Neoadjuvant Hormonal Therapy in Prostate Cancer: Pro and Con

 New Orleans—The advisability of neoadjuvant hormonal therapy in the management of prostate cancer is a hotly debated issue. At the American Society of Therapeutic Radiology and Oncology (ASTRO) spring refresher course, two opinion leaders in radiation oncology squared off on opposite sides of this issue.

Speaking for the use of neoadjuvant androgen suppression was William U. Shipley, MD, professor of radiation oncology, Harvard Medical School, and head of genitourinary oncology, Department of Radiation Oncology, Massachusetts General Hospital, Boston

“Neoadjuvant therapy, compared with adjuvant therapy, offers a shorter course of hormonal therapy, precedes rather than follows radical treatment, and is aimed at increasing local control rather than the control of micrometastases,” Dr. Shipley observed. “For locally advanced prostate tumors, neoadjuvant hormonal therapy is beneficial when combined with radiotherapy and should be the standard of care.”

Dr. Shipley believes there is a clear rationale for neoadjuvant androgen suppression. It downstages the tumor; achieves cytoreduction; decreases prostate volume (three studies show a 40% reduction with 3 months of therapy); triggers apoptosis of sensitive cells; and significantly alters histology.

“There is a significantly improved biological effect,” Dr. Shipley said. This may translate into an improved clinical situation in a number of ways:

A 40% reduction in prostate volume within 3 months of neoadjuvant androgen suppression.

Reduction in circulating cancer cells—from 37% to 20% with neoadjuvant androgen suppression.

Reduction in percentage of positive post-irradiation re-biopsy samples, in several series—Zelefsky et al (J Clin Oncol 16:3380, 1998), for example, found 44% positive biopsies with radiotherapy alone (70 to 76 Gy) vs 15% with radiotherapy plus neoadjuvant hormonal therapy.

 Sharp decline in PSA levels due to decline in testosterone—PSA is undetectable after neoadjuvant therapy in 33% of patients at 3 months and in 70% at 6 months.

Three phase III clinical trials showed a decrease in local tumor regrowth and occurrence of distant metastases, he said. With a median follow-up of 6.5 years, the RTOG trial of 456 patients with large tumors showed an advantage for neoadjuvant hormonal therapy. Use of flutamide (Eulexin) and goserelin (Zoladex) resulted in NED (no evidence of disease) status in 49% of patients vs 34% for radiotherapy alone, and a significant difference in local control, 78% vs 65%, Dr. Shipley reported.

On the other hand, he said, overall survival at 8 years, although there was a trend (P = .11), was not significantly different: 52% survival at 8 years in the combined group vs 43% in the radiotherapy alone group. But in the better-differentiated tumor subgroup, there is a significant survival difference of about 12%, Dr. Shipley noted.

“For T3 tumors, it stands to reason that cytoreduction is very important. Local control is a huge issue,” he remarked.

As for patients with smaller T1-T2 tumors, Dr. Shipley said the benefits of neoadjuvant hormonal therapy occur only when a large planning target volume increases the risk of morbidity from external beam radiotherapy or brachy-therapy. Hormonal therapy lowers the proportion of the organ receiving high radiation doses and spares more of the bladder and rectum.

There are no data yet to support improved survival in unselected stage T1-T2 patients, though clinical trials are underway to identify T1-T2 subsets likely to benefit, he added.

Speaking Against

Speaking against the use of neoadjuvant hormonal therapy was Gerald Hanks, MD, chairman, Department of Radiation Oncology, Fox Chase Cancer Center, and professor and chairman of radiation oncology, Temple University School of Medicine, Philadelphia.

Dr. Hanks argued that there are not enough class I data—results based on randomized controlled clinical trials—to validate this regimen. Currently, he sees no role, therefore, for neoadjuvant androgen deprivation in the management of prostate cancer.

“For most locally advanced prostate cancer patients, there is already class I evidence for how they should be treated. In the absence of a survival advantage of short-term hormones, I think the bad outweighs the good,” Dr. Hanks said. “To replace or add to the long-term strategies that are proven to have survival advantages at this point requires new randomized trials adding the neoadjuvant component to the proven management.”

Regarding the presumed gains from neoadjuvant androgen deprivation, he argued there is no evidence that (1) shrinking the prostate will reduce morbidity; (2) decreasing the number of clonogens will increase the cure rate; (3) micrometastases out of the radiation field will be eradicated; or (4) long-term neoadjuvant hormonal therapy is superior to short-term therapy.

Elaborating, he said that reanalysis of RTOG 86-10 and 85-31 reveals the relative risks for cause-specific failure and distant metastases are 1.0 each for long-term hormone therapy, but 2.1 for short-term therapy, no different from patients receiving no hormonal therapy.

In addition, Dr. Hanks pointed to a number or potential negative effects of androgen deprivation. Androgen deprivation could promote resistance (as could long-term hormone therapy); weaken bone (Diamond et al: Cancer 83:1561, 1998); suppress testosterone longer than intended; impair recovery of potency; diminish physical activity level and quality of life; and add to the cost of care without demonstrating cost-effectiveness, he said.

One recent study found that 3 to 6 months of neoadjuvant hormone therapy resulted in castrate levels of testosterone in patients and mean hypogonadal symptoms lasting more than 1 year (Oefelein et al: J Urol 160:1685, 1998). Another study at Fox Chase Cancer Center found that only 36% of patients retained potency after short-term androgen deprivation and radiotherapy vs 67% after radiotherapy alone.

“I think it is quite likely that if you give 3 to 4 months of androgen deprivation, you will cut in half the chances of recovering potency,” he commented.

Potency aside, many older patients also suffer a loss of “zip”—they become sedentary, gain weight, lose muscle mass, develop hot flashes, and lose libido. “This can be a difficult symptom complex. These are not trivial symptoms in a 70-year-old man,” he observed.

Neoadjuvant androgen deprivation does, however, give a false sense of cure and will delay PSA failure by 20 to 24 months, but no survival benefit has been associated with this delay, he emphasized.

Dr. Hanks stressed that current treatment standards provide very good outcomes for the vast majority of patients and “shouldn’t be messed with.” Even the “unfavorable group,” such as T2b and T3 patients with Gleason score 7 to 10, are still 80% free of disease at 5 years when they receive high-dose radiation therapy.