Moderately Hypofractionated Intensity Modulated Radiation Therapy With Simultaneous Integrated Boost for Prostate Cancer: Five-Year Toxicity Results From a Prospective Phase I/II Trial.

BACKGROUND: In this phase I/II trial, 5-year physician-assessed toxicity and patient reported quality of life data is reported for patients undergoing moderately hypofractionated intensity modulated radiation therapy (IMRT) for prostate cancer using a simultaneous integrated boost (SIB) and pelvic lymph node (LN) coverage. MATERIALS AND METHODS: Patients with T1-T2 localized prostate cancer were prospectively enrolled, receiving risk group based coverage of prostate ± seminal vesicles (SVs) ± pelvic lymph nodes (LNs). Low risk (LR) received 69.6 Gy/29 fractions to the prostate, while intermediate risk (IR) and high risk (HR) patients received 72 Gy/30fx to the prostate and 54Gy/30fx to the SVs. If predicted risk of LN involvement >15%, 50.4 Gy/30fx was delivered to pelvic LNs. Androgen deprivation therapy was given to IR and HR patients. RESULTS: There were 55 patients enrolled and 49 patients evaluable at a median follow up of 60 months. Included were 11 (20%) LR, 23 (41.8%) IR, and 21 (38.2%) HR patients. Pelvic LN treatment was given in 25 patients (51%). Prevalence rates of late grade 2 GI toxicity at 1, 3, and 5 years was 5.8, 3.9, and 5.8%, respectively, with no permanent grade 3 events. Prevalence rates of late grade 2 GU toxicity at 1, 3, and 5 years rates were 15.4, 7.7, and 13.5%, respectively, with three grade 3 events (5.8%). The biochemical relapse free survival at 5 years was 88.3%. There were no local, regional, or distant failures, with all patients still alive at last follow up. CONCLUSION: Moderate hypofractionation of localized prostate cancer utilizing a SIB technique and LN coverage produces tolerable acute/late toxicity. Given equivalent efficacy between moderate hypofractionation schedules, the optimal regimen will be determined by long-term toxicity reported from both the physician and patient perspective. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT01117935, Date of Registration: 5/6/2010.

Phase 1/2 study of hypofractionated intensity-modulated radiation therapy for prostate cancer including simultaneously integrated boost.

PURPOSE: This study evaluates the safety and efficacy of moderately hypofractionated radiation therapy (RT) with simultaneous integrated boost (HSIB) intensity modulated RT (IMRT) that includes coverage of the seminal vesicles (SVs) and pelvic lymph nodes (LNs). METHODS AND MATERIALS: Men with localized prostate cancer were prospectively enrolled in a phase 1/2 trial to receive HSIB-IMRT to the prostate, ± SV, ± pelvic LN using a risk-based method. Low-risk patients received 69.6 Gy to only the prostate in 29 fractions. Intermediate-risk (IR) and high-risk (HR) patients received 30 fractions with 72 Gy to the prostate, 54 Gy to the SV, and 50.4 Gy to the pelvic LN when risk of LN involvement exceeded 15% by the Roach formula. IR and HR patients received androgen deprivation therapy. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated with patient- and physician-reported surveys. RESULTS: Fifty-five men were enrolled, and 49 had at least 1 year of follow-up with 19.2% low-risk, 40.4% IR, and 40.4% HR disease. The median age was 69 years; median follow-up time was 36.9 months. Twenty-six patients received pelvic nodal HSIB-IMRT. At 2 years, the cumulative incidence of physician-reported late grade 2+ GU and GI toxicity was 32.6% and 18.4% respectively. At 2 years, only 10.2% grade 2+ GU toxicities and 2.0% grade 2+ GI toxicities remained unresolved. At last follow-up, the prevalence of unresolved physician-reported late grade 2+ GU and GI toxicity was 4.1% and 0%. The median patient-reported American Urologic Association-International Prostate Symptom Score fell from 10 at baseline to 7.5 at 2 years. The 3-year biochemical relapse-free survival rate for the cohort was 96%. CONCLUSIONS: HSIB-IMRT with risk-based nodal coverage results in excellent biochemical control. Although the cumulative incidence of physician-reported GU toxicity was higher than anticipated, late GI and GU toxicity was relatively transient.

Late toxicity in long-term survivors from a phase 2 study of concurrent radiation therapy, temozolomide and valproic acid for newly diagnosed glioblastoma.

BACKGROUND: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor activity shown to enhance overall survival and progression free survival in patients with newly diagnosed glioblastoma (GBM). This reports on the late toxicity of the VPA/radiotherapy (RT)/temozolomide (TMZ) combination in the long-term survivors of a phase 2 study evaluating this regimen. METHODS: 37 patients with newly diagnosed GBM were initially enrolled on this trial and received combination therapy. VPA/RT/TMZ related late toxicities were evaluated in the 6 patients that lived greater than 3 years using the Cancer Therapy and Evaluation Program Common Toxicity Criteria (CTC) Version 4.0 for toxicity and adverse event reporting as well as the RTOG/EORTC Radiation Morbidity Scoring Scheme. RESULTS: The median duration of follow-up for these 6 patients was 69.5m. In this cohort, the median OS was 73.8m (60.8-103.8m) and median PFS was 53.1m (37.3 - 103.8m). The most common late toxicity of VPA in conjunction with RT/TMZ were the CTC classifications of neurological, pain, and blood/ bone marrow toxicity and most were grade 1/2. There were only two grade 3/4 toxicities. CONCLUSIONS: The addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated with little late toxicity. Additionally, VPA may result in improved outcomes as compared to historical data and merits further study.

A Phase II Study to Prevent Radiation-induced Rectal Injury With Lovastatin.

PURPOSE: Physician reported symptomatic late rectal injury occurs in about 5% to 25% of patients treated with radiation therapy for prostate cancer, depending on the treatment technique. Patients, however, report clinically meaningful declines in bowel/rectal function regardless of the technique used. Lovastatin has been shown to protect mice from late radiation injury. This study was designed to determine if lovastatin might reduce the incidence of late rectal injury in patients receiving radiation therapy for prostate cancer. MATERIALS AND METHODS: Patients with adenocarcinoma of the prostate receiving radiotherapy with curative intent were eligible. A portion of the rectum had to receive at least 60 Gy. Gastrointestinal functioning was assessed using both physician-reported and patient-reported instruments at baseline and at prescribed intervals during and after treatment. Lovastatin (20 to 80 mg/d) was started on day 1 of radiation and continued for 12 months. Patients were followed for an additional 12 months. The primary endpoint was physician-reported rectal toxicity ≥grade 2 during the first 2 years after treatment. RESULTS: A total of 20/53 (38%) patients developed grade 2 or higher toxicity during the 2-year follow-up period. Seventeen patients had 1 or more unresolved gastrointestinal symptom at the end of 2 years, 3 (6%) of which were grade 2 and none were of higher grade. CONCLUSIONS: The primary endpoint of the study was not met. Lovastatin, as administered in this trial, did not reduce the incidence of grade 2 or higher rectal toxicity compared with historical controls.

A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma.

PURPOSE: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. METHODS AND MATERIALS: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). RESULTS: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. CONCLUSIONS: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

Simultaneous integrated boost intensity-modulated radiotherapy for locally advanced head-and-neck squamous cell carcinomas: II--clinical results.

PURPOSE: To perform a Phase I radiation dose-escalation trial to determine the maximal tolerable dose (MTD) deliverable to the gross tumor volume (GTV) using an accelerated fractionation with simultaneous integrated boost intensity-modulated radiotherapy regimen with parotid gland sparing as the sole therapy in the treatment of locally advanced head-and-neck squamous cell carcinoma. The primary objective was the definition of the MTD using established criteria of quantifying acute dose-limiting toxicity (DLT). Secondary objectives included analysis of failure patterns, tumor control rates, and toxicity. METHODS AND MATERIALS: Between July 1999 and June 2002, eligible patients with bulky Stage II to Stage IVB head-and-neck squamous cell carcinoma, excluding laryngeal primaries, were enrolled. Intensity-modulated radiotherapy was delivered with 6-MV photons using a "sliding-window" technique. Enrollment of 6 patients for each dose level was planned; if DLTs were seen in >2 of 6 patients, the previous dose was to be expanded by an additional 6 patients to confirm that dose level as the MTD. All schedules administered a total of 30 fractions, but with escalating doses per fraction (2.27, 2.36, and 2.46 Gy) to achieve a total dose to the GTV of 68.1, 70.8, and 73.8 Gy, respectively. The remaining target tissues were constrained to receive the same dose in all patients regardless of the GTV dose level. The clinical target volume, defined as tissue within 1 cm around the GTV (at high risk of subclinical disease), received 60 Gy in 30 fractions of 2.0 Gy. The electively irradiated target volume, defined as the clinically uninvolved lymph node-bearing tissues, received 54 Gy in 30 fractions of 1.8 Gy. The parotid glands were spared to the degree possible without compromising target coverage. Acute toxicity was scored weekly using National Cancer Institute Common Toxicity Criteria. DLT was defined as any Grade 4 acute toxicity or any acute toxicity requiring either a dose reduction or a treatment break of >5 treatment days. RESULTS: Of 18 men and 2 women (average age, 57 years; range, 37-80 years), 17 presented with oropharyngeal primary tumors, and 1 each with squamous cell carcinoma of the oral cavity, nasopharynx, and hypopharynx. None of the 6 patients at dose level 1, and 2 of the 6 patients initially enrolled at dose level 2, developed DLT. Both patients treated at dose level 3 required a 3-day treatment break and dose reduction after rapid development of Grade 3 toxicity (by Day 15). Six additional confirmatory patients subsequently enrolled at dose level 2 completed treatment without DLT. At least 50% of the total parotid gland volume received <30 Gy in 14 patients (average, 54% of volume), with an average mean dose of 32 Gy. In contrast, >/=50% of the distal parotid gland volume received <25 Gy in 15 patients (average, 63% of volume), with an average mean dose of 24 Gy. With a median follow-up of 20 months from the date of enrollment and 28 months for surviving patients, the actuarial 2-year local control (primary site), regional control (nodal sites), and distant control rate was 76.3%, 66.7%, and 71.8%, respectively. CONCLUSION: Dose level 2, 70.8 Gy in 30 fractions of 2.36 Gy, was defined as the MTD deliverable to the GTV using this accelerated fractionation with simultaneous integrated boost intensity-modulated radiotherapy regimen with parotid gland sparing as the sole treatment for locally advanced head-and-neck squamous cell carcinoma. Adequate parotid sparing was achievable in most cases. Early toxicity, tumor control, and survival rates compared favorably with the outcomes after other accelerated regimens.

Partial breast brachytherapy after lumpectomy: low-dose-rate and high-dose-rate experience.

PURPOSE: The use of partial breast brachytherapy (PBB) after lumpectomy for selected patients with early-stage breast cancer reduces the adjuvant radiotherapy treatment time to <1 week. Despite the advantages of accelerated treatment, maintaining an acceptable cosmetic outcome is important. In a cohort of patients who received low-dose-rate (LDR) or high-dose-rate (HDR) PBB after lumpectomy, the clinical characteristics and treatment parameters were analyzed to identify predictors for an unfavorable cosmetic outcome. METHODS AND MATERIALS: Early-stage breast cancer patients with clear resection margins and 0-3 positive lymph nodes were eligible for PBB. Uniform guidelines for target definition and brachytherapy catheter placement were applied. The HDR PBB dose was 34 Gy in 10 fractions within 5 days, and the LDR dose was 45 Gy given at a rate of 50 cGy/h. The end points included incidence of radiation recall reaction, telangiectasias, and cosmetic-altering fibrosis. RESULTS: Between 1995 and 2000, 44 patients with early-stage breast cancer received PBB without adjuvant external beam radiotherapy after lumpectomy (31 HDR PBB, 13 LDR PBB). After a median follow-up of 42 months (range 18-86), all patients remained locally controlled. The overall rate of good/excellent cosmetic outcome was 79.6% overall and 90% with HDR PBB. Radiation recall reactions occurred in 43% of patients (6 of 14) who received adriamycin. LDR PBB and adriamycin were significant predictors for late unfavorable cosmetic changes in univariate analysis (p = 0.003 and p = 0.005, respectively). CONCLUSION: Although a high rate of local control and good/excellent cosmetic outcome is provided with HDR PBB, the risk of unfavorable cosmetic changes when treated with both LDR PBB and adriamycin is noteworthy. This suggests that HDR PBB is preferred in patients for whom adriamycin is indicated.