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Purpose: Although a contemporary randomized clinical trial has led to the use of whole-pelvic radiation therapy (WPRT), long-term data evaluating a potential reduction in mortality are lacking and are addressed in the current study., Materials and Methods: From 2005 to 2015, 350 men with localized, unfavorable-risk prostate cancer (PC) were randomly assigned to receive androgen deprivation therapy (ADT) and RT plus docetaxel versus ADT and RT. Treatment of the pelvic lymph nodes was at the discretion of the treating physician. Multivariable Cox and Fine and Grays regression analyses were performed to assess whether a significant association existed between radiation treatment volume and all-cause mortality (ACM) and PC-specific mortality (PCSM), respectively, adjusting for known PC prognostic factors and comorbidity. An interaction term between age (categorized by dichotomization at 65 years to enable clinical interpretation and applicability of the results and which approximates the median (66 years [IQR, 61-70]) and radiation treatment volume was included in the analysis., Results: After a median follow-up of 10.20 years (IQR, 7.96-11.41), 89 men died (25.43%); of these, 42 died of PC (47.19%). Of the 350 randomly assigned patients, 88 (25.14%) received WPRT. In men younger than 65 years, WPRT was associated with a significantly lower ACM risk (adjusted hazard ratio [AHR], 0.33 [95% CI, 0.11 to 0.97]; P = .04) and lower PCSM risk (AHR, 0.17 [95% CI, 0.02 to 1.35]; P = .09) after adjusting for covariates, whereas this was not the case for men 65 years or older., Conclusion: WPRT has the potential to reduce mortality in younger men with unfavorable-risk PC.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice., Competing Interests: Rahul R. ParikhHonoraria: Mevion Medical SystemsNo other potential conflicts of interest were reported.

Purpose: We report the clinical outcomes of a randomized trial comparing prophylactic whole-pelvic nodal radiotherapy to prostate-only radiotherapy (PORT) in high-risk prostate cancer., Methods: This phase III, single center, randomized controlled trial enrolled eligible patients undergoing radical radiotherapy for node-negative prostate adenocarcinoma, with estimated nodal risk ≥ 20%. Randomization was 1:1 to PORT (68 Gy/25# to prostate) or whole-pelvic radiotherapy (WPRT, 68 Gy/25# to prostate, 50 Gy/25# to pelvic nodes, including common iliac) using computerized stratified block randomization, stratified by Gleason score, type of androgen deprivation, prostate-specific antigen at diagnosis, and prior transurethral resection of the prostate. All patients received image-guided, intensity-modulated radiotherapy and minimum 2 years of androgen deprivation therapy. The primary end point was 5-year biochemical failure-free survival (BFFS), and secondary end points were disease-free survival (DFS) and overall survival (OS)., Results: From November 2011 to August 2017, a total of 224 patients were randomly assigned (PORT = 114, WPRT = 110). At a median follow-up of 68 months, 36 biochemical failures (PORT = 25, WPRT = 7) and 24 deaths (PORT = 13, WPRT = 11) were recorded. Five-year BFFS was 95.0% (95% CI, 88.4 to 97.9) with WPRT versus 81.2% (95% CI, 71.6 to 87.8) with PORT, with an unadjusted hazard ratio (HR) of 0.23 (95% CI, 0.10 to 0.52; P < .0001). WPRT also showed higher 5-year DFS (89.5% v 77.2%; HR, 0.40; 95% CI, 0.22 to 0.73; P = .002), but 5-year OS did not appear to differ (92.5% v 90.8%; HR, 0.92; 95% CI, 0.41 to 2.05; P = .83). Distant metastasis-free survival was also higher with WPRT (95.9% v 89.2%; HR, 0.35; 95% CI, 0.15 to 0.82; P = .01). Benefit in BFFS and DFS was maintained across prognostic subgroups., Conclusion: Prophylactic pelvic irradiation for high-risk, locally advanced prostate cancer improved BFFS and DFS as compared with PORT, but OS did not appear to differ., Competing Interests: Vanita NoronhaResearch Funding: Amgen, Sanofi/Aventis, Dr Reddy's Laboratories, Intas, AstraZeneca Kumar PrabhashResearch Funding: Biocon, Dr Reddy's Laboratories, Fresenius Kabi, Alkem Laboratories, Natco Pharma, BDR Pharmaceutics, Roche Umesh MahantshettyResearch Funding: Varian Medical SystemsNo other potential conflicts of interest were reported.

Purpose: The primary objective was to determine if vaginal cuff brachytherapy and chemotherapy (VCB/C) increases recurrence-free survival (RFS) compared with pelvic radiation therapy (RT) in high-intermediate and high-risk early-stage endometrial carcinoma., Patients and Methods: A randomized phase III trial was performed in eligible patients with endometrial cancer. Eligible patients had International Federation of Gynecology and Obstetrics (2009) stage I endometrioid histology with Gynecologic Oncology Group protocol 33-based high-intermediate-risk criteria, stage II disease, or stage I to II serous or clear cell tumors. Treatment was randomly assigned between RT (45 to 50.4 Gy over 5 weeks) or VCB followed by intravenous paclitaxel 175 mg/m 2 (3 hours) plus carboplatin (area under the curve, 6) every 21 days for three cycles., Results: The median age of the 601 patients was 63 years, and 74% had stage I disease. Histologies included endometrioid (71%), serous (15%), and clear cell (5%). With a median follow-up of 53 months, the 60-month RFS was 0.76 (95% CI, 0.70 to 0.81) for RT and 0.76 (95% CI, 0.70 to 0.81) for VCB/C (hazard ratio, 0.92; 90% confidence limit, 0.69 to 1.23). The 60-month overall survival was 0.87 (95% CI, 0.83 to 0.91) for RT and 0.85 (95% CI, 0.81 to 0.90) for VCB/C (hazard ratio, 1.04; 90% confidence limit, 0.71 to 1.52). Vaginal and distant recurrence rates were similar between arms. Pelvic or para-aortic nodal recurrences were more common with VCB/C (9% v 4%). There was no heterogeneity of treatment effect with respect to RFS or overall survival among clinical or pathologic variables evaluated., Conclusion: Superiority of VCB/C compared with pelvic RT was not demonstrated. Acute toxicity was greater with VCB/C; late toxicity was similar. Pelvic RT alone remains an effective, well-tolerated, and appropriate adjuvant treatment in high-risk early-stage endometrial carcinomas of all histologies.

Purpose: There is a debate about the effectiveness and toxicity of pelvic lymph node (PLN) irradiation for the treatment of men with high-risk prostate cancer. This study compared the toxicity of intensity-modulated radiation therapy (IMRT) to the prostate and the pelvic lymph nodes (PPLN-IMRT) with prostate-only IMRT (PO-IMRT)., Materials and Methods: Patients with high-risk localized or locally advanced prostate cancer treated with IMRT in the English National Health Service between 2010 and 2013 were identified by using data from the Cancer Registry, the National Radiotherapy Dataset, and Hospital Episode Statistics, an administrative database of all hospital admissions. Follow-up was available up to December 31, 2015. Validated indicators were used to identify patients with severe toxicity according to the presence of both a procedure code and diagnostic code in patient Hospital Episode Statistics records. A competing risks regression analysis, with adjustment for patient and tumor characteristics, estimated subdistribution hazard ratios (sHRs) by comparing GI and genitourinary (GU) complications for PPLN-IMRT versus PO-IMRT., Results: Three-year cumulative incidence in the PPLN-IMRT (n = 780) and PO-IMRT (n = 3,065) groups was 14% for both groups for GI toxicity, and 9% and 8% for GU toxicity, respectively. Patients receiving PPLN-IMRT and PO-IMRT had similar levels of severe GI (adjusted sHR, 1.00; 95% CI, 0.80 to 1.24; P = .97) and GU (adjusted sHR, 1.10; 95% CI, 0.83 to 1.46; P = .50) toxicity rates., Conclusion: Including PLNs in radiation fields for high-risk or locally advanced prostate cancer is not associated with increased GI or GU toxicity at 3 years. Additional follow-up is required to answer questions about its impact on late GU toxicity. Results from ongoing trials will provide insight into the anticancer effectiveness of PLN irradiation.

Purpose NRG Oncology/RTOG 1203 was designed to compare patient-reported acute toxicity and health-related quality of life during treatment with standard pelvic radiation or intensity-modulated radiation therapy (IMRT) in women with cervical and endometrial cancer. Methods Patients were randomly assigned to standard four-field radiation therapy (RT) or IMRT radiation treatment. The primary end point was change in patient-reported acute GI toxicity from baseline to the end of RT, measured with the bowel domain of the Expanded Prostate Cancer Index Composite (EPIC). Secondary end points included change in patient-reported urinary toxicity, change in GI toxicity measured with the Patient-Reported Outcome Common Terminology Criteria for Adverse Events, and quality of life measured with the Trial Outcome Index. Results From 2012 to 2015, 289 patients were enrolled, of whom 278 were eligible. Between baseline and end of RT, the mean EPIC bowel score declined 23.6 points in the standard RT group and 18.6 points in the IMRT group ( P = .048), the mean EPIC urinary score declined 10.4 points in the standard RT group and 5.6 points in the IMRT group ( P = .03), and the mean Trial Outcome Index score declined 12.8 points in the standard RT group and 8.8 points in the IMRT group ( P = .06). At the end of RT, 51.9% of women who received standard RT and 33.7% who received IMRT reported frequent or almost constant diarrhea ( P = .01), and more patients who received standard RT were taking antidiarrheal medications four or more times daily (20.4% v 7.8%; P = .04). Conclusion Pelvic IMRT was associated with significantly less GI and urinary toxicity than standard RT from the patient's perspective.

Purpose: This follow-up of a randomized study was conducted to assess the long-term effects of external beam radiation therapy (EBRT) in the adjuvant treatment of early-stage endometrial cancer., Patients and Methods: Between 1968 and 1974, 568 patients with stage I endometrial cancer were included. After primary surgery, patients were randomly assigned to either vaginal radium brachytherapy followed by EBRT (n = 288) or brachytherapy alone (n = 280). Overall survival was analyzed by using the Kaplan-Meier method. A Cox proportional hazards model was used to estimate hazard ratios (HRs) with 95% CIs. We also conducted analyses stratified by age groups., Results: After median 20.5 years (range, 0 to 43.4 years) of follow-up, no statistically significant difference was revealed in overall survival (P = .186) between treatment groups. However, women younger than age 60 years had significantly higher mortality rates after EBRT (HR, 1.36; 95% CI, 1.06 to 1.76) than the control group. The risk of secondary cancer increased after EBRT, especially in women younger than age 60 years (HR, 2.02; 95% CI, 1.30 to 3.15)., Conclusion: We observed no survival benefit of external pelvic radiation in early-stage endometrial carcinoma. In women younger than age 60 years, pelvic radiation decreased survival and increased the risk of secondary cancer. Adjuvant EBRT should be used with caution, especially in women with a long life expectancy.

PURPOSE Studies on quality of life (QOL) among women with endometrial cancer have shown that patients who undergo pelvic radiotherapy report lower role functioning and more diarrhea and fatigue. In the Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) trial, patients with endometrial carcinoma were randomly assigned to receive external-beam radiotherapy (EBRT) or vaginal brachytherapy (VBT). QOL was evaluated by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and subscales from the prostate cancer module, PR-25, and the ovarian cancer module, OV-28. PATIENTS AND METHODS PORTEC-2 accrued 427 patients between 2002 and 2006, of whom 214 were randomly assigned to EBRT, and 213 were randomly assigned to VBT. Three-hundred forty-eight patients (81%) were evaluable for QOL. QOL outcomes were analyzed at a median follow-up of 2 years. Results At baseline after surgery, patient functioning was at the lowest level, and it increased during and after radiotherapy to reach a plateau after 12 months. Patients in the VBT group reported better social functioning (P < .002) and lower symptom scores for diarrhea, fecal leakage, the need to stay close to the toilet, and limitation in daily activities because of bowel symptoms (P < .001). At baseline, 15% of patients were sexually active; this increased significantly to 39% during the first year (P < .001). Sexual functioning and symptoms did not differ between the treatment groups. CONCLUSION Patients who received EBRT reported significantly higher levels of diarrhea and bowel symptoms. This resulted in a higher need to remain close to a toilet and, as a consequence, more limitation of daily activities because of bowel symptoms and decreased social functioning. Vaginal brachytherapy provides a better QOL, and should be the preferred treatment from a QOL perspective.

Purpose: Radiation induces germ-cell mutations in experimental animals that result in adverse pregnancy outcomes, as does uterine damage caused by high-dose radiotherapy. We assessed the risks for spontaneous abortion and stillbirths among cancer survivors who received radiotherapy and subsequently became pregnant., Patients and Methods: We identified 1,688 female survivors of childhood cancer in the Danish Cancer Registry. Radiation doses to the ovary and uterus were characterized as high to low. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified from nationwide registries. The proportions of pregnancies among survivors that resulted in a livebirth, stillbirth, or abortion were compared with the equivalent proportions among the two comparison groups, and proportion ratios (PRs) were computed with sisters as referent., Results: More than 34,000 pregnancies were evaluated, 1,479 of which were among cancer survivors. No significant differences were seen between survivors and comparison women in the proportions of livebirths, stillbirths, or all types of abortions combined. Survivors, however, had a 23% excess risk for spontaneous abortion (PR, 1.23; 95% CI, 1.0 to 1.5), related primarily to prior radiation treatments (PR, 1.58; 95% CI, 1.2 to 2.2) and especially high-dose radiotherapy to the ovaries and uterus (PR, 2.8; 95% CI, 1.7 to 4.7)., Conclusion: The pregnancy outcomes of survivors were similar to those of comparison women. A slight excess risk for spontaneous abortion may have resulted from uterine damage after high-dose pelvic radiotherapy, consistent with previous studies, although radiation-induced germinal mutations or decreased hypothalamic-pituitary-ovarian function could not be ruled out.

Purpose: To evaluate patient assessment of long-term effect of pelvic radiotherapy on bowel function., Patients and Methods: As part of a prospective randomized trial evaluating the impact of sucralfate on bowel function in patients receiving pelvic radiotherapy, patient-assessed bowel function data were collected during radiotherapy and again at 4 weeks and 1 year after completion of radiotherapy., Results: The number of bowel movements per day increased up to week 4 and then slowly decreased. At 1 year, the mean number of bowel movements per day had increased from 1.75 to 2.09 and the median from 1 to 2. All measures of adverse bowel function worsened during radiotherapy. Frequency of bowel movements and symptoms of frequency, nocturnal bowel movements, cramping, and bleeding returned close to baseline values by 1 year. Symptoms of urgency, clustering, and measures of incontinence were all persistent at 1 year. The mean increase in bowel function score at 1 year was 0.74 (range, -5 to 7)., Conclusion: Pelvic radiotherapy is associated with a slight increase in bowel movement frequency and decrease in several patient-reported measures of adverse bowel function. Several measures of adverse function persisted at 1 year.

Purpose: To report mature results of a randomized trial that compared extended-field radiotherapy (EFRT) versus pelvic radiotherapy with concomitant fluorouracil and cisplatin (CTRT) in women with locoregionally advanced carcinomas of the uterine cervix., Patients and Methods: Four hundred three women with cervical cancer were randomly assigned to receive either EFRT or CTRT. Patients were eligible if they had stage IIB to IVA disease, stage IB to IIA disease with a tumor diameter > or = 5 cm, or positive pelvic lymph nodes. Patients were stratified by stage and by method of lymph node evaluation., Results: The median follow-up time for 228 surviving patients was 6.6 years. The overall survival rate for patients treated with CTRT was significantly greater than that for patients treated with EFRT (67% v 41% at 8 years; P <.0001). There was an overall reduction in the risk of disease recurrence of 51% (95% CI, 36% to 66%) for patients who received CTRT. Patients with stage IB to IIB disease who received CTRT had better overall and disease-free survival than those treated with EFRT (P <.0001); 116 patients with stage III to IVA disease had better disease-free survival (P =.05) and a trend toward better overall survival (P =.07) if they were randomly assigned to CTRT. The rate of serious late complications of treatment was similar for the two treatment arms., Conclusion: Mature analysis confirms that the addition of fluorouracil and cisplatin to radiotherapy significantly improved the survival rate of women with locally advanced cervical cancer without increasing the rate of late treatment-related side effects.

Purpose: To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma., Patients and Methods: Patients with clinical stage IA(2), IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m(2) and a 96-hour infusion of fluorouracil 1,000 mg/m(2)/d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT., Results: Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients). Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 (P =.003) and 1.96 (P =. 007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group., Conclusion: The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.

Purpose: Pelvic radiation is standard treatment for women with stage IIb to IVa cervical cancer, but treatment results are disappointing, particularly for women with bulky tumors. We investigated the role of primary chemotherapy followed by pelvic radiotherapy in a randomized trial., Patients and Methods: Two hundred sixty patients with stage IIb and IVa cervical cancer received either standard pelvic radiotherapy or primary chemotherapy with cisplatin 60 mg/m2 and epirubicin 110 mg/m2 administered at 3-week intervals for three cycles, followed by pelvic radiotherapy., Results: Ninety-nine patients have relapsed with a median follow-up duration of 1.3 years; in 62 patients, the first site of progressive disease was the pelvis. Patients who received primary chemotherapy had a significantly higher pelvic failure rate than those who received radiotherapy alone (P < .003). Seventy-six patients have died, and those who received primary chemotherapy had significantly inferior survival compared with those who received radiotherapy alone (P = .02). Tumor response following chemotherapy was observed in 63%. After radiotherapy, tumor response occurred in 72% of those who received combined modality treatment, compared with 92% of those who received radiotherapy alone., Conclusion: Primary chemotherapy with epirubicin and cisplatin, although resulting in tumor response in a significant proportion of patients, is accompanied by an inferior local control rate and survival compared with standard pelvic radiotherapy alone.

Purpose: Radiotherapy, a cornerstone in the management of pelvic cancer, is accompanied by intestinal reactions. Therefore, we investigated the possible effects of sucralfate, an aluminium hydroxide complex of sulfated sucrose used in the treatment of gastric ulcer, in preventing radiation-induced diarrhea and bowel discomfort in patients treated with curative intention for pelvic cancer with external radiotherapy., Patients and Methods: The study was double-blind and placebo-controlled and included 70 patients with carcinoma in the prostate or urinary bladder without distant metastases (T1-4No1xMo) and a performance status of greater than or equal to 90% on the Karnofsky scale. Radiotherapy was conventionally delivered with high-energy photons (four-field technique, the total dose 64 Gy, 2 Gy daily, total treatment time 5 to 6 weeks). Dose granules of sucralfate or placebo were dispensed to each patient 2 weeks after radiation started and continued for 6 weeks. All analyses were performed blindly., Results: The frequency of defecation and stool consistency were significantly improved by sucralfate. Fourteen patients in the placebo group and three in the sucralfate group required symptomatic therapy with loperamide. One year later, the patients in the sucralfate group displayed significantly less problems with frequency of defecation, mucus, and blood in the stools compared with the placebo group. There was also a lower intake of loperamide and the weight decrease was less pronounced in the sucralfate group. There was no evidence of adverse effects associated with the use of sucralfate., Conclusion: It is suggested that sucralfate can be of beneficial value in diminishing bowel discomfort during treatment and, most importantly, sucralfate also reduces the late bowel disturbances that follow radiotherapeutic treatment of pelvic malignancies. The earlier proposed mechanisms of action (eg, protection of denuded mucosa, cytoprotective properties, binding bile acids) seem adequate to explain the present effects of sucralfate.

Patients with relapsed Hodgkin's disease who respond to salvage therapy are successfully treated with cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) followed by autologus bone marrow transplantation (ABMT). Because of heavy pretreatment including radiation to the pelvic site, marrow harvest was not feasible in those patients. We therefore used blood-derived hemopoietic precursor cells as an alternative stem-cell source to rescue them after superdose chemotherapy. Hemopoietic precursor cells were mobilized into the peripheral blood either by chemotherapeutic induction of transient myelosuppression followed by an overshooting of blood stem-cell concentration, or by continuous intravenous (IV) granulocyte-macrophage colony-stimulating factor (GM-CSF) administration. The median time to reach 1,000 WBC per microliter, 500 polymorphonuclear cells (PMN) per microliter, or 20,000 platelets per microliter was 10, 20.5, and 38 days, respectively, for 50% of all patients. The platelet counts of two patients never dropped below 20,000/microL following autologous blood stem-cell transplantation (ABSCT), whereas two other patients had to be supported with platelets for 75 and 86 days posttransplant until a stable peripheral platelet count of 20,000/microL was attained. Among the 11 assessable patients, seven are in unmaintained complete remission (CR) at a median follow-up of 318 days. This is a first report on a series of ABSCTs in patients with advanced Hodgkin's disease proving that, despite prior damage to the marrow site, the circulating stem-cell pool is still a sufficient source of hemopoietic precursor cells for stem-cell rescue.

The sperm production of 25 patients with Hodgkin's disease treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy was studied retrospectively. All but two patients also received radiotherapy treatment to pelvic and/or non-pelvic fields. Sperm counts were obtained from patients treated either with three or fewer (MOPP-2 group) or with five or more (MOPP-6 group) chemotherapy cycles. Recovery of spermatogenesis following treatment-induced azoospermia was significantly higher among the MOPP-2 patients (Mann-Whitney rank sum test, p = 0.001). Patients in this group who did not receive pelvic irradiation appeared to have greater recovery rates (p = 0.06). The results suggest that three cycles of MOPP chemotherapy represent a maximum exposure compatible with the recovery of spermatogenesis.

After hysterectomy, 156 evaluable patients with stage I (limited to the corpus) or stage II (limited to the corpus and cervix) uterine sarcomas were randomly assigned to adjuvant chemotherapy with Adriamycin (Adria Laboratories, Columbus, Ohio) for six months or to no further treatment. Pelvic irradiation (external or intracavitary) was optional before randomization. Of 75 patients receiving Adriamycin, 31 have suffered recurrences compared with 43 of 81 receiving no adjuvant chemotherapy. This difference is not statistically significant. Moreover, there is no difference in progression-free interval or survival. The optional radiotherapy did not influence the outcome although there was a suggestion that vaginal recurrence was decreased by pelvic radiotherapy. The recurrence rates in specific cell types (leiomyosarcoma, homologous mixed mesodermal sarcoma, or heterologous mixed mesodermal sarcoma) were not significantly different although the pattern of recurrence differed, with pulmonary metastases being more common in leiomyosarcoma and extrapulmonary recurrence being more common in mixed mesodermal sarcoma. The outcome with respect to chemotherapy was not altered even after adjusting for maldistribution of cases. Thus, we could not show a benefit for this dose schedule of Adriamycin as adjuvant treatment for uterine sarcomas.