Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial.

BACKGROUND: TGF-ß is an immunosuppressive cytokine that is upregulated in colorectal cancer. TGF-ß blockade improved response to chemoradiotherapy in preclinical models of colorectal adenocarcinoma. We aimed to test the hypothesis that adding the TGF-ß type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy would improve pathological complete response rates in patients with locally advanced rectal cancer. METHODS: This was an investigator-initiated, single-arm, phase 2 study done in two medical centres in Portland (OR, USA). Eligible patients had previously untreated, locally advanced, rectal adenocarcinoma, stage IIA-IIIC or IV as per the American Joint Committee on Cancer; Eastern Cooperative Oncology Group status 0-2; and were aged 18 years or older. Participants completed two 14-day courses of oral galunisertib 150 mg twice daily, before and during fluorouracil-based chemoradiotherapy (intravenous fluorouracil 225 mg/m2 over 24 h daily 7 days per week during radiotherapy or oral capecitabine 825 mg/m2 twice per day 5 days per week during radiotherapy; radiotherapy consisted of 50·4-54·0 Gy in 28-30 fractions). 5-9 weeks later, patients underwent response assessment. Patients with a complete response could opt for non-operative management and proceed to modified FOLFOX6 (intravenous leucovorin 400 mg/m2 on day 1, intravenous fluorouracil 400 mg/m2 on day 1 then 2400 mg/m2 over 46 h, and intravenous oxaliplatin 85 mg/m2 on day 1 delivered every 2 weeks for eight cycles) or CAPEOX (intravenous oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks for four cycles). Patients with less than complete response underwent surgical resection. The primary endpoint was complete response rate, which was a composite of pathological complete response in patients who proceeded to surgery, or clinical complete response maintained at 1 year after last therapy in patients with non-operative management. Safety was a coprimary endpoint. Both endpoints were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02688712, and is active but not recruiting. FINDINGS: Between Oct 19, 2016, and Aug 31, 2020, 38 participants were enrolled. 25 (71%) of the 35 patients who completed chemoradiotherapy proceeded to total mesorectal excision surgery, five (20%) of whom had pathological complete responses. Ten (29%) patients had non-operative management, three (30%) of whom ultimately chose to have total mesorectal excision. Two (67%) of those three patients had pathological complete responses. Of the remaining seven patients in the non-operative management group, five (71%) had clinical complete responses at 1 year after their last modified FOLFOX6 infusion. In total, 12 (32% [one-sided 95% CI ≥19%]) of 38 patients had a complete response. Common grade 3 adverse events during treatment included diarrhoea in six (16%) of 38 patients, and haematological toxicity in seven (18%) patients. Two (5%) patients had grade 4 adverse events, one related to chemoradiotherapy-induced diarrhoea and dehydration, and the other an intraoperative ischaemic event. No treatment-related deaths occurred. INTERPRETATION: The addition of galunisertib to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer improved the complete response rate to 32%, was well tolerated, and warrants further assessment in randomised trials. FUNDING: Eli Lilly via ExIST program, The Providence Foundation.

A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma.

BACKGROUND: Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50-54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with chemotherapy and immunotherapy. METHODS: To address this, we analyzed the effect of neoadjuvant standard fractionated and hypofractionated chemoradiation on immune cells in patients with locally advanced and borderline resectable pancreatic adenocarcinoma. RESULTS: We found that standard fractionated chemoradiation resulted in a significant and extended loss of lymphocytes that was not explained by a lack of homeostatic cytokines or response to cytokines. By contrast, treatment with hypofractionated radiation therapy avoided the loss of lymphocytes associated with conventional fractionation. CONCLUSION: Hypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells. TRIAL REGISTRATION: ClinicalTrials.gov NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.

Phase I and II Study of Induction Chemotherapy With Methotrexate, Rituximab, and Temozolomide, Followed By Whole-Brain Radiotherapy and Postirradiation Temozolomide for Primary CNS Lymphoma: NRG Oncology RTOG 0227.

PURPOSE: This study investigated the treatment of primary CNS lymphoma with methotrexate, temozolomide (TMZ), and rituximab, followed by hyperfractionated whole-brain radiotherapy (hWBRT) and subsequent TMZ. The primary phase I end point was the maximum tolerated dose of TMZ. The primary phase II end point was the 2-year overall survival (OS) rate. Secondary end points were preirradiation response rates, progression-free survival (PFS), neurologic toxicities, and quality of life. PATIENTS AND METHODS: The phase I study increased TMZ doses from 100 to 150 to 200 mg/m(2). Patients were treated with rituximab 375 mg/m(2) 3 days before cycle 1; methotrexate 3.5 g/m(2) with leucovorin on weeks 1, 3, 5, 7, and 9; TMZ daily for 5 days on weeks 4 and 8; hWBRT 1.2 Gy twice-daily on weeks 11 to 13 (36 Gy); and TMZ 200 mg/m(2) daily for 5 days every 28 days on weeks 14 to 50. RESULTS: Thirteen patients (one ineligible) were enrolled in phase I of the study. The maximum tolerated dose of TMZ was 100 mg/m(2). Dose-limiting toxicities were hepatic and renal. In phase II, 53 patients were treated. Median follow-up for living eligible patients was 3.6 years, and 2-year OS and PFS were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG-9310, 2-year OS and PFS were significantly improved (P = .006 and .030, respectively). In phase II, the objective response rate was 85.7%. Among patients, 66% (35 of 53) had grade 3 and 4 toxicities before hWBRT, and 45% (24 of 53) of patients experienced grade 3 and 4 toxicities attributable to post-hWBRT chemotherapy. Cognitive function and quality of life improved or stabilized after hWBRT. CONCLUSION: This regimen is safe, with the best 2-year OS and PFS achieved in any Radiation Therapy Oncology Group primary CNS lymphoma trial. Randomized trials that incorporate this regimen are needed to determine its efficacy compared with other strategies.

Vaginal brachytherapy alone is sufficient adjuvant treatment of surgical stage I endometrial cancer.

PURPOSE: To determine the efficacy and complications of adjuvant vaginal high-dose-rate brachytherapy alone for patients with Stage I endometrial cancer in whom complete surgical staging had been performed. METHODS AND MATERIALS: Between April 1998 and March 2004, 100 patients with Stage I endometrial cancer underwent surgical staging (total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic +/- paraaortic nodal sampling) and postoperative vaginal high-dose-rate brachytherapy at our institution. The total dose was 2100 cGy in three fractions. RESULTS: With a median follow-up of 23 months (range 2-62), no pelvic or vaginal recurrences developed. All patients underwent pelvic dissection, and 42% underwent paraaortic nodal dissection. A median of 29.5 pelvic nodes (range 1-67) was removed (84% had >10 pelvic nodes removed). Most patients (73%) had endometrioid (or unspecified) adenocarcinoma, 16% had papillary serous carcinoma, and 11% had other histologic types. The International Federation of Gynecology and Obstetrics stage and grade was Stage IA, grade III in 5; Stage IB, grade I, II, or III in 6, 27, or 20, respectively; and Stage IC, grade I, II, or III in 13, 17, or 10, respectively. The Common Toxicity Criteria (version 2.0) complications were mild (Grade 1-2) and consisted primarily of vaginal mucosal changes, temporary urinary irritation, and temporary diarrhea. CONCLUSION: Adjuvant vaginal high-dose-rate brachytherapy alone may be a safe and effective alternative to pelvic external beam radiotherapy for surgical Stage I endometrial cancer.

Prostate volume measurement by transrectal ultrasound and computed tomography before and after permanent prostate brachytherapy.

PURPOSE: To quantify prostate volume (pvol) changes with transrectal ultrasound (TRUS) immediately after permanent prostate brachytherapy (PPB) and to correlate these changes with postimplant computed tomography (CT) volumetrics. To provide data relevant to evaluating the potential of TRUS-based image fusion for intraoperative dosimetry. METHODS AND MATERIALS: Between July 2000 and January 2003, 177 patients underwent (125)I PPB monotherapy at our institution, and 165 patients provided research authorization. A total of 136 patients (82%) completed 4 imaging studies: planning TRUS, intraoperative pre- and postimplant TRUS, and CT. RESULTS: Mean planning TRUS pvol was 38.7 +/- 11.7 cc standard deviation (SD), 95% confidence interval (CI) (36.7, 40.7). Mean intraoperative TRUS pvol preimplant was 37.1 +/- 11.7 cc SD, 95% CI (35.1, 39.0), and postimplant was 44.5 +/- 15.1 cc SD, 95% CI (42.0, 47.1). The mean ratio of postimplant:preimplant intraoperative TRUS pvols was 1.2 +/- 0.2 SD, 95% CI (1.18, 1.24), and the difference in mean values was 7.5 cc (p < 0.0001). CT performed within 1 day revealed a mean pvol of 47.9 +/- 15.7 cc SD, 95% CI (45.2, 50.5). The mean volumetric ratio of CT to postimplant TRUS pvol was 1.13 +/- 0.36, 95% CI (1.07-1.19). CONCLUSIONS: Whereas mean preimplant step-section TRUS pvol measurements are similar, postimplant TRUS and CT measurements have greater variability that depend on initial pvol. CT-based pvol measurements determined a mean of 10.6 hours after implant were more likely to be identical to those of immediate postimplant TRUS in prostates >33 cc. These data are relevant for establishing accuracy in image-fusion based approaches being investigated for real-time intraoperative PPB dosimetry.

Prostate volume before and after permanent prostate brachytherapy in patients receiving neoadjuvant androgen suppression.

PURPOSE: Limited duration neoadjuvant cytoreductive hormonal therapy (NHT) is used before the definitive radiotherapeutic management of prostate cancer to decrease target volume size and/or to decrease urinary obstructive symptoms. The purpose of this study is to examine the effect of NHT on prostate volume before permanent prostate brachytherapy (PPB) and on prostatic edema after PPB. METHODS AND MATERIALS: Between May 1998 and February 2004, 408 patients underwent PPB at our institution and provided research authorization for the use of their records. Of these, 122 (30%) underwent NHT. Of the 122, 78 (64%) underwent transrectal ultrasound before the start of NHT. Patients undergoing PPB who received NHT were compared with a similar non-NHT group (N = 286). Detailed measurements of prostate volume were performed by transrectal ultrasound before and after NHT, if applicable. In addition, intraoperative preimplantation transrectal ultrasound and post-implantation transrectal ultrasound were also performed. Post-implantation computed tomography was per formed within 1 day of PPB. RESULTS: The mean duration of NHT was 4.0 +/- 1.1 months (range, 1-8 months). The mean prostate volume before NHT was 63.3 +/- 22.8 cc (range, 19-138 cc), and after NHT (before PPB), it was 41.6 +/- 16.4 cc (18-98 cc). The median prostate volume decrease after NHT was 22.7 cc or 34.9%. There was no significant difference in the degree of postimplantation prostate edema, as measured by the postimplantation to preimplantation ratio (1.18 +/- 0.05 [range, 0.8-1.9]) for the NHT group and 1.21 +/- 0.03 (range, 0.8-1.9) for the non-NHT group (P = 0.5). CONCLUSIONS: Prostate volume decreased by approximately one third after 4 months of NHT. NHT did not affect the degree of post-PPB prostatic edema.