trial was started back in 1996, the radiotherapy dose used for all three patient groups was 66 Gy, delivered to the prostate and seminal vesicles (excluding the pelvic nodes) over about 7 weeks. (A higher and more structurally “conformed” dose of radiation might be used if this trial was to be repeated today.) The NADT was initiated 2 months before radiation therapy for patients in Arm B and 5 months before radiotherapy for those in Arm C. NADT was given as a monthly subcutaneous depot injection of goserelin acetate (3.6 mg) together with flutamide (250 mg p.o., three times a day).
Here is what Denham et al. report as the results of this very important study:
- Data from 802/818 patients were eligible for analysis (270 in Arm A; 265 in Arm B; 267 in Arm C).
- The average (median) patient follow-up was 10.6 years.
- Compared with patients in Arm A, patients in Arm B showed
- A reduced cumulative incidence of PSA progression (adjusted hazard ratio [aHR] = 0.72; p=0.003)
- A lower likelihood of local progression (aHR = 0.49; p = 0.0005)
- A higher likelihood of event-free survival (aHR = 0.63; p < 0.0001)
- No significant effect on distant progression (aHR = 0.89; p = 0.550)
- No significant effect on prostate cancer-specific mortality (aHR = 0.86; p = 0.398)
- No significant effect on all-cause mortality (aHR = 0.84; p = 0.180)
- Also compared with patients in Arm A, patients in Arm C showed
- An even greater reduction in cumulative incidence of PSA progression (aHR = 0.57; p = 0.0001)
- An even lower likelihood of local progression (aHR = 0.45; p = 0.0001)
- An even higher likelihood of event-free survival (aHR = 0.51; p < 0.0001)
- A significantly lower risk for distant progression (aHR = 0.49; p = 0.001)
- A significant reduction in risk for prostate cancer-specific mortality (aHR = 0.49; p = 0.0008)
- A significant reduction in risk for all-cause mortality (aHR = 0.63; p = 0.0008)
- There was no increase in treatment-related morbidity associated with NADT within the first 5 years after randomization.
The authors state clearly that, in their view, “6 months of neoadjuvant androgen deprivation combined radiotherapy is an effective treatment option for locally advanced prostate cancer, particularly in men without nodal metastases or pre-existing metabolic comorbidities that could be exacerbated by prolonged androgen deprivation.”
Another way to look at these data is to say that, at 10.6 years of follow-up:
- Only 11 percent of the men in Arm C died of prostate cancer compared to 22 percent of the men in Arm A.
- 29 percent of the men in Arm C died from any cause compared to 43 percent of the men in Arm A.
This study would appear to provide definitive, level 1 data to confirm that a 6-month course of neoadjuvant hormone therapy, initiated 5 months prior to the start of radiation, is an appropriate form of treatment for all patients with potential or actual locally advanced prostate cancer who elect external beam radiation therapy (and perhaps other forms of radiation therapy such as brachytherapy or brachytherapy + external beam radiation) as their first-line treatment.
This is an important finding in that it provides clear evidence that a relatively brief period of hormone therapy can not only improve survival; it can also do this while significantly reducing the risks associated with longer periods of hormone therapy, which can include impotence, hot flashes, fatigue, elevated cholesterol levels, anemia, osteoporosis, metabolic syndrome, and effects on cognitive function.