RTOG 0518: randomized phase III trial to evaluate zoledronic acid for prevention of osteoporosis and associated fractures in prostate cancer patients.

BACKGROUND: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). METHODS: Eligible patients with T-scores of the hip (<-1.0, but >-2.5 vs >-1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. RESULTS: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm 1 and 34.8 months for Arm 2. Only two patients experienced a bone fracture (one in each arm) resulting in no difference in freedom from any bone fracture (P=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs -5%, P<0.0001), left total hip (1% vs -8%, P=0.0002), and left femoral neck (3% vs -8%, P=0.0007). CONCLUSIONS: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL.

Impact of sildenafil on marital and sexual adjustment in patients and their wives after radiotherapy and short-term androgen suppression for prostate cancer: analysis of RTOG 0215.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) 0215 investigated the efficacy of sildenafil in improving erectile dysfunction following radiotherapy and neoadjuvant/concurrent androgen deprivation therapy among prostate cancer patients and found a significant improvement on drug but only in 21% of study participants. This paper reports on a secondary aim to investigate the effect of sildenafil on overall sexual and marital adjustment among both patients and their wives. METHODS: RTOG 0215 was a placebo-controlled, double-blind, crossover trial of sildenafil. Participation of wives was optional. Twenty-four married heterosexual couples (33% of heterosexual couples in study) completed the Sexual Adjustment Questionnaire and Locke's Marital Adjustment Test. Treatment differences in mean change scores were evaluated by paired t-tests, and the proportion of patients achieving a clinically meaningful change was evaluated using chi-square tests. Spearman's correlation coefficients were used to determine the association of adjustment between patients and wives. RESULTS: There was no significant change in either sexual or marital adjustment for patients. For wives, there was a trend for improvement in sexual adjustment but no significant change in marital adjustment. Change in marital adjustment between patients and wives was weakly related (r(s) = 0.15, p = 0.48), and for sexual adjustment, there was a moderate, but nonsignificant relationship (r(s) = 0.40, p = 0.09). CONCLUSIONS: Larger studies are warranted to further examine possible differences in sexual experiences and treatment needs between prostate cancer patients and their wives, as well as to assess predictors of sildenafil response.

Adjuvant gemcitabine and concurrent radiation for patients with resected pancreatic cancer: a phase II study.

The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40 mg m(-2)) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy in 5(1/2) weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000 mg m(-2)) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35-79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control.

Symptom frequency and severity in patients with metastatic or locally recurrent lung cancer: a prospective study using the Lung Cancer Symptom Scale in a community hospital.

PURPOSE: To define symptoms and therapeutic requirements for patients with metastatic or locally recurrent lung cancer. METHODS AND MATERIALS: Data were collected from 69 consecutive patients with locally advanced lung cancer seen in consultation at a radiation oncology facility serving a community hospital in Virginia. The Lung Cancer Symptom Scale, a validated quality of life instrument, measured the incidence of symptoms in this group. RESULTS: Average survival for the entire group was 7 months. Fifty-seven patients received 81 courses of radiation therapy, 33 directed at thoracic disease and 48 delivered to sites of metastasis. Thirty-three percent of those who received radiation therapy required treatment to more than one anatomic site. Every patient was symptomatic at the time of consultation, with the number (p = 0.001) and severity (p = 0.001) of symptoms they suffered worse in the patient group seen 0 to 3 months prior to death rather than 4 to 6 months prior to death. With the exception of cough, symptoms were marked in their severity. CONCLUSIONS: Patients with advanced lung cancer suffer frequent and severe symptoms that worsen in the final months of life. The appropriate timing and combination of radiotherapy and chemotherapy are yet to be resolved. Future studies will require use of validated quality of life instruments to better catalogue palliation and treatment toxicity.

Radiation therapy in the management of rectal cancer.

Substantial advances have been made in the adjuvant management of patients with resectable rectal cancer. Increasing interest in patient quality of life has promoted the use of radiation therapy to enhance sphincter-preserving surgical approaches as an alternative to the standard abdominoperineal resection. Because of the suggestion of enhanced sphincter preservation with preoperative therapy and the potential advantage of decreased acute morbidity, randomized trials comparing preoperative and postoperative adjuvant combined modality therapy are ongoing. Recent progress in adjuvant postoperative treatment regimens relates to the integration of systemic therapy to radiation, and redefining the techniques for both modalities. The incorporation of improved radiation planning may reduce treatment-related bowel toxicity. The integration of novel chemotherapeutic agents in the adjuvant therapy of rectal cancer remains an active area of investigation.

Gemcitabine following radiotherapy with concurrent 5-fluorouracil for nonmetastatic adenocarcinoma of the pancreas.

Gemcitabine has been shown to be an active agent in the treatment of pancreatic cancer. This study was conducted to prospectively examine the tolerance and early efficacy of adjuvant gemcitabine following radiotherapy with concurrent 5-fluorouracil (5-FU) for nonmetastatic pancreatic adenocarcinoma. Twenty-three patients, median age 64 years, were treated with combined modality therapy. Nine patients underwent tumor resection before chemoradiation; 14 patients with locally unresectable tumors received definitive chemoradiation. Radiotherapy utilized four fields to the tumor and lymphatics to 45 Gy, plus a lateral boost to 50.4 Gy. Concurrent 5-FU 500 mg/m(2)/day was administered on days 1-3 and 29-31, followed by 4 months of gemcitabine 1,000 mg/m(2)/week for 3 weeks (fourth week break). Adjuvant gemcitabine was well tolerated. Eighty-three percent of the patients completed three to four cycles. The primary dose-limiting toxicity was leukopenia, which was observed in 10 patients (43%). Nonhematologic toxicities were reported in five patients (22%). There were no cases of gemcitabine-induced radiation recall and there have been no deaths attributed to treatment toxicity. Median follow-up for the 23 patients was 12 months (range, 5-50); the actuarial median survival was 13 months. This report confirms that adjuvant gemcitabine following radiotherapy with concurrent 5-FU for nonmetastatic pancreatic adenocarcinoma can be safely administered.

The ability of p53 to activate downstream genes p21(WAF1/cip1) and MDM2, and cell cycle arrest following DNA damage is delayed and attenuated in scid cells deficient in the DNA-dependent protein kinase.

scid mouse embryonic fibroblasts are deficient in DNA-dependent protein kinase activity due to a mutation in the C-terminal domain of the catalytic subunit (DNA-PKcs). When exposed to ionizing radiation, the increase in levels of p53 was the same as in normal mouse embryonic fibroblasts. However, the rise in p21(WAF1/cip1) and mdm2 was found to be delayed and attenuated, which correlated in time with delayed onset of G1/S arrest by flow cytometric analysis. The p53-dependent G1 checkpoint was not eliminated: inactivation of p53 by the E6 protein in scid cells resulted in the complete loss of detectable G1/S arrest after DNA damage. Immunofluorescence analysis of normal cells revealed p53 to be localized predominantly within the cytoplasm prior to irradiation and then translocate to the nucleus after irradiation. In contrast, scid cells show abnormal accumulation of p53 in the nucleus independent of irradiation, which was confirmed by immunoblot analysis of nuclear lysates. Taken together, these data suggest that loss of DNA-PK activity appears to attenuate the kinetics of p53 to activate downstream genes, implying that DNA-PK plays a role in post-translational modification of p53, without affecting the increase in levels of p53 in response to DNA damage.

Accelerated superfractionated radiotherapy for inflammatory breast carcinoma: complete response predicts outcome and allows for breast conservation.

PURPOSE: Chemotherapy and accelerated superfractionated radiotherapy were prospectively applied for inflammatory breast carcinoma with the intent of breast conservation. The efficacy, failure patterns, and patient tolerance utilizing this approach were analyzed. METHODS AND MATERIALS: Between 1983 and 1996, 52 patients with inflammatory breast carcinoma presented to the Medical College of Virginia Hospitals of VCU and the New England Medical Center. Thirty-eight of these patients were jointly evaluated in multidisciplinary breast clinics and managed according to a defined prospectively applied treatment policy. Patients received induction chemotherapy, accelerated superfractionated radiotherapy, selected use of mastectomy, and concluded with additional chemotherapy. The majority were treated with 1.5 Gy twice daily to field arrangements covering the entire breast and regional lymphatics. An additional 18-21 Gy was then delivered to the breast and clinically involved nodal regions. Total dose to clinically involved areas was 63-66 Gy. Following chemoradiotherapy, patients were evaluated with physical examination, mammogram, and fine needle aspiration x 3. Mastectomy was reserved for those patients with evidence of persistent or progressive disease in the involved breast. All patients received additional chemotherapy. RESULTS: Median age was 51 years. Median follow-up was 23.9 months (6-86) months. The breast preservation rate at the time of last follow-up was 74%. The treated breast or chest wall as the first site of failure occurred in only 13%, and the ultimate local control rate with the selected use of mastectomy was 74%. Ten patients underwent mastectomy, 2 of which had pathologically negative specimens despite a clinically palpable residual mass. Response to chemotherapy was predictive of treatment outcome. Of the 15 patients achieving a complete response, 87% remain locoregionally controlled without the use of mastectomy. Five-year overall survival for complete responders was 68%. This is in contrast to the 14% 5-year overall survival observed with incomplete responders. The 5-year actuarial disease-free survival and overall survival for the entire patient cohort was 11% and 33%, respectively. All patients tolerated irradiation with limited acute effects, of which all were managed conservatively. CONCLUSION: Our experience demonstrates that induction chemotherapy, accelerated superfractionated radiotherapy, and the selected use of mastectomy results in excellent locoregional control rates, is well tolerated, and optimizes breast preservation. Based on our present results, we recommend that a patient's response to induction chemotherapy guide the treatment approach used for locoregional disease, such that mastectomy be reserved for incomplete responders and avoided in those achieving a complete response.

Inactivation of p53 results in high rates of homologous recombination.

Using a plasmid substrate which integrates into the genome, we determined that the rate of homologous recombination was suppressed by p53. Human tumor cell lines, mutant or null for p53 had recombination rates 10000-times greater than primary fibroblasts. When isogenic cell pairs from tumor cells or primary fibroblasts were compared, differing only in one genetic change which inactivated p53, the recombination rate increased > 100-fold. Functional inactivation of p53 by dominant mutant p53, by large T antigen of SV40 virus, by E6 protein of human papilloma virus, or by genetic deletion led to the same result. Our results suggest that p53 suppresses spontaneous homologous recombination, and that p53 is not required for recombination to proceed. The mechanism of recombination suppression may be related to the reported association of p53 with Rad 51, but the functional consequences of this association are not yet established. It is suggested that suppression of homologous recombination is the means by which p53 maintains genetic stability.

Bladder preservation by combined modality therapy for invasive bladder cancer.

PURPOSE: To update the efficacy of a selective multimodality bladder-preserving approach by transurethral resection (TURBT), systemic chemotherapy, and radiation therapy. PATIENTS AND METHODS: From 1986 through 1993, 106 patients with muscle-invading clinical stage T2 to T4a,Nx,M0 bladder cancer were treated with induction by maximal TURBT and two cycles of chemotherapy (methotrexate, cisplatin, vinblastine [MCV]) followed by 39.6-Gy pelvic irradiation with concomitant cisplatin. Patients with a negative postinduction therapy tumor site biopsy and cytology (a T0 response, 70 patients) plus those with less than a T0 response but medically unfit for cystectomy (six patients), received consolidative chemoradiation to a total of 64.8 Gy. Surgical candidates with less than a T0 response (13 patients) and patients who could not tolerate the chemoradiation (six patients) went to immediate cystectomy. The median follow-up duration is 4.4 years. RESULTS: The 5-year actuarial overall survival and disease-specific survival rates of all patients are 52% and 60%, respectively. For clinical stage T2 patients, the actuarial overall survival rate is 63%, and for T3-4, 45%. Thirty-six patients (34%) underwent cystectomy, all with evidence of tumor activity, including 17 with an invasive recurrence. The 5-year overall survival rate with an intact functioning bladder is 43%. Among 76 patients who completed bladder-preserving therapy, the 5-year rate of freedom from an invasive bladder relapse is 79%. No patient required cystectomy for treatment-related bladder morbidity. CONCLUSION: Combined modality therapy with TURBT, chemotherapy, radiation, and selection for organ-conservation by response has a 52% overall survival rate. This result is similar to cystectomy-based studies for patients of similar age and clinical stages. The majority of the long-term survivors retain fully functional bladders.

Combined modality treatment with selective bladder conservation for invasive bladder cancer: long-term tolerance in the female patient.

PURPOSE: To assess the physical, psychological, social, and organ-specific long-term treatment sequelae occurring in women with muscle-invading bladder carcinoma treated with combined modality therapy that allowed for bladder conservation in 67% of patients. PATIENTS AND METHODS: Patients with muscle-invading (T2-4a,Nx,M0) bladder cancer were treated with maximal transurethral resection followed by induction chemoradiotherapy (cisplatin x 2 plus 40 Gy pelvic irradiation or the same preceded by 2 cycles of methotrexate, cisplatin, and vinblastine) between the years 1986 and 1994. Women who had a complete response and all those who were not candidates for cystectomy received consolidation therapy of additional cisplatin and tumor boost to 64.8 Gy. Women who were incomplete responders and those who developed recurrent invasive tumor underwent immediate radical cystectomy. Forty-two women were treated with this approach, 21 of whom (median age, 69 years; median follow-up time, 56 months) were available for and underwent a structured interview of treatment and health-related issues using a quantitative symptom score. RESULTS: All 21 patients have full urinary continence and no dysuria. Nineteen report unchanged or improved bladder capacity and function. No patient reported loss of bowel continence. Of the five women who were sexually active, two report an increase in intercourse frequency and one noted a decrease. There is no decrease in intercourse satisfaction or orgasm, and no dyspareunia or vaginal bleeding was noted. Eleven patients reported high levels of anxiety related to their bladder cancer before treatment. This was significantly reduced or absent in 9 of 11 after treatment. Actuarial overall survival for all 42 women was 58% at 5 years. Actuarial overall survival with an intact bladder was 47% at 5 years. DISCUSSION: This study shows that overall survival is high when chemoradiation and transurethral resection are used in potential bladder-sparing protocols for muscle-invading transitional cell carcinoma of the bladder in women. Furthermore, 67% of the women, including most long-term survivors, retain their bladders. The functional quality of the conserved organ, the rectum, and the vagina, as reported by the patients, was excellent.