Proton therapy of prostate cancer by anterior-oblique beams: implications of setup and anatomy variations.

Proton therapy of prostate by anterior beams could offer an attractive option for treating patients with hip prosthesis and limiting the high-dose exposure to the rectum. We investigated the impact of setup and anatomy variations on the anterior-oblique (AO) proton plan dose, and strategies to manage these effects via range verification and adaptive delivery. Ten patients treated by bilateral (BL) passive-scattering proton therapy (79.2 Gy in 44 fractions) who underwent weekly verification CT scans were selected. Plans with AO beams were additionally created. To isolate the effect of daily variations, initial AO plans did not include range uncertainty margins. The use of fixed planning margins and adaptive range adjustments to manage these effects was investigated. For each case, the planned dose was recalculated on weekly CTs, and accumulated on the simulation CT using deformable registration to approximate the delivered dose. Planned and accumulated doses were compared for each scenario to quantify dose deviations induced by variations. The possibility of estimating the necessary range adjustments before each treatment was explored by simulating the procedure of a diode-based in vivo range verification technique, which would potentially be used clinically. The average planned rectum, penile bulb and femoral heads mean doses were smaller for initial AO compared to BL plans (by 8.3, 16.1 and 25.9 Gy, respectively). After considering interfractional variations in AO plans, the target coverage was substantially reduced. The maximum reduction of V 79.2/D 95/D mean/EUD for AO (without distal margins) (25.3%/10.7/1.6/4.9 Gy, respectively) was considerably larger than BL plans. The loss of coverage was mainly related to changes in water equivalent path length of the prostate after fiducial-based setup, caused by discrepancies in patient anterior surface and bony-anatomy alignment. Target coverage was recovered partially when using fixed planning margins, and fully when applying adaptive range adjustments. The accumulated organs-at-risk dose for AO beams after range adjustment demonstrated full sparing of femoral heads and superior sparing of penile bulb and rectum compared to the conventional BL cases. Our study indicates that using AO beams makes prostate treatment more susceptible to target underdose induced by interfractional variations. Adaptive range verification/adjustment may facilitate the use of anterior beam approaches, and ensure adequate target coverage in every fraction of the treatment.

Primary radiotherapy vs conservative management for localized prostate cancer--a population-based study.

BACKGROUND: Radiotherapy is the most common curative cancer therapy used for elderly patients with localized prostate cancer. However, the effectiveness of this approach has not been established. The purpose of this study is to evaluate the long-term outcomes of primary radiotherapy compared with conservative management in order to facilitate treatment decisions. METHOD: This population-based study consisted of 57,749 patients with T1-T2 prostate cancers diagnosed during 1992-2007. We utilized an instrumental variable (IV) analytical approach with competing risk models to evaluate the outcomes of primary radiotherapy vs conservative management. The IV was comprised of combined health service areas with high- and low-use areas corresponding to the top and bottom tertile in radiotherapy usage rates. RESULTS: In patients with low-/intermediate-risk prostate cancer, 10-year prostate cancer-specific and overall survival was similar in high- and low-radiotherapy use areas (96.1 vs 95.4% and 56.6 vs 56.3%, respectively). In patients with high-risk disease, however, areas with high-radiotherapy use had a higher 10-year cancer-specific survival (90.2 vs 88.1%, difference 2.1%; 95% CI 0.3-4.0%) and 10-year overall survival (53.3 vs 50.2%, difference 3.1%; 95% CI 1.3-6.3%). Results were similar irrespective of the type of radiotherapy used. To assess the robustness of our choice of IV, we repeated the IV analytical approach using different IVs (using the median utilization rate as the cutoff) and found the results to be similar. CONCLUSIONS: Among men >65 years of age, the benefit of primary radiotherapy for localized disease is largely confined to patients with high-risk prostate cancer (Gleason scores 7-10).

Proton beam therapy and localised prostate cancer: current status and controversies.

Proton therapy is a promising, but costly, treatment for prostate cancer. Theoretical physical advantages exist; yet to date, it has been shown only to be comparably safe and effective when compared with the alternatives and not necessarily superior. If clinically meaningful benefits do exist for patients, more rigorous study will be needed to detect them and society will require this to justify the investment of time and money. New technical advances in proton beam delivery coupled with shortened overall treatment times and declining device costs have the potential to make this a more cost-effective therapy in the years ahead.

Selective bladder preservation for muscle-invasive transitional cell carcinoma of the urinary bladder.

Invasive transitional cell carcinoma (TCC) of the urinary bladder is traditionally treated with radical cystectomy. This approach results in great morbidity and lifestyle changes, and approximately half of the patients treated in this way will experience recurrent TCC despite surgery. An alternative approach using selective bladder-preservation techniques incorporates transurethral resection of bladder tumours, radiation therapy, and chemotherapy. Over the past 20 years, international experience has demonstrated that this approach is feasible, safe, and well tolerated. Furthermore, the long-term outcomes of overall survival and disease-free survival compare favourably with the outcomes from radical cystectomy. The most important predictor of response is stage, with significantly higher long-term survival in patients with T2 disease. Another important positive predictor of complete response to therapy is the ability of the urologic oncologist to remove all visible tumour through a transurethral approach prior to initiation of radiation therapy. A negative predictive factor is the presence of hydronephrosis, and age and gender do not affect disease-free survival. The majority of patients who enjoy long-term survival do so with an intact native bladder. Quality of life studies have demonstrated that the retained bladder functions well in nearly all of these patients. Selective bladder preservation will not entirely take the place of radical cystectomy, but should be offered as an important alternative to patients newly diagnosed with muscle-invasive TCC.

10-year outcome for men with localized prostate cancer treated with external radiation therapy: results of a cohort study.

PURPOSE: We determine the efficacy of conventional dose, external beam radiation for localized prostate cancer using cohort analysis with maximized followup. MATERIALS AND METHODS: A total of 205 men with T1-2 prostate cancer were treated with conventional external beam radiation to a median and modal dose of 68.4 Gy during a 16-month period from 1991 to 1993. Followup was maximized in these patients, and median followup for those alive with or without disease was 114 months. RESULTS: Median patient age at treatment was 72 years, and overall survival at 5 and 10 years was 78% and 53%, respectively. The actuarial risk of local failure was 18% at 10 years as was the risk of metastatic disease. The actuarial risk of being free of biochemical failure at 10 years (American Society for Therapeutic Radiology and Oncology definition) was 49%. That risk was 42% if the definition was used without backdating failure to a time between last low value and first increase. When a crude analysis of 10-year outcome was performed 127 of the 205 treated patients (62%) were still alive, including 59% with no evidence of biochemical failure and a median prostate specific antigen of 1.0 ng/ml. Of the 78 men (38% of total) who died during the 10 years 32 died either of or with recurrent cancer. CONCLUSIONS: Mature followup minimizes many of the biases seen in previously published radiation series. This study provides a yardstick against which newer radiation modalities may be measured.

Corticosteroid use after prostate brachytherapy reduces the risk of acute urinary retention.

OBJECTIVES: To evaluate the role of short-term steroids after prostate brachytherapy to reduce oedema and thus the risk of urinary retention associated with brachytherapy, as this can require surgical intervention and may even result in incontinence. PATIENTS AND METHODS: A retrospective review was conducted on 400 consecutive patients with early-stage prostate cancer who underwent ultrasonography-guided transperineal brachytherapy. Androgen deprivation was given to 146 patients for 3 months before the implant and 280 received a 2-week course of dexamethasone (4 mg twice daily for 1 week then 2 mg twice daily). Forty-five patients developed acute urinary retention at a median of 12 days after implantation. Univariate and multivariate analyses were used to evaluate the potential risk factors for urinary retention. RESULTS: Acute urinary retention developed in 11.1% of the patients and the risk was predicted by increasing prostate volume at the time of diagnosis. This risk was higher (18.8%) for men receiving no dexamethasone and lower (8.2%) for those who did. In the multivariate analysis the volume at diagnosis and the use of dexamethasone remained significant. The use of steroids counterbalanced the effect of increasing prostate volume on the incidence of retention. The risk of retention was higher in those men receiving androgen deprivation to shrink their prostates than in those whose prostates were of suitable size for implantation at the time of diagnosis. CONCLUSION: Reducing prostate volume by androgen deprivation before brachytherapy may be less important in preventing brachytherapy-related urinary retention than the use of corticosteroids to reduce oedema afterward.

Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer.

OBJECTIVES: To evaluate the outcomes of patients with muscle-invasive Stage T2-4a bladder carcinoma managed by transurethral surgery and concurrent chemoradiation. METHODS: A total of 190 patients were treated on institutional prospective protocols using concurrent cisplatin-containing chemotherapy and radiotherapy after rigorous transurethral resection of the bladder tumor. Patients were re-evaluated by repeated biopsy and urine cytologic analysis after 40 Gy, with the initial tumor response guiding subsequent therapy. One hundred twenty-one patients with a complete response by cytologic and histologic examination and those medically unfit for cystectomy received boost chemoradiation to 64 to 65 Gy. Those patients without a complete response were advised to undergo radical cystectomy. A total of 66 patients (35%) ultimately underwent radical cystectomy; 41 for less than a complete response and an additional 25 for recurrent invasive tumors. The median follow-up was 6.7 years for all surviving patients. RESULTS: The 5 and 10-year actuarial overall survival rate was 54% and 36%, respectively (Stage T2, 62% and 41%; Stage T3-T4a, 47% and 31%, respectively). The 5 and 10-year disease-specific survival rate was 63% and 59% (Stage T2, 74% and 66%; Stage T3-T4a, 53% and 52%), respectively. The 5 and 10-year disease-specific survival rate for patients with an intact bladder was 46% and 45% (Stage T2, 57% and 50%; Stage T3-T4a, 35% and 34%), respectively. The pelvic failure rate was 8.4%. No patient required cystectomy because of bladder morbidity. CONCLUSIONS: The 10-year overall survival and disease-specific survival rates are comparable with the results reported for contemporary radical cystectomy for patients of similar clinical and pathologic stage. One third of patients treated on protocol with the goal of bladder sparing ultimately required a cystectomy. A trimodality approach with bladder preservation based on the initial tumor response is, therefore, safe, with most long-term survivors retaining functional bladders.

Late normal tissue sequelae in the second decade after high dose radiation therapy with combined photons and conformal protons for locally advanced prostate cancer.

PURPOSE: We determined the long-term normal tissue effects of 77.4 Gy. delivered to the prostate in patients with locally advanced prostate cancer. METHODS AND MATERIALS: Between 1976 and 1992, 167 men with stages T3 to 4 prostate cancer were treated on protocol with 50.4 Gy. photons at 1.8 Gy. per fraction using a 4-field box arrangement, followed by a conformal perineal proton boost of 27 Gy. (cobalt Gy. equivalent) in 11 fractions. The chart was reviewed and 39 of the 42 surviving patients were interviewed. Median followup was 13.1 years (range 7 to 23). Normal tissue morbidity was recorded using Radiation Therapy Oncology Group criteria and the late effects normal tissue scale. RESULTS: The actuarial incidence of grade 2 or greater genitourinary morbidity was 59% at 15 years. However, these grade 2 or greater problems persisted to the time of the interview in only 7 of 39 cases. The actuarial incidence of grade 2 or greater hematuria was 21% at 5 years and 47% at 15. For grade 3 or greater hematuria the risk was 3% and 8% at 5 and 15 years, respectively. No patient required cystectomy but 1 required diversion for morbidity. Urethral stricture and urinary incontinence with pads needed developed in 4 and 3 men, respectively. This particular morbidity was strongly associated with previous or subsequent prostate surgery. The actuarial incidence of grade 2 or greater gastrointestinal morbidity was 13% at 5 and 15 years, while grade 1 rectal bleeding occurred in another 41%. CONCLUSIONS: High dose conformal radiation to the prostate is followed by a high rate of low grade rectal bleeding but a low rate of grade 2 or higher gastrointestinal morbidity. This rate is stable and does not increase beyond 5 years. Genitourinary morbidity continues to develop well into the second decade after treatment, although high grade morbidity is uncommon. These findings do not suggest that the modern trend toward high dose prostate treatment with conformal techniques will result in a high incidence of serious and permanent late sequelae but it appears that hematuria will be common.

Conservative management of prostate cancer in the prostate specific antigen era: the incidence and time course of subsequent therapy.

PURPOSE: The long natural history of early stage prostate cancer is well recognized and a conservative approach to the treatment of elderly men is often encouraged. We assessed the ability of patients and physicians to adhere to a policy of watchful waiting in the prostate specific antigen (PSA) era. MATERIALS AND METHODS: We retrospectively reviewed the records of all 199 men with stages T1-2 prostate cancer and PSA less than 20 ng./ml. who in our practice elected watchful waiting. Median followup in the population overall was 3.4 years. We performed Kaplan-Meier actuarial analysis of overall and disease specific survival, and most pertinent survival free from therapy. A questionnaire was administered to record the attitude of patients who ultimately proceeded to treatment to determine how therapy was triggered. RESULTS: Median patient age was 71 years and median PSA was 6.6 ng./ml. The tumor was impalpable in 52% of patients, Gleason sum was 6 or less in 80% and 11% used some form of herbal remedy or nutritional supplementation. Of the 37 men who died during observation, including 35 of co-morbid illness, only 6 underwent treatment. Overall survival at 5 and 7 years was 77% and 63% but disease specific survival was 98% and 98%, respectively. A total of 64 patients underwent treatment and actuarial freedom from treatment was 56% at 5 years, including 51% and 73% in those younger and older than 75 years at diagnosis. The likelihood of being alive and free from treatment was 43% at 5 years and 26% at 7. Of the 63 men treated 48 (76%) underwent radical therapy (brachytherapy in 17, external beam radiotherapy in 29 and prostatectomy in 2), while only 24% received androgen deprivation. The median PSA increase from diagnosis to treatment in treated patients was 2.9 ng./ml., and it was 0.9 ng./ml. from diagnosis to the last followup in those not treated. Of the treated patients 81% believed that the physician had initiated therapy due to a PSA increase or a nodule. However, physicians recorded having advocated treatment in only 24% of cases. CONCLUSIONS: When patients do not die of co-morbid illness, they are likely to proceed to therapy well within the first decade after diagnosis (57% by 5 years and 74% by 7). Therapy was usually definitive (radical) and triggered by slight, inevitable PSA increases. The patient perception was that the physicians initiated therapy in response to increasing PSA. However, the physicians more often perceived that treatment was initiated by patients. Therefore, watchful waiting in the PSA era often represents radical therapy delayed by a few years.

Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer.

BACKGROUND: Treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density and increases the risk of fracture in men with prostate cancer. We conducted a controlled study of the prevention of osteoporosis in men undergoing treatment with a gonadotropin-releasing hormone agonist. METHODS: In a 48-week, open-label study, we randomly assigned 47 men with advanced or recurrent prostate cancer and no bone metastases to receive either leuprolide alone or leuprolide and pamidronate (60 mg intravenously every 12 weeks). Bone mineral density of the lumbar spine and the proximal femur was measured by dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured by quantitative computed tomography. Forty-one men completed the study. RESULTS: In men treated with leuprolide alone, the mean (+/-SE) bone mineral density decreased by 3.3+/-0.7 percent in the lumbar spine, 2.1+/-0.6 percent in the trochanter, and 1.8+/-0.4 percent in the total hip, and the mean trabecular bone mineral density of the lumbar spine decreased by 8.5+/-1.8 percent (P<0.001 for each comparison with the base-line value). In contrast, the mean bone mineral density did not change significantly at any skeletal site in men treated with both leuprolide and pamidronate. There were significant differences between the two groups in the mean changes in bone mineral density at 48 weeks in the lumbar spine (P<0.001), trochanter (P = 0.003), total hip (P=0.005), and trabecular bone of the lumbar spine (P=0.02). CONCLUSIONS: Pamidronate prevents bone loss in the hip and lumbar spine in men receiving treatment for prostate cancer with a gonadotropin-releasing hormone agonist.

Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder.

OBJECTIVES: Although radical cystectomy remains the standard of care for invasive bladder cancer in the United States, many groups are exploring the use of trimodality therapy using transurethral resection of the bladder tumor, radiation, and chemotherapy in an attempt to spare patients the need for cystectomy. As transitional cell carcinoma often arises from a urothelial field change, there is concern that the retained bladder is at risk of subsequent superficial (Ta, T1, Tis) tumors, some of which may have lethal potential. This study reports the outcomes of those patients with superficial relapse of transitional cell carcinoma after trimodality therapy. METHODS: One hundred ninety patients were treated using a series of trimodality therapy protocols between 1986 and 1998. All patients received induction chemotherapy and radiation and were selected for bladder preservation on the basis of a cytologic and histologic complete response. One hundred twenty-one patients had a complete response and formed the subjects of this study. RESULTS: With a median follow-up of 6.7 years for patients still alive, 32 experienced a superficial relapse (26%). The median time to this failure was 2.1 years. Sixty percent of the superficial failures were carcinoma in situ (Tis) and 67% arose at the site of the original invasive tumor. The risk of superficial failure was higher among those who had Tis associated with their original muscle-invasive tumor. Twenty-seven of these 32 cases were managed conservatively with transurethral resection and intravesical therapy. The irradiated bladder tolerated this therapy well and only 3 patients required treatment breaks. The 5 and 8-year survival was comparable for those who experienced superficial failure (68% and 54%, respectively) and those who had no failure at all (n = 74, 69% and 61%, respectively). However, a substantially lower chance of being alive with the native bladder owing to the need for late salvage cystectomies (61% versus 34%) was found. Cystectomy became necessary in 31% (10 of 32) either because of additional superficial recurrence (n = 7) or progression to invasive disease (n = 3). CONCLUSIONS: A trimodality approach to transitional cell bladder cancer mandates lifelong cystoscopic surveillance. Although most completely responding patients retain their bladders free from invasive relapse, one quarter will develop superficial disease. This may be managed in the standard fashion with transurethral resection of the bladder tumor and intravesical therapies but carries an additional risk that late cystectomy will be required.

An organ-preserving approach to muscle-invading transitional cell cancer of the bladder.

Bladder-preserving treatment for muscle-invasive disease is based on the response of the tumor to induction combined modality therapy. In the future, an organ-conserving approach will be widely offered as a safe and reasonable alternative to radical cystectomy.

The Patterns of Care Survey of radiation therapy in localized prostate cancer: similarities between the practice nationally and in minority-rich areas.

PURPOSE: Over the last two decades, the chance for the cure of localized prostate cancer by radiation has been improved by the widespread use of PSA for early detection and by a number of technical advances in treatment delivery. This study was designed to determine whether the stage of presentation and the quality of radiation treatment delivered are comparable between Caucasian and minority patients nationally and within minority-rich areas. METHODS AND MATERIALS: A random survey conducted for the Patterns of Care Study in Radiation Oncology of 80 facilities treating patients with radiation in the USA. Of these, 67 comprise the "National Survey" and 13 a "Minority-Rich" survey (>40% of treated patients are minorities). Nine hundred twenty-six men with localized prostate cancer were treated in 1994. Five hundred ninety-five were in the national and 331 in the minority-rich survey. The main outcome measures were the clinical features of Caucasian and minority men at presentation and technical characteristics of the treatment delivered to them. RESULTS: African-American men presented with more advanced disease (higher-presenting PSA and T-stage) than Caucasians in both the national and the minority-rich surveys. Hispanics also presented with later disease and could be grouped with African-American men rather than Caucasians. Overall the stage and PSA at presentation was earlier than seen in the previous Patterns of Care Study survey of 1989. The quality of treatment delivered has improved since 1989, with no distinction seen between those facilities sampled nationally and those within minority-rich areas. CONCLUSION: African-American and Hispanic men with prostate cancer present for therapy at a later stage than Caucasian men, but when they do, the treatment received is of comparable quality.

Bladder preservation in muscle-invasive bladder cancer by conservative surgery and radiochemotherapy.

Organ preservation has been investigated in muscle-invasive bladder cancer over the past decades as an alternative to standard radical cystectomy. The results of large prospective protocols and population-based studies suggest that an organ-preserving approach is possible without deferring the survival probability. Organ preservation requires a trimodal schedule, including transurethral surgery (transurethral resection of bladder tumor (TURBT)), radiation, and chemotherapy. A complete TURBT is the most important single prognostic factor, and should be attempted. Radiotherapy, in conjunction with concurrent platinum-based chemotherapy, can control the vast majority of urothelial bladder tumors. The histologically-proven complete remission rates of macroscopic tumors (unresectable by TURBT) lie in the range of about 70%. After radiochemotherapy, a histological response evaluation with repeated TURBT is recommended. Patients with residual tumor require salvage cystectomy. In cases of complete remission, patients can maintain their bladders but they should be closely followed over years. The risk of severe late-radiation sequelae is low, in the range of less than 5%. About 75% of long-term survivors maintain a normally functioning bladder.