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American Society of Clinical Oncology 36th Annual Meeting
Day 3 - May 22, 2000

Prostate Cancer: New Insights Into Old Issues?

Nicholas J. Vogelzang, MD -- Writer: Michelle L. Plante, PharmD

During Monday's oral session, a number of presentations provided new data on screening and early diagnosis of prostate cancer, therapeutic strategies for locally advanced disease, and health-related quality of life, raising interesting discussions on the best strategy to pursue in a number of different clinical settings.

Pretreatment PSA as Predictor of Freedom From Biochemical Failure

Pretreatment prostate-specific antigen (pPSA) has been shown to be an independent predictor of freedom from biochemical failure (FFBCF) in prostate cancer. Dr. Roach and colleagues,[1] from the University of Southern California and University of Michigan, looked at whether the current Radiotherapy Oncology Group (RTOG) risk groups are still relevant in light of the widespread availability of pPSA. They also examined the influence of pPSA on the FFBCF within each risk group. They evaluated 927 patients from the 2 centers and applied the RTOG group and the FFBCF according to the ASTRO consensus definition.

Table 1. Influence of pPSA on the FFBCF

RTOG Risk Group RTOG 15-year % DSS (95% CI) 4-year %FFBCF 4-year %FFBCF:PSA
< 10 vs > 20
1: T1-2, GS 2-6 72 (62 - 83) 70 83 vs. 47
2: T3, GS 2-6 or
T1-2, GS 7		 61 (51 - 72) 60 76 vs. 45
3: T1-2, GS 8-10, or
T3, GS 7		 39 (26 - 60) 40 65 vs. 25
4. T3, GS 8-10 27 (20 - 37) 21 27 vs. 28

DSS = disease-specific survival; GS = Gleason score; T = tumor stage

The 4-year FFBCF correlated with the 15-year expected DSS stratified by risk group. The pPSA added significant prognostic value within groups 1, 2, and 3 concerning the likelihood of FFBCF. A pPSA of less than 10 was associated with better FFBCF by 10%, 15%, and 25% in groups 1, 2, and 3, respectively, and a pPSA of greater than 20 was associated with a worse (or lower) FFBCF by 25%, 15%, and 15% in groups 1, 2, and 3, respectively. In group 4 patients, pPSA added very little information. Dr. Roche suggested that pPSA values should be included in the risk stratification when designing prospective trials.

Dr. Victor D'Amico of Brigham and Women's Hospital and the Dana Farber Cancer Institute, Boston, Massachusetts, commenting on the Roach and Hanks papers, strongly supported the finding that FFBCF was a significant predictor of cancer-specific survival. He compared RTOG 8610 to RTOG 92-02. In RTOG 8610, the FFBCF with a 6.7-year follow-up was 39%, while in RTOG 92-02 the FFBCF was 53% with a 4.8-year-follow-up, perhaps suggesting the occurrence of stage migration or true improvement with therapy. The RTOG 92-02 data are also supported by the study recently published by Pound.[2] Although the direct connection between pPSA and time to death has not yet been determined in a single trial, all the trials should be used to support this principle, according to Dr. D'Amico. He also commented that FFBCF was predicted not only by pPSA, Gleason score, and tumor stage, but also by the percent of positive biopsies. Lastly, he commented that neither Dr. Roach nor Dr. Hanks specifically dealt with the radiation therapy dose found to be highly predictive by Dr. Kupelian at ASCO 1999.[3]

Is Long-term Androgen Suppression Beneficial in Locally Advanced Cancer?

Dr. G. E. Hanks[4] of the Fox Chase Cancer Center, Philadelphia, Pennsylvania, presented the results of RTOG protocol 92-02, which examined whether long-term androgen suppression following neoadjuvant hormonal cytoreduction and radiation therapy was beneficial in locally advanced prostate cancer. All patients received goserelin acetate and flutamide for 2 months before and for 2 months during radiation therapy. They were then randomized to receive no further therapy or 24 additional months of goserelin acetate alone. The median follow-up of the 1520 patients randomized was 4.8 years. There was a significant improvement in disease-free survival (54% vs 34%, P=.0001), local progression (6% vs 12%, P=.0001), distant metastasis (11% vs 17%, P=.001), and biochemical failure (20% vs 47%, P=.0001) in the goserelin group vs the group that received no long-term androgen suppression. The 5-year survival was not different between the 2 groups (78% vs 79%). Subset analysis of patients with a Gleason grade of 8-10 (22% of all patients) revealed a significant benefit deriving from prolonged androgen suppression. The overall survival in the 4-month group was 76% vs 89% in the long-term group, and the DSS was 69% vs 80%, respectively. Dr. Hanks suggested that longer duration of androgen suppression may be used as the standard for comparison in future clinical trials.

Quality of Life After Brachytherapy, Radical Prostatectomy, or External Beam Radiation Therapy

Dr. Sanda,[5] of the University of Michigan, presented a comparison of the health-related quality of life (HRQOL) of patients receiving brachytherapy (BT), radical prostatectomy (RP), or external beam radiation therapy (ERT) as primary therapy for localized breast cancer. This was a cross-sectional cohort survey of all patients who had received one of these therapies from June 1995 through May 1999. A number of validated measurements of quality of life were used, including the SF-36, FACT-P, AUA symptom score, and a 51-item modified UCLA prostate cancer index (Expanded Prostate cancer Index Composite [EPIC]). Of note, the EPIC index is a newly validated and utilized instrument unique to this study. A total of 1014 surveys were available for analysis (including 112 age-matched controls), with a similar percentage of survey responses in the 3 groups (73% to 76%). Median follow-up of the BT patients was 21 months, 29 months for the RP patients, and 30 months for the ERT patients (P=.01). Analysis of covariance however, controlled for the imbalances in the follow-up time.

Several significant differences in HRQOL were detected in the groups, including:

These results show that there are significant differences in the HRQOL following the different treatment modalities for localized prostate cancer, with ERT and RP comparing favorably to BT. The additional instrument used in the study, the EPIC survey, suggests that there is dissociation between "bother" and function. A limitation of this study is that no baseline data are available to ascertain whether patients choosing different types of therapy have baseline differences in symptoms. However, this type of QOL data should be shared with patients to help them make an informed decision for primary therapy.

PSA Screening: How Frequently Should it be Done?

Dr. G. Lu-Yao[6] presented data that demonstrated that less frequent PSA screening (ie, biennial as compared with annual) is not associated with an increased risk of nonlocalized cancer or prostate cancer-specific death. The investigators used SEER (Surveillance, Epidemiology and End Results) and Medicare data for 36,422 patients diagnosed with prostate cancer during 1989 and 1993. They excluded patients who had a PSA within 2 months of diagnosis. The risk of development of nonlocalized prostate cancer occurring during the follow-up period was 19%, regardless of whether the last PSA was 1, 2, or 3 years prior to diagnosis. By contrast, for patients whose last PSA was 3, 4, or 5 years prior to diagnosis, the risk of nonlocalized disease was 32%. They could not discern a difference in development of nonlocalized prostate cancer in patients whose PSA had been determined 13-24 months or 25-36 months previously. They also demonstrated that for patients who had PSA values obtained annually, the annual biopsy rate was 4.5%, vs 3.0% in those who had PSA values determined every 2 years and 0.5% in those who never had a PSA done prior to diagnosis. The authors concluded that PSA screening at 2- or 3-year intervals may be more cost-effective than annual screening, and should not have a negative impact on stage of disease at diagnosis or survival. This study has several limitations, including its retrospective design, the fact that it only included men 65 years of age or older, and the fact that PSA history may have not been complete. Dr. Roach questioned the authors' conclusions, saying that the study did not have an adequate follow-up, particularly in view of the fact that pretreatment PSA levels do not predict 5-year mortality but may predict longer survival in this patient population. This study has significant potential cost implications for future PSA screening studies. A randomized trial of 1-year vs 3-year screening intervals should now be considered.

Management of Hormone-Refractory Prostate Cancer

Dr. S. Fossa[7] of the presented the results from the European Organization for Research and Treatment of Cancer (EORTC) 30903 trial comparing flutamide to prednisone in symptomatic hormone-refractory metastatic prostate cancer. Patients with painful hormone-refractory metastatic prostate cancer were randomized to receive either prednisone at 20 mg per day (n = 101) or flutamide at 750 mg per day (n = 100). The median overall survival was 11 months in both arms. Efficacy was measured subjectively according to performance status change, WHO pain score, dose of analgesics, and need for radiation therapy. There was no difference in the efficacy of the 2 groups, but overall quality of life was better in the patients on prednisone with less nausea/vomiting, less pain, and less diarrhea.

Dr. S. Halabi[8] of Duke University, Raleigh, North Carolina, presented the results of the Cancer and Leukemia Group B (CALGB) 9480 trial comparing 3 different doses of suramin for the treatment of hormone-refractory prostate cancer. Three hundred ninety patients were randomized to receive either 3.19 g/m2, 5.32 g/m2, or 7.66 g/m2 on days 1, 2, 8, and 9 of a 28-day cycle for 3 cycles. The overall median survival was 14 months, with an objective response rate of 10% and a time to disease progression of 3 months. The results of the different dose groups are shown in the Table.

Table. 2 Comparison of 3 Doses of Suramin for Treatment of Hormone-Refractory Prostate Cancer

Dose Objective RR 75% PSA Decline Median Survival All Grade 3 & 4 Toxicity
3.19 g/m2 7% (3-13) 6% 14 months 66%
5.32 g/m2 7% (3 -14) 6% 14 months 79%
7.66 g/m2 16% (10-24) 8% 13 months 84%
P value .032 NS .687 .002
The toxicity of suramin was dose related. These results demonstrate that dose escalation of suramin produces more toxicity without an increase in survival. Suramin does not appear to have a therapeutic role in hormone-refractory prostate cancer, in spite of excellent preclinical data and positive phase II trial results.

Mitoxantrone for Early-Stage Prostate Cancer?

The discussant Dr. Malcolm Moore,[9] of the University of Toronto, Ontario, Canada, reviewed the potential rationale for trials of chemotherapy in early-stage prostate cancer, before the development of hormone-refractory prostate cancer. Quoting the abstract presented by Dr. J. Wang of the Imperial School of Medicine, London, England, presented earlier in the meeting, he noted that in that small trial of 96 patients, the median survival of patients treated with adjuvant mitoxantrone plus hormone therapy was 80 months vs 30 months in the hormone alone group (P=.04). Furthermore, the trial presented by Dr. M. Gregurich of US Oncology, Houston, Texas, supports the activity of mitoxantrone in hormone-refractory prostate cancer. In this trial of 120 patients, mitoxantrone did not improve overall survival but did improve median time to progression and the 50% PSA decline rate (48% vs 24%) compared with prednisone alone. Dr. Moore strongly urged randomized clinical trials using mitoxantrone and other chemotherapy agents earlier in the course of prostate cancer. Such a trial is currently under way by the Southwest Oncology Group.

In Summary...

Factors predictive of survival following treatment of local prostate cancer are now widely known and accepted. Using PSA screening to detect prostate cancer at an earlier stage will improve the prognosis and care of localized prostate cancer, prevent development of hormone-refractory prostate cancer, and enable more effective use of adjuvant hormone and chemotherapy regimens. For earlier-stage prostate cancer, external beam radiation, radical prostatectomy, and brachytherapy are probably equivalent in terms of survival, but QOL differences will inform physician and patient choices in this difficult area. Given the continuing dismal results of therapy for hormone-refractory prostate cancer, continued emphasis on early detection and cure of early disease must continue.

References

  1. Roach M, Weinberg V, McLaughlin P, et al. Does pretreatment PSA add to predicting long term survival from prostate cancer? Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1282.
  2. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-1597.
  3. Kupelian AK. Improvement in survival for patients with localized prostate cancer treated with higher than standard radiation doses. American Society of Clinical Oncology 35th Annual Meeting, May 1999; Atlanta, Georgia. Abstract 1226.
  4. Hanks GE, Lu J, Machtay M, et al. RTOG protocol 92-02: a phase III trial of the use of long term androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1284.
  5. Sanda MG, Dunn RL, Sandler HM, et al. Comparison of health-related quality of life (HRQOL) after brachytherapy, radical prostatectomy, or external beam radiation for localized prostate cancer. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1285.
  6. Lu-Yao G, Yao S. Prostate specific antigen testing frequency and subsequent risk of incurable prostate cancer and cancer deaths. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1287.
  7. Fossa S, Slee P, Brausi M, et al. A phase III trial of flutamide (F) versus prednisone (P) in hormone resistant metastatic prostate cancer (HRMPC) (EORTC 30903). Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1289.
  8. Halabi S, Small E, Ansari RH, et al. Results of CALGB 9480, a phase III trial of 3 different doses of suramin for the treatment of hormone refractory prostate cancer. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1291.
  9. Moore MJ. Chemotherapy in early-stage prostate cancer. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Discussion.
  10. Wang J, Halford S, Rigg A, Roylance R, Lynch M, Waxman J. Adjuvant mitoxantrone chemotherapy in advanced prostate cancer. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1322
  11. Gregurich MA. Phase III study of mitoxantrone/low-dose prednisone versus low-dose prednisone along in patients with asymptomatic hormone-refractory carcinoma of the prostate. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 1321.

Analysis of 9 Prostate Cancer Studies Shows Equal Survival Rates for Surgery, Implants, Beam


May 25, 2000
MedscapeWire

Cancer researchers from the United States and Europe reported that based on an analysis of 9 landmark studies involving 6877 patients with prostate cancer, the survival rates for patients in the early stages of the disease were roughly the same - and very high - regardless of the type of therapy used.

The importance of the comparative results is that survival rates among the patients after 5 years were in the 85% to 95% rate, reflecting the progress made across all modalities of treatment in recent years. It also indicates that if the cancer is discovered early, as it is in roughly 3 of 4 cases, the choice of treatment can be made by the patient on other comparative factors, such as length of incapacitation, costs, and the likelihood of adverse effects such as incontinence and impotence.

The clinical studies used the same criteria to classify selection and outcome data in patients who were treated with the most common methods of prostate cancer therapy, including surgical removal of the prostate (radical prostatectomy), radiation beam, and permanent or temporary radiation implants (brachytherapy).

The findings were reported and discussed at the joint meeting in Virginia of the American Brachytherapy Society (ABS), Groupe European de Curietherapie and European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) and the Grupo Latino Americano de Curieterapie (GLAC).

"For the first time ever, each clinical researcher started at the same point with the same definitions to determine patient outcomes based on the type of therapy and the classification of the tumor state," said Dr. James Fontanesi, president of the ABS. "In the past, comparative studies and comparisons of studies were difficult to do because researchers were starting at different points.

"In preparation for this conference, our goals were to set up a series of studies that were truly comparable and of clinical importance," he said. "Finally, we convinced some of the most prominent specialists in the world to participate, which speaks even more to validity."

Prostate cancer is the second most common cancer in men in the United States, and it kills about 37,000 males annually, mostly older than 50 years. But there has been intense debate over which method of treatment should be used based on survival rates, as well as lifestyle issues such as posttreatment incontinence and impotence and the total cost of treatment. Additionally, specialists often recommend that some elderly patients with slow-progressing tumors not be treated at all.

Centers involved in the comparative studies were Baylor University (Houston, Texas), Fox Chase Cancer Center (Philadelphia, Pennsylvania), Wayne State University (Detroit, Michigan), William Beaumont Hospital (Royal Oak, Michigan), Keil (Germany), Seattle Prostate Institute (Washington), and Arizona Oncology Center (Scottsdale).

Medscape Wire is prepared by Deborah Flapan, associate editor at Medscape. Send press releases and comments to medscapewire2@mail.medscape.com.