Current status and progress of concurrent chemoradiotherapy in patients with locally advanced non-small cell lung cancer prior to the approval of durvalumab.

BACKGROUND: The standard treatment for patients with unresectable locally advanced (LA) non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT). Consolidation therapy with durvalumab after CRT demonstrated survival benefits and was approved in Japan in July 2018. The use of immune checkpoint inhibitors (ICIs) is entering routine oncological practice, and here we investigate the feasibility of concurrent CRT for LA-NSCLC patients based on the PACIFIC criteria. METHODS: We performed a retrospective study to evaluate the feasibility and efficacy of concurrent CRT prior to the approval of durvalumab. We assessed consecutive patients with LA-NSCLC treated with CRT between January 2012 and June 2018. RESULTS: We analyzed a total of 108 consecutive patients who received radical thoracic radiotherapy and concurrent platinum-based chemotherapy. Of those patients, 105 (97%) completed the planned radiotherapy. Radiation pneumonitis was observed in 93 patients (85%), with a median of 130 days (range: 41-317 days) from the initiation of radiation to the onset of the complication. Among the patients, 74 (69%) were considered eligible for consolidation therapy with durvalumab. The overall response rate was 64%, and the two-year survival rate was 63%. Patients who received an ICI after relapse were associated with significantly better survival than those who did not receive an ICI (two-year survival rate: 87% vs. 41%, respectively; P = 0.001). CONCLUSIONS: Prior to the approval of durvalumab, the clinical application of ICIs improved the outcome of patients with relapsed NSCLC after CRT for LA-NSCLC. The management of radiation pneumonitis remains a challenge following the approval of durvalumab.

Dosimetric factors associated with long-term patient-reported outcomes after definitive radiotherapy of patients with head and neck cancer.

BACKGROUND: The aim of this study was to explore the relationships between dosimetric parameters of organs at risk and patient-reported outcomes (PRO) after radiotherapy of patients with head and neck cancer. METHODS: PRO data of 53 patients with head and neck cancer treated with radiotherapy were prospectively collected. These data concerned health-related quality of life (HRQOL) and were collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and head and neck cancer module (QLQ-H&N35). Patients were divided into "severe-deterioration" and "mild-deterioration" groups on the basis of degree of deterioration HRQOL > 6 months after completing treatment. The relationships between HRQOL deteriorations and patient-related or dosimetry-related factors were evaluated. P < 0.0013 according to Bonferroni correction was considered to denote statistical significance. RESULTS: Regarding "trouble with social eating (HNSO)" and "coughing (HNCO)," there were significant differences between the severe-deterioration and mild-deterioration groups in mean dosages to the superior pharyngeal constrictor muscle (SPC) (HNSO: 62.5 Gy vs 54.2 Gy; p = 0.00029, and HNCO: 61.5 Gy vs 54.1 Gy; p = 0.0012) and parotid gland (HNSO: 24.1 Gy vs 20.5 Gy; p = 0.000056, and HNCO: 24.2 Gy vs 20.3 Gy; p = 0.00043). Regarding "nausea and vomiting," there was a significant difference between the two groups in the mean dosage to the middle pharyngeal constrictor muscle (MPC: 61.9 Gy vs. 58.4Gy; P = 0.00059). CONCLUSIONS: We found that dosages to the SPC and parotid gland were associated with severe deterioration in HRQOL attributable to difficulty in HNSO and HNCO, whereas dosage to the MPC was associated with severe deterioration attributable to nausea and vomiting.

Evaluation of concurrent chemoradiotherapy for locally advanced NSCLC according to EGFR mutation status.

Concurrent chemoradiotherapy (cCRT) is the standard treatment for patients with locally advanced non-small cell lung cancer (LA-NSCLC). However, the efficacy and safety of this treatment has not been compared between patients who possess epidermal growth factor receptor (EGFR) mutations and patients with wild-type EGFR. The objective of the present study was to evaluate the effect of the presence of EGFR gene mutations in patients with LA-NSCLC receiving cCRT. Between January 2007 and December 2013, the records of 64 patients were reviewed retrospectively. The data were statistically analyzed to evaluate the efficacy of cCRT according to EGFR mutation status. In total, 15/64 were revealed to possess EGFR mutations, 23%, and comprised the mutant EGFR group. The progression-free survival time was significantly shorter in the mutant EGFR group compared with the patient group with tumors exhibiting wild-type EGFR, 6.3 and 9.5 months, respectively (P<0.001). The overall survival rate was longer in the mutant EGFR group compared with the wild-type EGFR group, although the difference was not statistically significant, 37.1 and 21.1 months, respectively (P=0.26). The disease recurred in all of the patients of the mutant EGFR group, whilst the recurrence rate in the wild-type EGFR group was 89%. The frequency of distant metastasis was significantly higher in the mutant EGFR group compared with the wild-type EGFR group. In conclusion, these data suggest that additional studies are required to identify strategies for reinforcing the efficacy of cCRT, with a focus on the potential use of EGFR tyrosine kinase inhibitors for patients exhibiting an EGFR mutation.

Clinical outcomes of stage I and IIA non-small cell lung cancer patients treated with stereotactic body radiotherapy using a real-time tumor-tracking radiotherapy system.

PURPOSE: To investigate the clinical outcomes of stage I and IIA non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT) using a real-time tumor-tracking radiotherapy (RTRT) system. MATERIALS AND METHODS: Patterns-of-care in SBRT using RTRT for histologically proven, peripherally located, stage I and IIA NSCLC was retrospectively investigated in four institutions by an identical clinical report format. Patterns-of-outcomes was also investigated in the same manner. RESULTS: From September 2000 to April 2012, 283 patients with 286 tumors were identified. The median age was 78 years (52-90) and the maximum tumor diameters were 9 to 65 mm with a median of 24 mm. The calculated biologically effective dose (10) at the isocenter using the linear-quadratic model was from 66 Gy to 126 Gy with a median of 106 Gy. With a median follow-up period of 28 months (range 0-127), the overall survival rate for the entire group, for stage IA, and for stage IB + IIA was 75%, 79%, and 65% at 2 years, and 64%, 70%, and 50% at 3 years, respectively. In the multivariate analysis, the favorable predictive factor was female for overall survival. There were no differences between the clinical outcomes at the four institutions. Grade 2, 3, 4, and 5 radiation pneumonitis was experienced by 29 (10.2%), 9 (3.2%), 0, and 0 patients. The subgroup analyses revealed that compared to margins from gross tumor volume (GTV) to planning target volume (PTV) ≥ 10 mm, margins < 10 mm did not worsen the overall survival and local control rates, while reducing the risk of radiation pneumonitis. CONCLUSIONS: This multi-institutional retrospective study showed that the results were consistent with the recent patterns-of-care and patterns-of-outcome analysis of SBRT. A prospective study will be required to evaluate SBRT using a RTRT system with margins from GTV to PTV < 10mm.

Comparison of three different techniques of low-dose-rate seed implantation for prostate cancer.

PURPOSE: Three different techniques of low-dose-rate seed implantation for prostate cancer have been used since its use started in our hospital. The purpose of this study was to compare the results of the three different techniques. MATERIAL AND METHODS: The data of 305 prostate cancer patients who underwent low-dose-rate seed implantation were retrospectively analyzed. Pre-plan technique (n = 27), intraoperative pre-plan technique (n = 86), and interactive plan technique (n = 192) were tried in chronological order. The prescribed dose was set at 145 Gy. RESULTS: Median follow-up was 66 months (range: 12-94 months). The 5-year biochemical control rate was 95.5% (pre-plan group: 100%, intraoperative pre-plan group: 90.7%, interactive plan group: 97.0%; p = 0.08). Dosimetric parameters were generally increased from the pre-plan group to the interactive group. The differences in some dosimetric parameters between the planning phase and the CT analysis were significantly reduced with the interactive plan compared to the other techniques. The interactive plan showed a significant reduction of the seed migration rate compared to the two other groups. Acute genitourinary toxicity, acute gastrointestinal toxicity, frequency, and urinary retention increased gradually from the pre-plan period to the interactive plan period. CONCLUSIONS: There was no significant difference in biochemical control among the three groups. Dose-volume parameters were increased from the pre-plan technique to the interactive plan technique. However, this may not necessarily be due to technical improvements, since dose escalation was started during the same period. Lower seed migration rates and the smaller differences between the planning phase and CT analysis with the interactive plan technique suggest the superiority of this technique to the two other techniques.

Assessment of transposed ovarian movement: how much of a safety margin should be added during pelvic radiotherapy?

The purpose of this study was to analyze transposed ovarian movement. Data from 27 patients who underwent ovarian transposition after surgical treatment for uterine cancer were retrospectively analyzed. Computed tomography (CT) images including transposed ovaries were superimposed on other CT images acquired at different times, and were matched on bony structures. Differences in ovarian position between the CT images were measured. The planning organ at risk volume (PRV) margins were calculated from the formula of the 90% reference intervals (RIs) and the 95% RI, which were defined as mean ± 1.65 standard deviation (SD) and mean ± 1.96 SD, respectively. The 90% RI in the cranial, caudal, anterior, posterior, left and right directions were 1.5, 1.5, 1.4, 1.0, 1.7 and 0.9 cm, respectively. The 95% RI in the corresponding directions were 1.5, 2.0, 1.7, 1.2, 1.9 and 1.2 cm, respectively. These data suggest that bilateral ovaries need a PRV margin of ∼2 cm in all directions. The present study suggests that a transposed ovary needs the same PRV margin as a normal ovary (∼2 cm). Even after transposition, ovaries should be kept away from the radiation field to take into consideration the degree of ovarian movement.

Catheter displacement prior to the delivery of high-dose-rate brachytherapy in the treatment of prostate cancer patients.

PURPOSE: The purpose of this work was to report measured catheter displacement prior to the delivery of high-dose-rate brachytherapy (HDR) in the treatment of prostate cancer. MATERIAL AND METHODS: Data from 30 prostate cancer patients treated with HDR brachytherapy were analyzed retrospectively. Eighteen transperineal hollow catheters were inserted under transrectal ultrasound guidance. Gold marker seeds were also placed transperineally into the base and apex of the prostate gland. Five treatment fractions of 7.5 Gy each were administered over 3 days. The patient underwent CT scanning prior to each treatment fraction. Catheter displacement was measured from the pre-treatment CT dataset reconstructed at 1.25 mm slice thickness. RESULTS: Most of catheters were displaced in the caudal direction. Variations of 18 catheters for each patient were small (standard deviations < 1 mm for all but one patient). Mean displacements relative to the apex marker were 6 ± 4 mm, 12 ± 6 mm, 12 ± 6 mm, 12 ± 6 mm, and 12 ± 6 mm from plan to 1(st), 2(nd), 3(rd), 4(th), and 5(th) fractions, respectively. CONCLUSIONS: Our results indicate that catheter positions must be confirmed and if required, adjusted, prior to every treatment fraction for the precise treatment delivery of HDR brachytherapy, and to potentially reduce over-dosage to the bulbo-membranous urethra.

A prospective quasi-randomized comparison of intraoperatively built custom-linked seeds versus loose seeds for prostate brachytherapy.

PURPOSE: To compare dosimetric parameters, seed migration rates, operation times, and acute toxicities of intraoperatively built custom-linked (IBCL) seeds with those of loose seeds for prostate brachytherapy. METHODS AND MATERIALS: Participants were 140 patients with low or intermediate prostate cancer prospectively allocated to an IBCL seed group (n=74) or a loose seed group (n=66), using quasirandomization (allocated by week of the month). All patients underwent prostate brachytherapy using an interactive plan technique. Computed tomography and plain radiography were performed the next day and 1 month after brachytherapy. The primary endpoint was detection of a 5% difference in dose to 90% of prostate volume on postimplant computed tomography 1 month after treatment. Seed migration was defined as a seed position >1 cm from the cluster of other seeds on radiography. A seed dropped into the seminal vesicle was also defined as a migrated seed. RESULTS: Dosimetric parameters including the primary endpoint did not differ significantly between groups, but seed migration rate was significantly lower in the IBCL seed group (0%) than in the loose seed group (55%; P<.001). Mean operation time was slightly but significantly longer in the IBCL seed group (57 min) than in the loose seed group (50 min; P<.001). No significant differences in acute toxicities were seen between groups (median follow-up, 9 months). CONCLUSIONS: This prospective quasirandomized control trial showed no dosimetric differences between IBCL seed and loose seed groups. However, a strong trend toward decreased postimplant seed migration was shown in the IBCL seed group.

125Iodine monotherapy for Japanese men with low- and intermediate-risk prostate cancer: outcomes after 5 years of follow-up.

Data from 305 Japanese men with low-risk (n = 175) or intermediate-risk (n = 130) prostate cancer who underwent (125)I monotherapy were retrospectively analyzed. Of the 305 patients, 93 received hormonal therapy for a median of 6 months (range, 1-33 months) before implantation. The prescribed dose to the prostate plus 3- to 5-mm margin was set at 145 Gy. The mean dose to 90% of the prostate volume at 1 month (D90) and the prostate volume receiving at least 100% dose at 1 month (V100) were 173.4 Gy and 95.8%, respectively. The median follow-up was 66 months (range, 12-94 months). The 5-year biochemical non-evidence of disease rate was 95.5% (low-risk, 94.2%; intermediate-risk, 97.3%). The 5-year freedom from clinical failure rate was 98.9% (low-risk, 98.9%; intermediate-risk, 99.2%).The initial prostate-specific antigen level was identified as a significant predictive factor for biochemical recurrence (P = 0.029). The late Grade 3 genitourinary toxicity rate was 2.0%. No patients displayed late gastrointestinal toxicity of Grade 3 or worse. Monotherapy with (125)I showed excellent outcomes with limited morbidity for Japanese men with low- and intermediate-risk prostate cancer after 5 years of follow-up.

Clinical outcomes of 849 laryngeal cancers treated in the past 40 years: are we succeeding?

OBJECTIVE: We analyzed the clinical outcomes of 849 laryngeal cancers treated in the past 40 years, which overlapped with the era of the global treatment shift. METHODS: To compare the chronological outcomes, patients were divided into four groups according to their registration year as 1972-82, 1983-92, 1993-2002 and 2003-12; treatment trends, larynx preservation rate and overall survival rate were compared. RESULTS: There were 104, 173, 253 and 319 patients registered in 1972-82, 1983-92, 1993-2002 and 2003-12, respectively. Five-year overall survival rates were 74, 76.5, 75.6 and 82.2% in 1972-82, 1983-92, 1993-2002 and 2003-12, respectively. The five-year larynx preservation rates were 65.5, 75.7, 75.4 and 80.9% in 1972-82, 1983-92, 1993-2002 and 2003-12, respectively. CONCLUSIONS: The number of patients treated at our institute increased, and the overall survival and larynx preservation rates exhibited favorable improvements over the past four decades. In the analysis of nonsurgical options, S1 combined radiotherapy showed superiority over concurrent chemoradiotherapy and radiotherapy in larynx preservation, and S1 combined radiotherapy, concurrent chemoradiotherapy and Tegafur Uracil combined radiotherapy showed superiority over radiotherapy in overall survival. In nonsurgical approaches, proper case selection is the key to success and may be much more important than pursuing radiotherapy dose escalation. In the analysis of surgical options, laser and supracricoid laryngectomy with cricohyoidoepiglottopexy contributed to larynx preservation in early- and intermediate-stage cancers, respectively. Supracricoid laryngectomy with cricohyoidoepiglottopexy demonstrated overall survival not worse than total laryngectomy, which is the prerequisite treatment basis for larynx preservation options. We must make extra efforts in pursuing an ideal balance between nonsurgical and surgical larynx preservation options.

High-dose-rate brachytherapy and hypofractionated external beam radiotherapy combined with long-term hormonal therapy for high-risk and very high-risk prostate cancer: outcomes after 5-year follow-up.

The purpose of this study was to report the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) for National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer. Data from 178 HR (n = 96, 54%) and VHR (n = 82, 46%) prostate cancer patients who underwent (192)Ir-HDR brachytherapy and hypofractionated EBRT with long-term ADT between 2003 and 2008 were retrospectively analyzed. The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After five fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administered. All patients initially underwent ≥ 6 months of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after EBRT. The median follow-up was 61 months (range, 25-94 months) from the start of radiotherapy. The 5-year biochemical non-evidence of disease, freedom from clinical failure and overall survival rates were 90.6% (HR, 97.8%; VHR, 81.9%), 95.2% (HR, 97.7%; VHR, 92.1%), and 96.9% (HR, 100%; VHR, 93.3%), respectively. The highest Radiation Therapy Oncology Group-defined late genitourinary toxicities were Grade 2 in 7.3% of patients and Grade 3 in 9.6%. The highest late gastrointestinal toxicities were Grade 2 in 2.8% of patients and Grade 3 in 0%. Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.

Clinical outcome of supracricoid laryngectomy with cricohyoidoepiglottopexy: radiation failure versus previously untreated patients.

OBJECTIVE: A history of radiation therapy is known to be a major risk factor promoting post-surgical complications. By comparing the clinical outcomes of supracricoid laryngectomy with cricohyoidoepiglottopexy (SCL-CHEP) in irradiated and non-irradiated patients, we investigated the usefulness of salvage SCL-CHEP. METHODS: 73 patients who received SCL-CHEP between 1997 and 2010 (30 had received radiation therapy preoperatively and 43 had not). Staging error, wound infection, accuracy of surgical margin determination, acquired laryngeal function, and prognosis were compared between the two groups. RESULTS: Staging error occurred in 6/30 (20%) irradiated and 14/43 (33%) non-irradiated patients. An intraoperative margin study demonstrated a dysplastic or positive margin in 15/30 (50%) irradiated and 13/43 (30%) non-irradiated patients. Wound infection developed in 12/30 (40%) irradiated and 7/43 (16%) non-irradiated patients (P<0.05). Delayed wound infection was identified in four patients with a radiation dose over 65Gy. Swallowing function (ability to eat in public) was acquired in 28/30 (93%) irradiated and 39/43 (91%) non-irradiated patients. Five-year larynx preservation rates were 94% in irradiated and 91% in non-irradiated patients. Five-year overall survival rates were 81% in irradiated and 87% in non-irradiated patients. CONCLUSIONS: Risk of infection was significantly higher in irradiated patients; delayed infection should be appropriately managed. Functional and oncological results were stable regardless of radiation history. We encourage head and neck surgeons to take reasonable risks in performing salvage SCL-CHEP.