Andrew C. von Eschenbach

PROSTATE CANCER RADIATION DOSE RESPONSE: RESULTS OF THE M. D. ANDERSON PHASE III RANDOMIZED TRIAL

PURPOSE A randomized radiotherapy dose escalation trial was undertaken between 1993 and 1998 to compare the efficacy of 70 vs. 78 Gy in controlling prostate cancer. METHODS AND MATERIALS A total of 305 Stage T1-T3 patients were entered into the trial and, of these, 301 with a median follow-up of 60 months, were assessable. Of the 301 patients, 150 were in the 70 Gy arm and 151 were in the 78 Gy arm. The primary end point was freedom from failure (FFF), including biochemical failure, which was defined as 3 rises in the prostate-specific antigen (PSA) level. Kaplan-Meier survival analyses were calculated from the completion of radiotherapy. The log-rank test was used to compare the groups. Cox proportional hazard regression analysis was used to examine the independence of study randomization in multivariate analysis. RESULTS There was an even distribution of patients by randomization arm and stage, Gleason score, and pretreatment PSA level. The FFF rates for the 70- and 78 Gy arms at 6 years were 64% and 70%, respectively (p = 0.03). Dose escalation to 78 Gy preferentially benefited those with a pretreatment PSA >10 ng/mL; the FFF rate was 62% for the 78 Gy arm vs. 43% for those who received 70 Gy (p = 0.01). For patients with a pretreatment PSA <or=10 ng/mL, no significant dose response was found, with an average 6-year FFF rate of about 75%. Although no difference occurred in overall survival, the freedom from distant metastasis rate was higher for those with PSA levels >10 ng/mL who were treated to 78 Gy (98% vs. 88% at 6 years, p = 0.056). Rectal side effects were also significantly greater in the 78 Gy group. Grade 2 or higher toxicity rates at 6 years were 12% and 26% for the 70 Gy and 78 Gy arms, respectively (p = 0.001). Grade 2 or higher bladder complications were similar at 10%. For patients in the 78 Gy arm, Grade 2 or higher rectal toxicity correlated highly with the proportion of the rectum treated to >70 Gy. CONCLUSION An increase of 8 Gy resulted in a highly significant improvement in FFF for patients at intermediate-to-high risk, although the rectal reactions were also increased. Dose escalation techniques that limit the rectal volume that receives >or=70 Gy to <25% should be used.

American Cancer Society guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers. Also: update 2001--testing for early lung cancer detection.

Updates to the American Cancer Society (ACS) guidelines regarding screening for the early detection of prostate, colorectal, and endometrial cancers, based on the recommendations of recent ACS workshops, are presented. Additionally, the authors review the “cancer‐related check‐up,” clinical encounters that provide case‐finding and health counseling opportunities. Finally, the ACS is issuing an updated narrative related to testing for early lung cancer detection for clinicians and individuals at high risk of lung cancer in light of emerging data on new imaging technologies.

Preliminary Results of a Randomized Radiotherapy Dose-Escalation Study Comparing 70 Gy With 78 Gy for Prostate Cancer

PURPOSE To determine the effect of radiotherapy dose on prostate cancer patient outcome and biopsy positivity in a phase III trial. PATIENTS AND METHODS A total of 305 stage T1 through T3 patients were randomized to receive 70 Gy or 78 Gy of external-beam radiotherapy between 1993 and 1998. Of these, 301 were assessable; stratification was based on pretreatment prostate-specific antigen level (PSA). Dose was prescribed to the isocenter at 2 Gy per fraction. All patients underwent planning pelvic computed tomography scan to confirm prostate position. Treatment failure was defined as an increasing PSA on three consecutive follow-up visits or the initiation of salvage treatment. Median follow-up was 40 months. RESULTS One hundred fifty patients were randomized to the 70-Gy arm and 151 to the 78-Gy arm. The difference in freedom from biochemical and/or disease failure (FFF) rates of 69% and 79% for the 70-Gy and 78-Gy groups, respectively, at 5 years was marginally significant (log-rank P: =.058). Multiple-covariate Cox proportional hazards regression showed that the study randomization was an independent correlate of FFF, along with pretreatment PSA, Gleason score, and stage. The patients who benefited most from the 8-Gy dose escalation were those with a pretreatment PSA of more than 10 ng/mL; 5-year FFF rates were 48% and 75% (P: =.011) for the 70-Gy and 78-Gy arms, respectively. There was no difference between the arms ( approximately 80% 5-year FFF) when the pretreatment PSA was < or = 10 ng/mL. CONCLUSION A modest dose increase of 8 Gy using conformal radiotherapy resulted in a substantial improvement in prostate cancer FFF rates for patients with a pretreatment PSA of more than 10 ng/mL. These findings document that local persistence of prostate cancer in intermediate- to high-risk patients is a major problem when doses of 70 Gy or less are used.

The Efficacy and Complications of Salvage Cryotherapy of the Prostate

PURPOSE A phase I/II study was done to evaluate the efficacy and complications of salvage cryotherapy as a treatment for locally recurrent prostate cancer following full dose radiation therapy and/or systemic therapy. The efficacy of single and double freeze-thaw cycles was compared using posttreatment prostate specific antigen (PSA) levels and prostate biopsies as end points. MATERIALS AND METHODS A total of 150 patients with locally recurrent prostate cancer following radiation, hormonal therapy and/or systemic chemotherapy underwent salvage cryotherapy using a single (71 men, mean followup 17.3 months) or double (79 men, mean followup 10.0 months) freeze-thaw cycle. PSA was measured approximately every 3 months postoperatively and sextant biopsies were repeated 6 months postoperatively. Complications were assessed by retrospective chart review and a mailed quality of life survey. RESULTS Overall, 45 patients (31%) had persistently undetectable PSA. Patients with a history of radiation therapy only who underwent a double freeze-thaw cycle had a higher negative biopsy rate (93 versus 71%, p < 0.02) and lower biochemical failure rate (defined as an increase in serum PSA of 0.2 ng./ml. above the nadir value, 44 versus 65%, p < 0.03) than those who underwent a single freeze-thaw cycle. The main complications of salvage cryotherapy were urinary incontinence (73% of the patients), obstructive symptoms (67%), impotence (72%) and severe perineal pain (8%). CONCLUSIONS Salvage cryotherapy impacts local tumor control as evident by the high frequency of negative posttreatment biopsies. A double freeze-thaw cycle appears more effective than a single cycle. Like salvage prostatectomy, salvage cryotherapy causes significant morbidity.

Stage C adenocarcinoma of the prostate. An analysis of 551 patients treated with external beam radiation

We retrospectively reviewed records of 551 patients with clinical Stage C prostatic adenocarcinoma treated with 60 to 70 Gy external beam radiation. Elective pelvic node irradiation was given to 247 patients (45%). Follow‐up for all surviving patients ranged from 16 to 201 months (median, 6.5 years; mean, 7 years). The 5‐, 10‐, and 15‐year uncorrected actuarial survival rates were 72%, 47%, and 27%, respectively. Disease‐free survival rates were 59%, 46%, and 40% at the corresponding times. Actuarial local control rates were 88%, 81%, and 75% at 5, 10, and 15 years, respectively. Disease‐free survival was adversely affected by high pathologic grade, disease fixed to the pelvic sidewall, invasion of the bladder, prior transurethral resection, hydronephrosis, and elevated serum levels of prostatic acid phosphatase and creatinine. Elective pelvic node irradiation did not improve the outcome. Complications of treatment were acceptable: minor anorectal and/or urinary symptoms, 11%; mild to moderate complications, 19%; serious problems requiring surgery, 3%. It is concluded that localized, high‐energy external beam irradiation provides excellent local control of disease, low morbidity, and 5‐, 10‐, and 15‐year survival rates that have not been rivaled by other treatment.

Prostate-specific antigen and radiation therapy for clinically localized prostate cancer

PURPOSE This study was undertaken to: (a) define the prognostic significance of pretreatment serum prostate-specific antigen (PSA) levels in localized prostate cancer treated with radiation; (b) define the prognostic usefulness of postradiation PSA levels; (c) evaluate the outcome of radiation using PSA as an endpoint. METHODS AND MATERIALS Disease outcome in 707 patients with Stages T1 (205 men), T2 (256 men), T3 (239 men), and T4 (7 men), receiving definitive external radiation as sole therapy, was evaluated using univariate and multivariate techniques. RESULTS At a mean follow-up of 31 months, 157 patients (22%) developed relapse or a rising PSA. Multivariate analysis revealed pretreatment PSA level to be the most significant prognostic factor, with lesser though significant contributions due to Gleason grade (2-6 vs. 7-10) and transurethral resection in T3/T4 disease. The following four prognostic groupings were defined: group I, PSA < or = 4 ng/ml, any grade; group II, 4 < PSA < or = 20, grades 2-6; group III, 4 < PSA < or = 20, grades 7-10; group IV, PSA > 20, any grade. Five-year actuarial relapse rates in these groups were: I, 12%; II, 34%; III, 40%; and IV, 81%. Posttreatment nadir PSA was an independent determinant of outcome and only patients with nadir values < 1 ng/ml fared well (5-year relapse rate 20%). Using rising PSA as an endpoint the 461 patients with T1/T2 disease had an actuarial freedom from disease rate of 70% at 5 years, which appeared to plateau, suggesting that many were cured. No plateau was evident for T3/T4 disease. CONCLUSION Pretreatment serum PSA is the single most important predictor of disease outcome after radiation for local prostate cancer. Tumor grade has a lesser though significant prognostic role. Postirradiation nadir PSA value during the first year is a sensitive indicator of response to treatment. Only nadir values < 1 ng/ml are associated with a favorable outlook. A significant fraction of men with T1/T2 disease may be cured with radiation. There was no evidence for a cured fraction among patients with T3/T4 disease.

External beam radiotherapy dose response characteristics of 1127 men with prostate cancer treated in the PSA era

PURPOSE To characterize the relationship of radiotherapy dose to prostate cancer patient outcome, with an emphasis on the influence of pretreatment prognostic variables. METHODS AND MATERIALS The 1127 Stage T1-T4 prostate cancer patients examined were treated consecutively with definitive external beam radiotherapy at the University of Texas-M.D. Anderson Cancer Center from 1987 to 1997. All had a pretreatment prostate-specific antigen (PSA) level. Treatment failure was defined as two consecutive PSA elevations on follow-up. There were 994 patients treated with a four-field box throughout to 60-70 Gy after a small reduction at 46 Gy and 161 treated with a six-field conformal boost after 46 Gy to 74-78 Gy. No patient received neoadjuvant or adjuvant androgen ablation. Median follow-up was 51.8 months. RESULTS Patients were divided into three radiotherapy dose groups consisting of </=67 Gy (n = 500), >67-77 Gy (n = 495), and >77 Gy (n = 132). Relative to other prognostic factors, there were fewer patients treated to the highest dose level with a pretreatment PSA (PSAB) </=4 or >20 ng/ml, Stage T3/T4 disease, or a Gleason score of 2-6. Actuarial 4-year freedom from biochemical failure (bNED) rates for the entire cohort were 54%, 71%, and 77% (p < 0.0001) for the low-, intermediate-, and high-dose groups. PSAB, palpable stage, and Gleason score were also highly significant. In Cox proportional hazards regression, dose (p < 0. 0001 as a continuous or categorical variable) was an independent predictor of bNED, as were the other prognostic factors. Pairwise univariate comparisons showed that an increase in dose from </=67 Gy to >67-77 Gy was associated with improved bNED rates for all PSAB (</=10 and >10), stage (T1/T2 and T3/T4), and Gleason score (2-6 and 7-10) subgroups tested. In contrast, the only prognostic group that benefited from raising dose from >67-77 Gy to >77 Gy was patients with a PSAB >10 ng/ml; although trends were noted for Stage T1/T2 and Gleason 2-6 patients. Patients with the combined features of a PSAB >10 ng/ml and Stage T1/T2 disease had 4-year bNED rates of 61% and 93% at the intermediate- and high-dose levels. A strongly significant linear association between dose (60-78 Gy) and 4-year actuarial bNED was demonstrated for patients with these intermediate-risk features. CONCLUSION Prostate cancer dose response to external beam radiotherapy should be considered in the context of pretreatment prognostic factors. Our data indicate that, for favorable patients with a PSAB of </=10 ng/ml, intermediate doses of >67-77 Gy provide the same rate of control as higher doses. However, longer follow-up may reveal a benefit to dose escalation >77 Gy, even in this favorable subset. Substantial and clinically relevant enhancements in bNED were seen at all dose levels for moderate-risk patients, such as those having a PSAB >10 ng/ml and Stage T1/T2 disease. Sustained bNED was not realized for high-risk patients, even using 78 Gy; these patients may be best treated with higher doses, whole pelvic irradiation, and/or androgen ablation plus radiation.

Prostate‐specific antigen. An important marker for prostate cancer treated by external beam radiation therapy

Background. Prostate‐specific antigen (PSA) is a valuable serum marker for prostate cancer. However, the prognostic importance of baseline PSA values in relation to other prognostic factors has not been elucidated. The incidence of postradiation rising PSA values has not been documented, and the extent to which PSA influences the assessment of radiation therapy is unclear. This study was designed to address these issues.

Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: Long-term results of a prospective randomized study

Seventy-eight patients with clinical Stage C adenocarcinoma of the prostate were prospectively randomized to receive either radiation alone or radiation and adjuvant estrogen (diethylstilbestrol). No patient had received any prior definitive treatment for cancer. Forty patients were randomized to receive radiotherapy only and 38 patients to receive radiotherapy and estrogen. The median follow-up for all surviving patients was 14.5 years. Whether analyzed according to the original randomization or according to the treatment actually received, disease-free survival in the adjuvant estrogen group was strikingly and significantly higher than in the radiation-only group. At 5, 10, and 15 years patients receiving adjuvant estrogen had respective disease-free survival rates of 71%, 63%, and 63% compared with 49%, 43%, and 35% in patients having radiation only (p = 0.008). However, because of greater intercurrent disease-related mortality in patients receiving estrogen, there was no improvement in survival. This study suggests that a prospective randomized evaluation of early androgen deprivation with orchiectomy or with one of the nonestrogenic agents should be undertaken and that patients receiving early androgen deprivation should not be included in series reporting on the curative potential of radiation as a single modality.

Salvage Cryotherapy for Recurrent Prostate Cancer After Radiotherapy: Variables Affecting Patient Outcome

PURPOSE To determine the long-term disease-specific survival (DSS) and disease-free survival (DFS) rates after salvage cryotherapy for locally recurrent adenocarcinoma of the prostate and to identify pretreatment factors that have an impact on DSS and DFS. PATIENTS AND METHODS Between July 1992 and January 1995, 131 patients who had received definitive radiation therapy (XRT) underwent salvage cryotherapy for locally recurrent adenocarcinoma of the prostate. Cryotherapy failure was defined as an increasing postcryotherapy prostate-specific antigen (PSA) level of > or = 2 ng/mL above the postcryotherapy nadir, a positive prostate biopsy, or radiographic evidence of metastatic disease. Clinical variables were studied to determine whether there was an association with the DSS and DFS. RESULTS The median follow-up was 4.8 years. The 5-year DSS rates were 87% for patients with a precryotherapy Gleason score < or = 8 and 63% for those with Gleason scores of 9 and 10 (P =.012). The 5-year DFS rates were 57% for patients with a precryotherapy PSA level of < or = 10 ng/mL and 23% for those with a PSA level greater than 10 ng/mL (P =.0004). The 5-year DSS rates for patients with a pre-XRT clinical stage of T1 to T2 and those with a clinical stage of T3 to T4 were 94% and 72%, respectively (P =.0041). The 5-year DFS rates for these groups were 90% and 69%, respectively (P =.0057). CONCLUSION Androgen-independent local recurrences, Gleason score, and pre-XRT clinical stage were important factors that had an impact on DSS and DFS. The subset of patients cured by salvage cryotherapy seems to be small, and patient selection is important.