Barry E. Epstein

DOSE ESCALATION WITH 3D CONFORMAL TREATMENT: FIVE YEAR OUTCOMES, TREATMENT OPTIMIZATION, AND FUTURE DIRECTIONS

PURPOSE To report the 5-year outcomes of dose escalation with 3D conformal treatment (3DCRT) of prostate cancer. METHODS AND MATERIALS Two hundred thirty-two consecutive patients were treated with 3DCRT alone between 6/89 and 10/92 with ICRU reporting point dose that increased from 63 to 79 Gy. The median follow-up was 60 months, and any patient free of clinical or biochemical evidence of disease was termed bNED. Biochemical failure was defined as prostate-specific antigen (PSA) rising on two consecutive recordings and exceeding 1.5 ng/ml. Morbidity was reported by the Radiation Therapy Oncology Group (RTOG) scale, the Late Effects Normal Tissue (LENT) scale, and a Fox Chase modification of the latter (FC-LENT). All patients were treated with a four-field technique with a 1 cm clinical target volume (CTV) to planning target volume (PTV) margin to the prostate or prostate boost; the CTV and gross tumor volume (GTV) were the same. Actuarial rates of outcome were calculated by Kaplan-Meier and cumulative incidence methods and compared using the log rank and Grays test statistic, respectively. Cox regression models were used to establish prognostic factors predictive of the various measures of outcome. Five-year Kaplan-Meier bNED rates were utilized by dose group to estimate logit response models for bNED and late morbidity. RESULTS PSA <10 ng/ml: No dose response was demonstrated using estimated bNED rates or by analysis of PSA nadir vs. dose. PSA 10-19.9 ng/ml: A bNED dose response was demonstrated (p = 0.02) using the log rank test. The logit response model showed 5-year bNED rates of 35% at 70 Gy and 75% at 76 Gy (p = 0.0049) and illustrated the relative ineffectiveness of conventional dose treatment. PSA 20+ ng/ml: A bNED dose response was demonstrated (p = 0.02) using the log rank test. The logit response model indicated a 5-year bNED rate of 10% at 70 Gy and 32% at 76 Gy (p = 0.10). Morbidity: Dose response was demonstrated for FC-LENT grade 2 and grade 3,4 GI morbidity and for LENT grade 2 GU sequelae. RTOG grade 3,4 GI morbidity at 5 years was <1%. Factors associated with bNED, cause-specific survival, and metastasis were studied using Cox multivariate analysis. Pretreatment PSA (p = 0.0001), Gleason score 7-10 (p = 0.0001), and dose (p = 0.017) were significantly predictive of bNED. For each 1 Gy increase in dose, the hazard of bNED failure decreased by 8%. Palpation stage was associated with cause-specific survival (p = 0.002) and distant metastasis (p = 0.0004). Gleason score was also predictive of distant metastasis (p = 0.02). CONCLUSIONS A dose response was observed for patients with pretreatment PSA >10 ng/ml based on 5-year bNED results. No dose response was observed for patients with pretreatment PSA < 10 ng/ml. Dose response was observed for FC-LENT grade 2 and grade 3,4 GI sequelae and for LENT grade 2 GU sequelae. Optimization of treatment was made possible by the results in this report. The improvement in 5-year bNED rates for patients with PSA levels > 10 ng/ml strongly suggests that clinical trials employing radiation should investigate the use of 3DCRT and prostate doses of 76-80 Gy.

Dose response in prostate cancer with 8–12 years’ follow-up

PURPOSE This communication reports the long-term results of the original group of prostate cancer patients who participated in the first prospective Fox Chase Cancer Center radiation dose escalation study for which 8-12 years of follow-up is now available. METHODS AND MATERIALS Between March 1, 1989 and October 31, 1992, 232 patients with clinically localized prostate cancer received three-dimensional conformal radiotherapy only at Fox Chase Cancer Center in a prospective dose-escalation study. Of these patients, 229 were assessable. The 8-, 10-, and 12-year actuarial rates of biochemical control (biochemically no evidence of disease [bNED]), freedom from distant metastasis (FDM), and morbidity were calculated. The Cox proportional hazards model was used to assess multivariately the predictors of bNED control and FDM, including pretreatment prostate-specific antigen (PSA) level (continuous), tumor stage (T1/T2a vs. T2b/T3), Gleason score (2-6 vs. 7-10), and radiation dose (continuous). The median total dose for all patients was 74 Gy (range 67-81). The median follow-up for living patients was 110 months (range 89-147). bNED control was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. RESULTS The actuarial bNED control for all patients included in this series was 55% at 5 years, 48% at 10 years, and 48% at 12 years. Patients with pretreatment PSA levels of 10-20 ng/mL had statistically significant differences (19% vs. 31% vs. 84%, p = 0.0003) in bNED control when stratified by dose (<71.5, 71.5-75.6, and > 75.6 Gy, respectively) on univariate analysis. For the 229 patients with follow-up, 124 (54%) were clinically and biochemically without evidence of disease. Sixty-nine patients were alive at the time of last follow-up, and 55 patients were dead of intercurrent disease. On multivariate analysis, radiation dose was a statistically significant predictor of bNED control for all patients and for unfavorable patients with a pretreatment PSA <10 ng/mL. For the patients with a pretreatment PSA level of 10-20 ng/mL, the radiation dose was a statistically significant predictor across all groups. No radiation dose response was seen for those patients with a pretreatment PSA level >20 ng/mL, although large numbers of patients are required to demonstrate a difference. The radiation dose, Gleason score, and palpation T stage were significant predictors for the entire patient set, as well as for those with pretreatment PSA levels between 10 and 20 ng/mL. The FDM rate for all patients included in this series was 89%, 83%, and 83% at 5, 10, and 12 years, respectively. For patients with pretreatment PSA levels <10 ng/mL, all four covariates (radiation dose, Gleason score, pretreatment PSA, and palpation T stage) were significant predictors of distance metastasis. Using the Radiation Therapy Oncology Group morbidity scale, no difference was noted in the frequency of Grade 2 and 3 genitourinary and Grade 3 gastrointestinal morbidity when patients in this data set were stratified by radiation dose. However, a significant increase occurred in Grade 2 gastrointestinal complications as the radiation dose increased. CONCLUSION The long-term results of the original Fox Chase radiation dose escalation study with >9 years of median follow-up confirm the existence of a dose response for both bNED control and FDM. The dose response in prostate cancer is real, and the absence of biochemical recurrence after 8 years demonstrates the lack of late failure and suggests cure.

OPTIMIZATION OF CONFORMAL RADIATION TREATMENT OF PROSTATE CANCER: REPORT OF A DOSE ESCALATION STUDY

PURPOSE The development of conformal radiation technique including improved patient immobilization has allowed us to test the value of dose escalation in optimizing the radiation treatment of prostate cancer. METHODS AND MATERIALS Outcome is reported for 233 consecutive patients treated with conformal technique between March 1989 and October 1992. Dose was escalated from 68 Gy to 79 Gy. Patient status is reported at 3 years follow-up, which is available in all alive patients. Pretreatment and serial posttreatment prostate specific antigen (PSA) values are available for all patients. Biochemical freedom of disease (bNED) defines failure as PSA > 1.5 ngm/ml and rising on two consecutive measures. Dose response for bNED control of cancer and late morbidity are represented by logit response models fitted to the data. Kaplan-Meier methods, the log rank test, and Cox Regression models are also used. RESULTS No dose response is observed for bNED survival for patients with pretreatment PSA <10 ngm/ml comparing patients treated above or below 71.5 Gy or on multivariate analysis. Dose response is observed for bNED survival for pretreatment PSA groups of 10-19.9 ngm/ml and 20+ ngm/ml. The dose associated with 50% bNED survival at 3 years is 64 Gy and 76 Gy, respectively. The slope of the dose responses are 13 and 9%, respectively. Dose response is demonstrated for Grade 2 gastrointestinal (GI), Grade 2 genitourinary (GU), and Grade 3,4 combined GI and GU late morbidity. The slopes of the morbidity responses are steeper than for cancer control (19 to 21%). CONCLUSIONS Patients with pretreatment PSA < 10 ngm/ml do not benefit from dose escalation, and the serious late morbidity of conformal radiation at 70 Gy is < 3%. Patients with PSA values 10-19.9 ngm/ml and 20+ ngm/ml benefit from dose escalation beyond 70 Gy. Treatment beyond 75 Gy results in > 10% serious morbidity unless special precautions are taken to protect the rectal mucosa. All levels of severity of radiation morbidity show a dose response and combined with the dose response for bNED survival these data allow the optimization of treatment.

Conformal static field radiation therapy treatment of early prostate cancer versus non-conformal techniques: A reduction in acute morbidity

Patients with early prostate cancer have been definitively treated using our previously described technique of CT-based 3D treatment planning and beams eye view techniques with patients immobilized in alpha cradle casts. An average of 14% bladder (range 6-31%) and 14% rectal (range 7-25%) volume receiving a given dose was eliminated using four conformally blocked fields, with a 1.5 cm margin around the prostate contour, when compared to stage matched controls. Treatment-related acute morbidity was compared for 26 patients treated by the conformal techniques (CG) since April 1989 and 20 consecutive patients treated immediately prior to the conformal techniques with prostate only fields from May 1985-March 1989 (NCG). Acute urinary symptoms (frequency, dysuria, hematuria) or acute rectal symptoms (diarrhea, tenesmus, blood) occurred in 77% (20/26) of the CG versus 80% (16/20) of the NCG patients. Only 31% (8/26) of the CG versus 60% (12/20) of the NCG patients (p < .05) experienced symptoms to a degree which prompted physician intervention (medication and/or interruption of treatment). Two of 26 CG patients (8%) required medication for both bladder and rectal symptoms compared to 5/20 (25%) NCG patients (p = .09). Symptoms persisted for an average of 2.5 weeks versus 3.5 weeks in the CG and NCG groups, respectively. Persistent symptoms at or beyond the 1 month follow-up were present in 3/26 (11%) CG patients (average duration 1.5 months) and were present in 4/20 (20%) of the NCG patients (average duration 2.5 months). Thus, although the percentage of patients who experience acute irritation of the bladder and/or rectum is similar in the two groups, it appears that the percentage requiring medication and/or interruption of treatment is significantly less when 3D treatment planning, rigid immobilization, and conformal blocks are used. The amount of bladder and rectal tissue that is eliminated by our conformal technique is important as shown clinically by the lesser severity and shorter duration of acute symptomatology.

Conformal technique dose escalation for prostate cancer: Biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen ≥10 ng/ml

PURPOSE Conformal radiation technology results in fewer late complications and allows testing of the value of higher doses in prostate cancer. METHODS AND MATERIALS We report the biochemical freedom from disease (bNED) rates (bNED failure is Prostate Specific Antigen (PSA) > or = 1.5 ng/ml and rising) at 2 and 3 years for 375 consecutive patients treated with conformal technique from 66 to 79 Gy. Median follow-up was 21 months. Biochemical freedom from disease was analyzed for patients treated above and below 71 Gy as well as above and below 73 Gy. Each dose group was subdivided by pretreatment PSA level (< 10, 10-19.9, and > or = 20 ng/ml). Dose was stated to be at the center of the prostate gland. RESULTS There was significant improvement in bNED survival for all patients divided by a dose above or below 71 Gy (p = 0.007) and a marginal improvement above or below 73 Gy (p = 0.07). Subdividing by pretreatment PSA level showed no benefit to the PSA < 10 ng/ml group at the higher dose but there was a significant improvement at 71 and 73 Gy for pretreatment PSA 10-19.9 ng/ml (p = 0.03 and 0.05, respectively) and for pretreatment PSA > or = 20 ng/ml (p = 0.003 and 0.02, respectively). CONCLUSIONS Increasing dose above 71 or 73 Gy did not result in improved bNED survival for patients with pretreatment PSA < 10 ng/ml at 2 or 3 years. Further dose escalation studies may not be useful in these patients. A significant improvement in bNED survival was noted for patients with pretreatment PSA > or = 10 ng/ml treated above 71 or 73 Gy; further dose escalation studies are warranted.

Factors influencing incidence of acute grade 2 morbidity in conformal and standard radiation treatment of prostate cancer

PURPOSE The fundament hypothesis of conformal radiation therapy is that tumor control can be increased by using conformal treatment techniques that allow a higher tumor dose while maintaining an acceptable level of complications. To test this hypothesis, it is necessary first to estimate the incidence of morbidity for both standard and conformal fields. In this study, we examine factors that influence the incidence of acute grade 2 morbidity in patients treated with conformal and standard radiation treatment for prostate cancer. METHODS AND MATERIALS Two hundred and forty-seven consecutive patients treated with conformal technique are combined with and compared to 162 consecutive patients treated with standard techniques. The conformal technique includes special immobilization by a cast, careful identification of the target volume in three dimensions, localization of the inferior border of the prostate using the retrograde urethrogram, and individually shaped portals that conform to the Planning Target Volume (PTV). Univariate analysis compares differences in the incidence of RTOG-EORTC grade two acute morbidity by technique, T stage, age, irradiated volume, and dose. Multivariate logistic regression includes these same variables. RESULTS In nearly all categories, the conformal treatment group experienced significantly fewer acute grade 2 complications than the standard treatment group. Only volume (prostate +/- whole pelvis) and technique (conformal vs. standard) were significantly related to incidence of morbidity on multivariate analysis. When dose is treated as a continuous variable (rather than being dichotomized into two levels), a trend is observed on multivariate analysis, but it does not reach significant levels. The incidence of acute grade 2 morbidity in patients 65 years or older is significantly reduced by use of the conformal technique. CONCLUSION The conformal technique is associated with fewer grade 2 acute toxicities for all patients. This conclusion is valid irrespective of selection criteria except in a few cases. Older age is associated with increased toxicity only with the standard technique and not then at a statistically significant level. Elderly patients should not be excluded from external beam radiation because of increased morbidity especially if conformal treatment is available. Volume is not significantly related to morbidity in patients with standard treatment, but it is for conformal treatment. Furthermore, it remains significant in a multivariate analysis that also shows the advantage of conformal treatment. Grade 2 acute toxicities are more volume dependent than dose dependent.

PROSTATIC-SPECIFIC ANTIGEN DOUBLING TIMES IN PATIENTS WITH PROSTATE CANCER: A POTENTIALLY USEFUL REFLECTION OF TUMOR DOUBLING TIME

PURPOSE This study was undertaken to investigate the relationship of prostatic specific antigen doubling time with disease progression in irradiated patients whose only sign of failure was an abnormal prostatic specific antigen. METHODS AND MATERIALS Post irradiation patients whose only sign of failure was an elevated prostatic specific antigen were followed without treatment. The prostatic specific antigen doubling time was determined and compared to original characteristics of disease, time to elevation of prostatic specific antigen after treatment and time to a second sign of failure. RESULTS The prostatic specific antigen doubling times varied from 1.2 months to 36 months. The original grade and stage correlated with the doubling time as did the intervals to elevation of prostatic specific antigen and to a second sign of failure. CONCLUSION We recommended delaying intervention until the prostatic antigen doubling time can be calculated for patients with prostatic specific antigen elevation as the only sign of failure. Patients with short doubling times (< 9 months) can be promptly treated while those with longer doubling times (> 1 year) may have androgen suppression delayed avoiding the cost and morbidity of that treatment.

Radiation therapy techniques and dose selection in the treatment of prostate cancer

A dose response for local control of cancer of the prostate is shown, and normal tissue irradiated volume and complications are diminished with conformal radiation therapy techniques in prostate cancer. Refinements in techniques and technology, as well as phase II trials are underway. Should these studies prove dose escalation to be safe, a phase III trial comparing standard techniques and dose with conformal high dose radiotherapy is warranted for patients with adenocarcinoma of the prostate. If a phase III study is positive, then it will confirm that local control of prostate cancer can be improved with conformal therapy techniques without increasing the morbidity of treatment. However, if this is proven to be true only for institutions with highly specialized equipment, then this finding will have very little impact on the total treatment of prostate cancer or consequences of this disease. A truly successful trial will produce results that can be duplicated in modern radiation therapy centers that have conscientiously maintained current, but not necessarily esoteric technology; it is in the best interests of our patients and our colleagues to develop treatment technologies that can be implemented at all institutional strata.