6 months of neoadjuvant ADT doubles survival when given with radiation therapy

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.

12 Responses

  1. It seems this study focused on radiation as a first-line treatment. Do you think this study also supports the use of (6 months of) hormone therapy in connection with salvage radiation?

  2. That is a difficult question to answer, but here’s one way to look at a possible set of answers.

    If it appears to be clear that the recurrence is truly local to the prostate bed, then there would be a strong argument that adding 6 months of neoadjuvant ADT to salvage radiation might be a good idea (based on the study data presented above).

    By contrast, if it appears clear that the recurrence has extended into the lymph nodes, then there is a strong argument that at least 2 years of neoadjuvant and adjuvant radiation would be wise (based on earlier studies).

    When the site of recurrence of the cancer is unknown, all bets are off. Such a patient could have truly metastatic prostate cancer to bone or elsewhere but no visible evidence of such a metastasis. In such a case, hormone therapy might well drive down the PSA for the duration of the hormone therapy, but the PSA would rise again as soon as hormone therapy was stopped because the radiation would have had no meaningful effect on the cancer.

  3. Many studies corroborate these findings for external beam only treatment. Not so clear, however, is the role of ADT when combo RT therapy or HDR are used. There are studies (A. Martinez and others) showing no gain and some possible negatives from ADT use with intermediate and advanced prostate.

  4. I am not aware of any large, randomized, double-blind studies comparing the effectiveness and safety of either brachytherapy alone or a combination of brachytherapy and EBRT with and without ADT in the treatment of men with localized or locally advanced prostate cancer.

  5. … which is a retrospective analysis of a single institution case series, and therefore has limited value as clinical evidence. It’s not “wrong.” It just doesn’t come close to the level of evidence supposedly attributable to a double-blind, randomized trial.

  6. I recall reading a Canadian study report on a similar subject a few months ago. The initial conclusion was that a fairly long period of ADT prior to and during external beam radiation treatment was required to provide the most effective outcome. After a re-analysis of the data it was found that the outcomes were more dependent on the PSA level at onset of EBRT than on the actual time of ADT prior to commencement of the EBRT. I wonder if the authors of the present study have the data to examine this aspect of the study?

  7. Also note the 66 Gy dosage of these treatments, not comparable to today’s 77?

  8. Dear Bill: We carefully point that out in the commentary above.

  9. Unfortunately there is still no panacea for definitive treatment and cure of prostate cancer. I always think of it as a sneaky, insidious disease which is likely to last in the population until a really major breakthrough is made; this seems to be an awful long way off at present.

    I have T3b, stage III, Gleason 8 with seminal vesicle involvement, which after ADT and EBRT has the PSA increasing from 0.1 to 0.3 in the last 3 months, so am trawling the net looking for crumbs of comfort. It looks as though abiraterone and denosumb only can increase life for a few months. Another major consideration is that it is an excruciatingly painful end to a man’s life.

  10. Thanks for breaking these data down into the raw numbers. It’s nearly impossible for me to draw any conclusion from hazard ratios, which is the only way I’ve seen these data presented elsewhere.

  11. What’s good about this trial — beyond the tight design and good population size — is that the subjects weren’t a bunch of Gleason 6s and 7s that would have survived even if they had been treated by a witch doctor.

    These guys were all palpable tumors, T2s, T3s and T4s.

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