Late genitourinary toxicity in salvage radiotherapy for prostate cancer after radical prostatectomy: impact of daily fraction doses.

OBJECTIVE: To evaluate the impact of daily fraction doses on late genitourinary (GU) toxicity after salvage radiotherapy (SRT) for prostate cancer. METHODS: This multi-institutional retrospective study included 212 patients who underwent SRT between 2008 and 2018. All patients received image-guided intensity-modulated SRT at a median dose of 67.2 Gy in 1.8-2.3 Gy/fraction. The cumulative rates of late grade ≥2 GU and gastrointestinal (GI) toxicities were compared using Gray test, stratified by the ≤2.0 Gy/fraction (n = 137) and ≥2.1 Gy/fraction groups (n = 75), followed by multivariate analyses. The total dose was represented as an equivalent dose in 2-Gy fractions (EQD2) with α/ß = 3 Gy. RESULTS: After a median follow-up of 63 months, the cumulative rates of 5-year late grade ≥2 GU and GI toxicities were 14% and 2.5%, respectively. The cumulative rates of 5-year late grade ≥2 GU toxicity in the ≥2.1 Gy/fraction and ≤2.0 Gy/fraction groups were 22% and 10%, respectively (P = .020). In the multivariate analysis, ≥2.1 Gy/fraction was still associated with an increased risk of late grade ≥2 GU toxicity (hazard ratio, 2.37; 95% confidence interval, 1.12-4.99; P = .023), while the total dose was not significant. CONCLUSION: The present results showed that ≥2.1 Gy/fraction resulted in a higher incidence of late grade ≥2 GU toxicity in SRT. ADVANCES IN KNOWLEDGE: The impact of fraction doses on late GU toxicity after SRT remains unknown. The results suggest that higher fraction doses may increase the risk of late GU toxicity in SRT.

Impact of radiation doses on clinical relapse of biochemically recurrent prostate cancer after prostatectomy.

The relationship between radiation doses and clinical relapse in patients receiving salvage radiotherapy (SRT) for biochemical recurrence (BCR) after radical prostatectomy (RP) remains unclear. We identified 292 eligible patients treated with SRT between 2005 and 2018 at 15 institutions. Clinical relapse-free survival (cRFS) between the ≥ 66 Gy (n = 226) and < 66 Gy groups (n = 66) were compared using the Log-rank test, followed by univariate and multivariate analyses and a subgroup analysis. After a median follow-up of 73 months, 6-year biochemical relapse-free survival, cRFS, cancer-specific survival, and overall survival rates were 58, 92, 98, and 94%, respectively. Six-year cRFS rates in the ≥ 66 Gy and < 66 Gy groups were 94 and 87%, respectively (p = 0.022). The multivariate analysis revealed that Gleason score ≥ 8, seminal vesicle involvement, PSA at BCR after RP ≥ 0.5 ng/ml, and a dose < 66 Gy correlated with clinical relapse (p = 0.015, 0.012, 0.024, and 0.0018, respectively). The subgroup analysis showed the consistent benefit of a dose ≥ 66 Gy in patients across most subgroups. Doses ≥ 66 Gy were found to significantly, albeit borderline, increase the risk of late grade ≥ 2 GU toxicity compared to doses < 66 Gy (14% vs. 3.2%, p = 0.055). This large multi-institutional retrospective study demonstrated that a higher SRT dose (≥ 66 Gy) resulted in superior cRFS.

Importance of the Number and Location of Lymph Node Metastasis in Oropharyngeal Cancer.

BACKGROUND/AIM: The 8th edition of the American Joint Committee on Cancer staging system classifies oropharyngeal cancer (OPC) by the expression of p16. The discrepancy observed in this system between pathological and clinical N-stages in p16-positive OPC has provoked controversy. Therefore, this study investigated prognostic factors not included in the new staging system for p16-positive OPC patients. PATIENTS AND METHODS: Patients with non-metastatic OPC receiving radiotherapy were reviewed. Clinical lymph node statuses were reassessed based on contrast-enhanced computed tomography and fluorodeoxyglucose positron emission tomography. Overall survival (OS) and cause-specific survival (CSS) were analyzed using multivariate analyses to adjust baseline imbalances. RESULTS: In total, 166 OPC patients were reviewed. Among them, 81 patients with p16-positive were analyzed. Three or more lymph node metastases (LNM) were observed in 21 p16-positive OPCs. Retropharyngeal lymph node metastasis (Rp) was found in 12. Three-year OS, CSS, and progression-free survival rates in p16-positive patients were 76, 88, and 81%, respectively. In multivariate analyses of p16-positive OPC, LNM ≥3 was a prognostic factor of OS (hazard ratio=9.30, p<0.001) and CSS (hazard ratio=17.80, p=0.005). Rp was associated with poor CSS (hazard ratio=8.73, p=0.03). In N0-1 p16-positive patients, LNM ≥3 trended to be associated with poor OS (hazard ratio=3.93, p=0.06). CSS in patients with Rp was unfavorable (hazard ratio=70.16, p=0.05). CONCLUSION: LNM ≥3 and Rp may be predictive of OS and CCS in p16-positive OPC. These are also possibly used to subcategorize p16-positive cN0-1 OPC. Further validation of lymph node staging is needed to refine the clinical staging system.

Survey of malignant pleural mesothelioma treatment in Japan: Patterns of practice and clinical outcomes in tomotherapy facilities.

We conducted a nationwide survey of tomotherapy for malignant pleural mesothelioma (MPM) in Japan. Fifty-six facilities were surveyed and data on 31 patients treated curatively between 2008 and 2017 were collected from 14 facilities. Twenty patients received hemithorax irradiation after extrapleural pneumonectomy (EPP) (first group). Five patients received irradiation without EPP (second group), while six received salvage radiotherapy for local recurrence (salvage group). Among the seven patients not undergoing EPP, five (four in the second group and one in the salvage group) were treated with lung sparing pleural irradiation (LSPI) and two with irradiation to visible tumors. Two-year overall survival (OS) rates in the first and second groups were 33% and 60%, respectively (median, 13 vs 30 months, P = 0.82). In the first and second groups, 2-year local control (LC) rates were 53 and 67%, respectively (P = 0.54) and 2-year progression-free survival (PFS) rates were 16% and 60%, respectively (P = 0.07). Distant metastases occurred in 15 patients in the first group and three in the second group. In the salvage group, the median OS was 18 months. Recurrence was observed in the irradiated volume in four patients. The contralateral lung dose was higher in LSPI than in hemithorax irradiation plans (mean, 11.0 ± 2.2 vs 6.1 ± 3.1 Gy, P = 0.002). Grade 3 or 5 lung toxicity was observed in two patients receiving EPP and hemithorax irradiation, but not in those undergoing LSPI. In conclusion, outcomes of EPP and hemithorax irradiation were not satisfactory, whereas LSPI appeared promising and encouraging.

Vaginal Fistulas of the Bladder and Small Bowel After Two-Dimensional Intracavitary Brachytherapy in a Patient With Cervical Cancer.

Image-guided brachytherapy (IGBT) is commonly used for patients with cervical cancer, but two-dimensional intracavitary brachytherapy (2D-ICBT) is also still utilized for certain patients. We report a patient with cervical cancer who developed vaginal fistulas of the bladder and small bowel after chemoradiotherapy with 2D-ICBT. A 61-year-old woman with stage IIB cervical cancer underwent a combination of external beam radiotherapy (EBRT) at a dose of 50.4 Gy in 28 fractions and 2D-ICBT at a dose of 22 Gy in four fractions. As packs were well inserted around the uterus in all fractions of 2D-ICBT, the doses to the surrounding organs at risk (OAR) could be likely to be kept at low levels. She developed a huge fistula between the vagina and bladder approximately 2.5 years after radiotherapy (RT). She also developed a fistula between the vagina and small bowel approximately seven years after RT and underwent bypass from the small bowel to the transverse colon. The OAR were delineated using computed tomography for EBRT planning, and the cumulative dose of 2D-ICBT plus EBRT was evaluated as the source of toxicity. The cumulative dose converted to the equivalent dose in 2-Gy fractions (EQD2) was calculated using the linear-quadratic model with α/ß = 3 for the OAR. The cumulative EQD2 values of the minimum dose to the most irradiated 2 cc (D2cc) of the bladder and small bowel were 90.2 Gy and 79.5 Gy, respectively. These values exceeded the upper limits of the dosimetric criteria of the OAR, suggesting an association with both vaginal fistulas. As the adoption of IGBT is too slow in some countries, it is noteworthy that a reduced bladder volume may result in a significant increase in the dose to the small bowel and bladder in 2D-ICBT.

Early salvage radiotherapy in patients with biochemical recurrence after radical prostatectomy: Its impact and optimal candidate.

AIM: We aimed to identify the optimal candidates for early salvage radiotherapy (SRT) among patients with biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS: This multi-institutional retrospective study included 371 patients treated using SRT after RP. The median (range) PSA level at BCR was 0.36 (0.10-2.00) ng/mL. The association between early SRT (ie, starting PSA level < 0.50) and BCR after SRT was tested in each subgroup according to our own risk stratification. RESULTS: The median follow-up time was 51 months. By multivariate analysis, pT3b, Gleason score ≥ 8, negative surgical margins, PSA doubling time < 6 months, and non-early SRT were associated with BCR after SRT. Patients were stratified by four risk factors other than non-early SRT: (1) low risk (0 risk factor), (2) intermediate risk (1 risk factor), and (3) high risk (≥2 risk factors). The BCR-free survival was higher in the early SRT group than the nonearly SRT group in the high-risk subgroup (P = 0.020), whereas that was similar between two groups in the low-risk and intermediate-risk subgroups (P = .79 and .18, respectively). Multivariate analysis revealed that early SRT was beneficial for the high-risk subgroup (P = .032), whereas early SRT was not associated with improved outcomes in the low-risk and intermediate-risk subgroups (P = .92 and 1.0, respectively). CONCLUSIONS: This study suggested that early SRT seemed to contribute to better biochemical control for patients with more adverse features, whereas no benefit was observed in men with no adverse features.

Impact of advanced radiotherapy techniques and dose intensification on toxicity of salvage radiotherapy after radical prostatectomy.

The safety and efficacy of dose-escalated radiotherapy with intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) remain unclear in salvage radiotherapy (SRT) after radical prostatectomy. We examined the impact of these advanced radiotherapy techniques and dose intensification on the toxicity of SRT. This multi-institutional retrospective study included 421 patients who underwent SRT at the median dose of 66 Gy in 2-Gy fractions. IMRT and IGRT were used for 225 (53%) and 321 (76%) patients, respectively. At the median follow-up of 50 months, the cumulative incidence of late grade 2 or higher gastrointestinal (GI) and genitourinary (GU) toxicities was 4.8% and 24%, respectively. Multivariate analysis revealed that the non-use of either IMRT or IGRT, or both (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.8-5.4, p < 0.001) and use of whole-pelvic radiotherapy (HR 7.6, CI 1.0-56, p = 0.048) were associated with late GI toxicity, whereas a higher dose ≥68 Gy was the only factor associated with GU toxicities (HR 3.1, CI 1.3-7.4, p = 0.012). This study suggested that the incidence of GI toxicities can be reduced by IMRT and IGRT in SRT, whereas dose intensification may increase GU toxicity even with these advanced techniques.