Acute adverse events of ultra-hypofractionated whole-breast irradiation after breast-conserving surgery for early breast cancer in Japan: an interim analysis of the multi-institutional phase II UPBEAT study.

BACKGROUND: The applicability of ultra-hypofractionated (ultra-HF) whole-breast irradiation (WBI) remains unknown in Japanese women. This study aimed to evaluate the safety and efficacy of this approach among Japanese women and report the results of an interim analysis performed to assess acute adverse events (AEs) and determine whether it was safe to continue this study. METHODS: We enrolled Japanese women with invasive breast cancer or ductal carcinoma in situ who had undergone breast-conserving surgery, were aged ≥ 40 years, had pathological stages of Tis-T3 N0-N1, and had negative surgical margins. Ultra-HF-WBI was delivered at 26 Gy in five fractions over one week. When the number of enrolled patients reached 28, patient registration was paused for three months. The endpoint of the interim analysis was the proportion of acute AEs of grade ≥ 2 (Common Terminology Criteria for Adverse Events v5.0) within three months. RESULTS: Of the 28 patients enrolled from seven institutes, 26 received ultra-HF-WBI, and 2 were excluded due to postoperative infections. No AEs of grade ≥ 3 occurred. One patient (4%) experienced grade 2 radiation dermatitis, and 18 (69%) had grade 1 radiation dermatitis. The other acute grade 1 AEs experienced were skin hyperpigmentation (n = 10, 38%); breast pain (n = 4, 15%); superficial soft tissue fibrosis (n = 3, 12%); and fatigue (n = 1, 4%). No other acute AEs of grade ≥ 2 were detected. CONCLUSIONS: Acute AEs following ultra-HF-WBI were within acceptable limits among Japanese women, indicating that the continuation of the study was appropriate.

Impact of prostate position-based image-guidance in intensity-modulated radiation therapy for localized prostate cancer.

BACKGROUND/PURPOSE: The long-term clinical impact of prostate position-based image-guided radiotherapy (IGRT) for localized prostate cancer remains unclear. MATERIALS AND METHODS: We retrospectively compared clinical outcomes following intensity-modulated radiation therapy (IMRT) with cone-beam computed tomography-based prostate position-based IGRT (P-IGRT) or without P-IGRT (non-P-IGRT). From June 2011, we applied P-IGRT in IMRT for intermediate-risk (IR) prostate cancer (PCa) (D'Amico risk classification) (76 Gy in 38 fractions, with smaller margins). Clinical outcomes of patients who received P-IGRT between June 2011 and June 2019 were retrospectively compared with those of patients with IR PCa who received IMRT without P-IGRT between October 2002 and May 2011 in our institution (74 Gy in 37 fractions). RESULTS: A total of 222 consecutive patients were analyzed: 114 in the P-IGRT cohort and 108 in the non-P-IGRT cohort. The median follow-up period after IMRT was 7.1 years for the P-IGRT cohort and 10.8 years for the non-P-IGRT cohort. The biochemical failure-free rate was significantly better in the P-IGRT cohort (94.9% for the P-IGRT cohort vs 82.7% for the non-P-IGRT cohort at 10 years, p = 0.041). The rate of rectal bleeding which needs intervention including the use of suppositories was significantly lower in the P-IGRT cohort (p < 0.001). CONCLUSIONS: The use of P-IGRT with higher doses and smaller margins was correlated with significantly better biochemical control, and a lower incidence of rectal bleeding in IMRT for intermediate-risk prostate cancer. The enhanced accuracy using P-IGRT has the potential to independently improve disease control and reduce late rectal bleeding.

Long-Term Outcomes of a Prospective Study on Highly Hypofractionated Intensity Modulated Radiation Therapy for Localized Prostate Cancer for 3 Weeks.

PURPOSE: Reports of radiation therapy for prostate cancer using dose fractions between moderate hypofractionation and ultrahypofractionation are limited. This pilot study involved the application of highly hypofractionated intensity modulated radiation therapy (IMRT) in 15 fractions for 3 weeks and the number of fractions was intermediate between the 2 previously mentioned dose fractions. The long-term outcomes are reported. METHODS AND MATERIALS: From April 2014 to September 2015, patients with low- to intermediate-risk prostate cancer received 54 Gy in 15 fractions (3.6 Gy per fraction) for 3 weeks using IMRT without intraprostatic fiducial markers or a rectal hydrogel spacer. Neoadjuvant hormone therapy (HT) was administered for 4 to 8 months. Adjuvant HT was not administered to any patients. Rates of biochemical relapse-free survival, clinical relapse-free survival, overall survival, and the cumulative incidence of late grade ≥2 toxicities were analyzed. RESULTS: Twenty-five patients were enrolled in this prospective study; 24 of them were treated with highly hypofractionated IMRT (17% had low-risk and 83% had intermediate-risk disease). The median neoadjuvant HT duration was 5.3 months. The median follow-up period was 77 months (range, 57-87 months). Biochemical relapse-free survival, clinical relapse-free survival, and overall survival rates were 91.7%, 95.8%, and 95.8% at 5 years, and 87.5%, 86.3%, and 95.8% at 7 years, respectively. Neither grade ≥2 late gastrointestinal toxicity nor grade ≥3 late genitourinary toxicity was observed. The cumulative incidence rates of grade 2 genitourinary toxicity were 8.5% and 18.3% at 5 and 7 years, respectively. CONCLUSIONS: Highly hypofractionated IMRT delivering 54 Gy in 15 fractions for 3 weeks for prostate cancer without intraprostatic fiducial markers facilitated favorable oncological outcomes without severe complications. This treatment approach may be a possible alternative to moderate hypofractionation, but further validation is needed.

Ten-year outcomes of whole-pelvic intensity-modulated radiation therapy for prostate cancer with regional lymph node metastasis.

BACKGROUND: Management of pelvic node-positive prostate cancer has been challenging and controversial. We conducted a study to evaluate the outcomes of whole-pelvic (WP) simultaneous integrated boost (SIB) intensity-modulated radiation therapy (IMRT) combined with androgen deprivation therapy (ADT). METHODS: A total of 67 consecutive patients with cT1c-4N1M0 prostate cancer were definitively treated by WP SIB-IMRT. Neoadjuvant ADT (median: 8.3 months) was administered in all cases. WP SIB-IMRT was designed to simultaneously deliver 78, 66.3, and 58.5 Gy in 39 fractions to the prostate plus seminal vesicles, metastatic lymph nodes (LNs), and the pelvic LN region, respectively. Adjuvant ADT (median: 24.7 months) was administered in 66 patients. RESULTS: The median follow-up period was 81.6 months (range: 30.5-160.7). Biochemical relapse-free, overall, and prostate cancer-specific survival rates at 10 years were 59.8%, 79.6%, and 86.3%, respectively. Loco-regional recurrence was not observed. Being in International Society of Urological Pathology grade group 5 and having a posttreatment detectable nadir prostate-specific antigen (PSA) level (≥0.010 ng/ml) were significantly associated with worse prostate cancer-specific survival and progression of castration resistance. The 10-year cumulative incidence rates of grade 2 and 3 late toxicities were, respectively, 1.5% and 0% for genitourinary, 0% and 1.5% for gastrointestinal events. No grade 4 acute or late toxicities were observed. CONCLUSIONS: WP SIB-IMRT can be safely administered to patients with pelvic node-positive prostate cancer. Since grade group 5 and detectable nadir PSA levels are risks for castration resistance, we may need to increase the intensity of treatment for such cases.

Whole brain radiation therapy for primary central nervous system marginal zone lymphoma: a case report.

A standard radiation therapy protocol for primary central nervous system marginal zone lymphoma (CNS-MZL) has not been established. The International Lymphoma Radiation Oncology Group suggested a radiation therapy dose of 30-36 Gy for lesions of well-defined CNS-MZL. We report a case of relatively low-dose whole brain radiation therapy (WBRT) for ill-defined CNS-MZL. A 56-year-old man who presented with sudden left-sided convulsions and impaired consciousness was diagnosed with CNS-MZL. The tumor had an ill-defined lesion, without cerebrospinal fluid involvement. WBRT, consisting of 25.2 Gy in 14 fractions, was administered owing to the difficulty in target delineation for focal radiation therapy. No chemotherapy was administered during the treatment course. After the 36-month follow-up period, the patient maintained complete remission without neurological disorders. This report describes the usefulness of relatively low-dose WBRT for ill-defined CNS-MZL.

A pilot study of highly hypofractionated intensity-modulated radiation therapy over 3 weeks for localized prostate cancer.

The purpose of this pilot study was to evaluate the feasibility of highly hypofractionated intensity-modulated radiation therapy (IMRT) in 15 fractions over 3 weeks for treating localized prostate cancer based on prostate position-based image-guided radiation therapy. Twenty-five patients with National Comprehensive Cancer Network (NCCN) very low- to unfavorable intermediate-risk prostate cancer were enrolled in this study from April 2014 to September 2015 to receive highly hypofractionated IMRT (without intraprostatic fiducial markers) delivering 54 Gy in 15 fractions over 3 weeks. Patients with intermediate-risk disease underwent neoadjuvant androgen suppression for 4-8 months. Twenty-four patients were treated with highly hypofractionated IMRT, and one was treated with conventionally fractionated IMRT because the dose constraint of the small bowel seemed difficult to achieve during the simulation. Seventeen percent had very low- or low-risk, 42% had favorable intermediate-risk, and 42% had unfavorable intermediate-risk disease according to NCCN guidelines. The median follow-up period was 31 months (range, 24-42 months). No Grade ≥3 acute toxicity was observed, and the incidence rates of Grade 2 acute genitourinary and gastrointestinal toxicities were 21% and 4%, respectively. No Grade ≥2 late toxicity was observed. Biochemical relapse was observed in one patient at 15 months, and the biochemical relapse-free survival rate was 95.8% at 2 years. A prostate-specific antigen bounce of ≥0.4 ng/ml was observed in 11 patients (46%). The highly hypofractionated IMRT regimen is feasible in patients with localized prostate cancer and is more convenient than conventionally fractionated schedules for patients and health-care providers.

Decreased acute toxicities of intensity-modulated radiation therapy for localized prostate cancer with prostate-based versus bone-based image guidance.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) is a major therapeutic option for localized prostate cancer. Image-guided radiation therapy (IGRT) allows tumor visualization and corrects the errors caused by daily internal movement of the prostate. The current study retrospectively compared the acute toxicities and biochemical tumor control outcomes of prostate IMRT achieved using two IGRT techniques: bony structure-based IGRT (B-IGRT) and prostate-based IGRT (P-IGRT). METHODS: Between February 2011 and July 2014, 96 patients with low- or intermediate-risk prostate cancer were treated using P-IGRT based on cone-beam computed tomography (CBCT; 76 Gy) without fiducial markers. This group of patients was compared with a similar cohort of 96 patients who were treated with B-IGRT (74 Gy) between July 2007 and September 2011. The planning target volume (PTV) margins were 1-3 mm smaller in the P-IGRT group than in the B-IGRT group. RESULTS: The median follow-up periods for all patients, the P-IGRT group, and the B-IGRT group were 42, 32, and 64 months, respectively. A significantly lower incidence of acute grade 2 or higher gastrointestinal toxicities was observed in the P-IGRT group compared with the B-IGRT group (3 vs. 11%; p = 0.049). The prostate-specific antigen failure-free survival rates at 3 years were 95.5 and 92.7% for the P-IGRT and B-IGRT groups, respectively (p = 0.534). CONCLUSIONS: IMRT with P-IGRT allows PTV margin reduction without sacrificing tumor control, which successfully reduces acute rectal toxicity compared with IMRT with B-IGRT.

Correlation between urinary dose and delayed radiation cystitis after 78 Gy intensity-modulated radiotherapy for high-risk prostate cancer: A 10-year follow-up study of genitourinary toxicity in clinical practice.

PURPOSE: To investigate the factors associated with the risk of long-term genitourinary (GU) toxicity among high-risk prostate cancer (PC) patients treated with high-dose intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Between 2000 and 2011, PC patients treated with 78 Gy in 39 fractions delivered by IMRT combined with neo-adjuvant hormonal therapy were selected from among our database. GU toxicities and clinical factors, as well as separate anatomical urinary structures, were evaluated in terms of their associations. RESULTS: A total of 309 patients was included in this study. The median follow-up was 104 months (range: 24-143 months). The most frequently observed late grade ≥2 GU toxicity was hematuria (11.2%: 10-year actuarial risk) with radiation cystitis observed in the majority of patients. In univariate analysis, late grade ≥2 hematuria was associated with the exposure to doses >75 Gy (V75) of the bladder neck and V70 of the bladder wall, as well as with T stage. V75 of the bladder neck remained significant in multivariate analysis (p = 0.049). CONCLUSIONS: At the 10-year follow up of high-dose IMRT, a major concern was proved to be delayed cystitis related to the higher volume of bladder neck dose exposed excess over 75 Gy.

Ten-year outcomes of intensity-modulated radiation therapy combined with neoadjuvant hormonal therapy for intermediate- and high-risk patients with T1c-T2N0M0 prostate cancer.

BACKGROUND: We aimed to analyze the 10-year outcomes of intensity-modulated radiation therapy (IMRT) combined with neoadjuvant hormonal therapy (HT) for patients with intermediate- and high-risk T1c-T2N0M0 prostate cancer. METHODS: Fifty patients with T1c-T2N0M0 prostate cancer, who were treated with high-dose IMRT combined with neoadjuvant HT, were evaluated. Of these patients, 19 and 31 were classified into the intermediate- and high-risk groups, respectively. Neoadjuvant HT was administered over a median duration of 6 months; 74 and 78 Gy in 2 Gy per fraction were essentially delivered to the intermediate- and high-risk cases, respectively. Adjuvant HT was not administered to any of the patients after the completion of IMRT. RESULTS: Over a median follow-up period of 118 months, the 10-year prostate-specific antigen failure-free survival, prostate-specific antigen failure-free, salvage hormonal therapy-free, prostate cancer-specific survival, and overall survival rates were 70.2 %, 78.7 %, 89.2 %, 100 %, and 88.8 %, respectively. No grade 3 or higher acute or late toxicities were observed. The 10-year likelihoods of developing grade 2 late urinary and rectal toxicities were 13.7 % and 4.2 %, respectively. Compared with the outcomes of a cohort of historical controls who were locally irradiated with 70 Gy by three-dimensional conformal radiotherapy, the prostate-specific antigen failure-free rate was significantly better in the IMRT groups (78.7 % vs. 53.4 % at 10 years; p = 0.027). CONCLUSIONS: High-dose IMRT combined with neoadjuvant HT achieved not only high prostate-specific antigen control, but also excellent survival outcomes with acceptable morbidities, for a Japanese cohort of intermediate- and high-risk T1c-T2N0M0 prostate cancer patients, and these results warrant further investigation.

Clinical effect of multileaf collimator width on the incidence of late rectal bleeding after high-dose intensity-modulated radiotherapy for localized prostate carcinoma.

BACKGROUND: Several studies have confirmed a dosimetric advantage associated with use of a smaller leaf in intensity-modulated radiation therapy (IMRT). However, no studies have identified any clinical benefits. We investigated the effect of a smaller multileaf collimator (MLC) width on the onset of late rectal bleeding after high-dose prostate IMRT. MATERIALS AND METHODS: Two hundred and five prostate cancer patients were treated with a total dose of 78 Gy in 39 fractions by use of a dynamic MLC technique; however, two different MLC were used: a 10-mm-wide device and a 5-mm-wide device. Gastrointestinal toxicity and several clinical factors were assessed. RESULTS: The 5-year actuarial risk of grade 2 or higher rectal bleeding was 6.9 % for the 10-mm-wide group (n = 132) and 1.8 % for the 5-mm-wide group (n = 73) (p = 0.04). The median estimated rectal doses for the two groups were 55.1 and 50.6 Gy (p < 0.001), respectively. Univariate analysis showed that acute toxicity, rectal V30-60, median rectal dose, normal tissue complication probability (NTCP), and MLC type were significant predictive factors for late rectal toxicity. In multivariate analysis, acute toxicity and NTCP remained significant. CONCLUSION: In our planning approach for prostate IMRT, a decrease in MLC width from 10 to 5 mm contributed to further rectal dose reduction, which was the most important predictor of late rectal toxicity.