Effect of Androgen Deprivation Therapy on Other-Cause of Mortality in Elderly Patients with Clinically Localized Prostate Cancer Treated with Modern Radiotherapy: Is There a Negative Impact?

The influence of androgen deprivation therapy (ADT) on other-cause of mortality (OCM) was investigated in patients with localized prostate cancer treated with modern high-dose radiotherapy. A retrospective review was conducted on 1125 patients with localized prostate cancer treated with high-dose radiotherapy, including image-guided, intensity-modulated radiotherapy or brachytherapy with a median follow-up of 80.7 months. Overall survival rate was no different between ADT (+) and ADT (-) group in high-, intermediate-, and low-risk groups. OCM was found in 71 patients, consisting of 4% (10/258) in the ADT (-) group and 7% (61/858) in the ADT (+) group (p = 0.0422). The 10-year OCM-free survival rate (OCMFS), if divided by the duration of ADT (ADT naïve (ADT (-)), ADT <2-year, and ADT ≥2-year groups), showed statistical significance, and was 90.7%, 88.2%, and 78.6% (p = 0.0039) for the ADT (-), ADT <2-year, and ADT ≥2-year groups, respectively. In patients aged ≥75 years, 10-year OCMFS for ADT (-), ADT <2-, and ADT ≥2-year groups was 93.5% (at 115.6 months), 85.6%, and 60.7% (p = 0.0189), respectively, whereas it was 90.7%, 89.9%, and 89.0% (p = 0.4716), respectively, in their younger counterparts. In localized prostate cancer patients, treatment with longer ADT for ≥2 years potentially increases the risk of OCM, especially in patients aged ≥75 years.

Radiothrerapy for Elderly Patients Aged ≥75 Years with Clinically Localized Prostate Cancer-Is There a Role of Brachytherapy?

We compared radiotherapy outcomes between 241 elderly patients aged ≥75 years and 867 younger controls (age <75 years) with clinically localized prostate cancer. The elderly group showed an equivalent actuarial seven-year biochemical failure-free survival rate (7y-bNED) (94.9%) to the younger control group (96.4%, p = 0.593). The incidence of late genitourinary (GU) and gastrointestinal (GI) toxicities grade ≥2 was also similar between the elderly and younger cohorts, while no grade ≥4 adverse events occurred. We also examined the role of brachytherapy (BT) in the elderly group, in comparison with image-guided intensity-modulated radiotherapy (IG-IMRT). BT showed superior 7y-bNED (94.1%) than IG-IMRT (84.6%, p = 0.0183) in elderly patients, which was 100% (100% for BT and 100% for IG-IMRT, p > 0.999) for the low-risk group, 94.6% (92.8% and 100%, p = 0.203) for the intermediate-risk group, and 80.5% (91.2% and 73.6%, p = 0.0195) for the high-risk group. BT showed higher GU toxicity and equivalent GI toxicity to IG-IMRT. In conclusion, elderly patients showed bNED and toxicity that were equivalent to those observed in younger controls, and BT is a plausible option also for healthy elderly with potential to improve bNED, with higher but acceptable GU toxicity.

Author Correction: Comparison of Image-Guided Intensity-Modulated Radiotherapy and Low-dose Rate Brachytherapy with or without External Beam Radiotherapy in Patients with Localized Prostate Cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

High-Dose-Rate Brachytherapy Monotherapy versus Image-Guided Intensity-Modulated Radiotherapy with Helical Tomotherapy for Patients with Localized Prostate Cancer.

The aim of this paper is to compare outcomes between high-dose-rate interstitial brachytherapy (HDR-BT) monotherapy and image-guided intensity-modulated radiotherapy (IG-IMRT) for localized prostate cancer. We examined 353 HDR-BT and 270 IG-IMRT patients. To reduce background selection bias, we used the method of inverse probability treatment weighting (IPTW) with propensity scores. The actuarial five-year biochemical failure-free survival rates were 92.9% and 96.7% (p = 0.1847; p = 0.077 in IPTW) for HDR-BT and IG-IMRT, respectively; they were 100% and 95.8% (p = 0.286) for the low-risk group, 95.6% and 92% (p = 0.42) for the intermediate-risk group, 90.4% and 84.9% (p = 0.1059; p = 0.04 in IPTW) for the high-risk group, and 87.1% and 89.2% (p = 0.3816) for the very-high-risk group. In the assessment of accumulated incidences of grade ≥ 2 toxicity (Common Terminology Criteria for Adverse Events version 4.0) at five years, HDR-BT monotherapy showed higher genitourinary toxicity (11.9%) than IG-IMRT (3.3%) (p < 0.0001). The gastrointestinal toxicity was equivalent for HDR-BT (2.3%) and IG-IMRT (5.5%) (p = 0.063). No Grade 4 or 5 toxicity was detected in either modality. HDR-BT showed higher genitourinary toxicity than IG-IMRT. HDR-BT and IG-IMRT showed equivalent outcomes in low-, intermediate-, and very-high-risk groups. For high-risk patients, HDR-BT showed potential to improve prostate-specific antigen (PSA) control rate compared to IG-IMRT.

Definitive chemoradiotherapy for anal canal cancer: single-center experience.

BACKGROUND: Chemoradiotherapy (CRT) is a standard treatment for anal canal cancer although many patients with anal canal cancer undergo surgery in Japan. The efficacy of CRT for anal canal cancer was evaluated retrospectively. METHODS: Medical charts of 13 patients with anal canal cancer treated by definitive CRT from October 2004 to May 2016 were reviewed. Twelve patients had squamous cell carcinoma and one had adeno-squamous carcinoma. PET/CT simulation was performed in nine patients. The median total dose was 59.4 Gy (range 57.6-63.4 Gy) with fractions of 1.8-2.0 Gy. Ten patients received chemotherapy with mitomycin C (10 mg/m2) and fluorouracil (5-FU) (800 mg/m2 over 4 days) in weeks 1 and 5, while two patients were treated with cisplatin (40 mg) and 5-FU (750 mg over 5 days) in weeks 1 and 5. One elderly patient received radiotherapy (RT) alone. RESULTS: All 13 patients were alive after a median follow-up period of 102 months (range 16-121 months). Local failure only occurred in the patient with adeno-squamous cell carcinoma, while there was no loco-regional recurrence or distant metastasis in the other 12 patients. The 5-year loco-regional control rate (LRC) and 5-year overall survival rate (OS) were 92% and 100%, respectively. Acute toxicities of ≥ grade 3 were observed in six patients (46%), mainly being dermatitis around the anal verge, and late toxicity of ≥ grade 3 occurred in one patient. CONCLUSION: CRT for squamous cell carcinoma of the anal canal achieved good LRC and OS with acceptable toxicities.

Comparison of Image-Guided Intensity-Modulated Radiotherapy and Low-dose Rate Brachytherapy with or without External Beam Radiotherapy in Patients with Localized Prostate Cancer.

To compare the outcome of low-dose rate brachytherapy (LDR-BT) and image-guided intensity-modulated radiotherapy (IG-IMRT) for localized prostate cancer, we examined 488 LDR-BT and 269 IG-IMRT patients. IG-IMRT treated older and advanced disease with more hormonal therapy than LDR-BT, which excluded T3b-T4 tumor and initial PSA > 50 ng/ml. The actuarial five-year biochemical failure-free survival rate was 88.7% and 96.7% (p = 0.0003) in IG-IMRT and LDR-BT, respectively; it was 88.2% (85.1% for IG-IMRT and 94.9% for LDR-BT, p = 0.0578) for the high-risk group, 95.2% (91.6% and 97.0%, p = 0.3361) for the intermediate IG-IMRT and 96.8% (95.7% and 97%, p = 0.8625) for the low-risk group. Inverse probability of treatment weighting (IPTW) involving propensity scores was used to reduce background selection bias. IPTW showed a statistically significant difference between LDR-BT and IG-IMRT in high risk (p = 0.0009) and high risk excluding T3-4/initial PSA > 50 ng/ml group (p = 0.0073). IG-IMRT showed more gastrointestinal toxicity (p = 0.0023) and less genitourinary toxicity (p < 0.0001) than LDR-BT. LDR-BT and IG-IMRT showed equivocal outcome in low- and intermediate-risk groups. For selected high-risk patients, LDR-BT showed more potential to improve PSA control rate than IG-IMRT.

Long-term Outcomes of a Dose-reduction Trial to Decrease Late Gastrointestinal Toxicity in Patients with Prostate Cancer Receiving Soft Tissue-matched Image-guided Intensity-modulated Radiotherapy.

BACKGROUND/AIM: We experienced an unexpected high incidence of gastrointestinal (GI) toxicity in patients undergoing image-guided intensity-modulated radiotherapy (IG-IMRT) using helical tomotherapy in our initial 2.2 Gy/fraction schedule for prostate cancer; hence, a dose-reduction trial from 2.2 Gy to 2 Gy/fraction was conducted using modified planning target volume (PTV) contouring. PATIENTS AND METHODS: We compared 130 patients treated using 2.2 Gy/fraction (Group A) and 144 treated using the 2 Gy/fraction (Group B) with modified PTV (excluding rectal volume) with a median follow-up period of 62 months. Prescribed dose was 72.6-74.8 Gy in 33-34 fractions (Group A) and 72-74 Gy in 36-37 fractions (Group B). RESULTS: Patients in Group B had a reduced rectal and bladder V10-V70 and were irradiated at the maximal dose. Their cumulative incidence of grade ≤2 GI toxicity at 5 years improved from 10.1% [95% confidence interval (CI), 4.9-15.3%] to 1.4% (0-3.3%). Grade 2≤ urinary toxicity also decreased from 5.5% (1.5-9.4%) in Group A to 1.4% (0-3.3%, p=0.0167) in Group B. The biochemical failure-free 5-year survival rate was 89.1% (95%CI=83.6-95.4%) and 87.5% (82.0-92.9%, p=0.75) in groups A and B, respectively. CONCLUSION: The reduced dose fraction schedule decreased the incidence of late GI toxicity without compromising prostate-specific antigen control. Careful target volume definition and fraction size are important even for IG-IMRT.

Interfractional Rectal Displacement Requiring Repeated Precaution Did Not Correlate to Biochemical Control and Rectal Toxicity in Patients with Prostate Cancer Treated with Image-guided Intensity-modulated Radiation Therapy.

AIM: To investigate the correlation between frequency of action level of interfractional rectal displacement requiring repeated precaution in patients with prostate cancer and late toxicity from image-guided intensity-modulated radiation therapy (IG-IMRT) using helical tomotherapy. PATIENTS AND METHODS: We examined 264 patients who underwent IG-IMRT during 2007-2011. Megavoltage computed tomographic (MVCT) images were acquired before radiation therapy and was examined with soft-tissue matching by comparing treatment planning images within 9,345 fractions. Displacement of the anterior rectal region larger than 5 mm, requiring repeated precaution, was defined as the level of rectal displacement requiring action (ARD). RESULTS: ARD was identified in 815 (7.7%) out of 9,345 fractions and at least once in 82% (216/264) of patients. The highest incidence of ARD (11%) was found during the initial week of treatment (first five and next five fractions), after which the incidence decreased to 6% (p<0.0001). Patients with lean body (lower body mass index (BMI) tended to have a higher incidence of ARD. We identified 16 (6%) cases of gastrointestinal toxicity and 12 (4.5%) genitourinary toxicities as a late adverse reaction (3 months or later after IG-IMRT). There was no correlation between ARD and late toxicity. Prostate-specific antigen (PSA) control was also similar (p=0.12) between those with ARD (96% at 5 year) and those without ARD (88%). CONCLUSION: ARD occurred predominantly in lean patients, during the initial week of treatment and became less likely over time. ARD was not correlated to late toxicity and PSA control, therefore, IG-IMRT technique was able to adequately control error due to interfractional prostate and rectal motion.

A prospective clinical trial of tumor hypoxia imaging with 18F-fluoromisonidazole positron emission tomography and computed tomography (F-MISO PET/CT) before and during radiation therapy.

To visualize intratumoral hypoxic areas and their reoxygenation before and during fractionated radiation therapy (RT), (18)F-fluoromisonidazole positron emission tomography and computed tomography (F-MISO PET/CT) were performed. A total of 10 patients, consisting of four with head and neck cancers, four with gastrointestinal cancers, one with lung cancer, and one with uterine cancer, were included. F-MISO PET/CT was performed twice, before RT and during fractionated RT of approximately 20 Gy/10 fractions, for eight of the 10 patients. F-MISO maximum standardized uptake values (SUVmax) of normal muscles and tumors were measured. The tumor-to-muscle (T/M) ratios of F-MISO SUVmax were also calculated. Mean SUVmax ± standard deviation (SD) of normal muscles was 1.25 ± 0.17, and SUVmax above the mean + 2 SD (≥1.60 SUV) was regarded as a hypoxic area. Nine of the 10 tumors had an F-MISO SUVmax of ≥1.60. All eight tumors examined twice showed a decrease in the SUVmax, T/M ratio, or percentage of hypoxic volume (F-MISO ≥1.60) at approximately 20 Gy, indicating reoxygenation. In conclusion, accumulation of F-MISO of ≥1.60 SUV was regarded as an intratumoral hypoxic area in our F-MISO PET/CT system. Most human tumors (90%) in this small series had hypoxic areas before RT, although hypoxic volume was minimal (0.0-0.3%) for four of the 10 tumors. In addition, reoxygenation was observed in most tumors at two weeks of fractionated RT.

A phase I study of S-1 with concurrent radiotherapy in elderly patients with locally advanced non-small cell lung cancer.

BACKGROUND: A phase I study was performed to evaluate dose-limiting toxicity and the recommended dose for the oral fluoropyrimidine S-1 administered concurrently with thoracic radiotherapy (TRT) in elderly (≥ 70 years of age) patients with locally advanced non-small cell lung cancer. METHODS: S-1 was administered on days 1 to 14 and 22 to 35 at oral doses of 65 or 80 mg m(-2) day(-1). TRT was administered in 2-Gy fractions five times weekly for a total dose of 60 Gy. Twelve previously untreated patients were treated with S-1 at 65 (n=6) or 80 (n=6) mg m(-2) day(-1). RESULTS: All patients completed the planned 60 Gy of TRT. Dose-limiting toxicity included pneumonitis (n=2), infection (n=1), and stomatitis (n=1), each of grade 3, but each event was reversible. The recommended dose for S-1 was determined to be 80 mg m(-2) day(-1). No patient experienced toxicity of grade 4. The dose intensity of S-1 was well maintained and the combination of S-1 plus TRT was well tolerated overall. The overall response rate was 83.3 %, with a median survival time of 34.0 months. CONCLUSIONS: Administration of S-1 at 80 mg m(-2) day(-1) on days 1 to 14 and 22 to 35 can be safely combined with concurrent TRT in elderly patients with locally advanced non-small cell lung cancer.

Randomized clinical trial of postoperative strontium-90 radiation therapy for pterygia: treatment using 30 Gy/3 fractions vs. 40 Gy/4 fractions.

BACKGROUND AND PURPOSE: Postoperative adjuvant treatment with strontium-90 radiation therapy (RT) is a proven technique for reducing the recurrence of pterygium. This randomized trial was conducted to evaluate whether a total dose of 40 Gy provides a better local control rate than a total dose of 30 Gy for surgically resected pterygia. PATIENTS AND METHODS: A single institutional randomized trial was conducted. Between 1999 and 2003, 74 pterygia in 71 patients were randomly allocated to 30 Gy/3 fractions/15 days (arm A) or to 40 Gy/4 fractions/22 days (arm B). Only primary pterygia for which RT could be started within 3 days of surgical resection were included. Postoperative RT was given by a strontium-90 eye applicator, and a dose of 10 Gy per fraction was delivered in weekly fractions (day 1, 8, 15, 22). RESULTS: Of the 74 pterygia treated, 73 in 70 patients were analyzed. Of the 73 pterygia, 41 were allocated to arm A, and the remaining 32 to arm B. The 2-year local control rates for arm A and arm B were 85% and 75%, respectively, without significant difference. No serious acute and late complications were noted in either arm. CONCLUSION: Our new standard fractionation for postoperative RT for pterygia is 30 Gy/3 fractions.

Definitive radiation therapy for moderately advanced laryngeal cancer: effects of accelerated hyperfractionation.

OBJECTIVE: The purpose of this retrospective study was to analyze the results of accelerated hyperfractionation for patients with moderately advanced (T2 and T3) laryngeal cancer. METHODS: Between 1998 and 2007, 9 supraglottic carcinomas (6 T2N0M0, 2 T2N2M0, 1 T3N0M0), 30 glottic carcinomas (25 T2N0M0, 5 T3N0M0), and 1 T2N0M0 subglottic carcinoma were treated with definitive radiotherapy using accelerated hyperfractionation without concurrent chemotherapy. The dose-fractionation for 35 patients was 72.8 Gy/56 fractions/5.6 weeks, and that for four patients treated between 1998 and 2001 was 72 Gy/60 fractions/6 weeks. One patient who had been treated with steroid therapy for systemic lupus erythematosus was treated by 67.8 Gy/44 fractions/4.4 weeks. RESULTS: The local control and overall survival probabilities at 5 years for supraglottic carcinomas were 75% and 86%, respectively. Those for glottic carcinomas were 80% and 92%, respectively. The 5-year local control probabilities for T2 and T3 tumors were 85% and 56%, respectively. This excellent local control rate especially for T2 laryngeal carcinomas may be attributable to the effect of accelerated hyperfractionation. No late toxicities of grade 2 or more was noted among the 39 patients treated with 72.8 Gy/56 fractions or 72 Gy/60 fractions. CONCLUSION: Accelerated hyperfractionation of 72.8 Gy/56 fractions/5.6 weeks using 1.3 Gy/fraction seems a safe and effective dose-fractionation for patients with moderately advanced laryngeal carcinomas.

A two-step intensity-modulated radiation therapy method for nasopharyngeal cancer: the Kinki University experience.

OBJECTIVE: The aim of this study was to analyze the clinical results of our adaptive radiation therapy scheme of a two-step intensity-modulated radiotherapy (IMRT) method for nasopharyngeal cancer (NPC) at Kinki University Hospital. METHODS: Between 2000 and 2007, 35 patients with Stage I-IVB NPC treated by IMRT were included. For all patients, treatment-planning computed tomography was done twice before and during IMRT to a total dose of 60-70 Gy/28-35 fractions (median 68 Gy). Chemotherapy (cisplatin 80 mg/m(2)/3 weeks x 1-3 courses) was given concurrently with IMRT for 31 patients. RESULTS: The 3- and 5-year overall survival rates for the 31 patients treated with concurrent chemotherapy were 88% and 83%, respectively. The 3- and 5-year loco-regional control rates for the 31 patients were 93% and 87%, respectively. Planning target volume delineation for the primary site or involved nodes was insufficient for three early cases, resulting in marginal recurrence in the three patients (9%). Except for one patient with early death, xerostomia scores at 1-2 years were: Grade 0, 11; Grade 1, 17; Grade 2, 5; Grade 3, 1. CONCLUSIONS: Excellent overall survival and loco-regional control rates were obtained by a two-step IMRT method with concurrent chemotherapy for NPC, although marginal recurrence was noted in some early cases.