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.

Selective dose escalation of chemoradiotherapy for esophageal cancer: role of treatment intensification.

This ongoing phase II study is designed to assess the outcomes (survival and failure patterns) of therapy for localized esophageal cancer with conventional dose radiation (50.4 Gy) with concurrent continuous infusion 5-fluorouracil (5-FU) and weekly carboplatin/paclitaxel. Patients with less than complete response or partial response received dose escalation of radiation to 59.4 Gy with the same chemotherapy. This report details the results of the first 18 patients treated. From July 2000 to June 2003, we prospectively enrolled 18 patients with T1-4, N0-1, M0-1a esophageal carcinoma to receive paclitaxel 45 mg/m 2 intravenously over 1 hour and carboplatin AUC 2 intravenously over 30 minutes on days 1, 8, 15, 22, 29, and 36. 5-Fluorouracil 225 mg/m2 was delivered as a continuous infusion on days 1 through 38. Radiation therapy was given 1.8 Gy x 5 days/week x 5.5 weeks (50.4 Gy in 28 fractions). After 6 to 8 weeks, patients underwent repeat staging with computed tomography scan, endoscopic ultrasound, and biopsy. Patients with a positive biopsy, or less than partial response by computed tomography and endoscopic ultrasound, received a boost of 9 Gy with the same concurrent chemotherapy. Patients were followed every 4 months with computed tomography/endoscopic ultrasound the first year and every 6 months thereafter. Median follow-up was 19 months. Eleven of 18 patients (61.1%) attained a complete response/partial response; six of 18 (33.3%) received a boost. Overall survival was 30% at 3 years, with a median of 25 months. Patients with less than 10% pretreatment weight loss had an overall survival of 36% with a median of 26 months. In patients with more than 10% pretreatment weight loss, median survival was 14 months with 0% surviving at 2 years. Local/regional control was 67% (no-boost patients [78%]; boost patients [40%]). Progression-free survival was 31% at 3 years, with a median of 14 months. Distant metastasis-free survival was 40% at 3 years, with a median of 27 months. Seventy-nine percent of patients required at least one dose reduction in chemotherapy because of toxicities. Radiation delays ranged from 0 to 62 days, with a median of 7 days. Grade 2/3 acute esophagitis was experienced by 89% and 39% of patients, respectively; 28% of patients developed esophageal strictures requiring dilatations. The combination of continuous-infusion 5-FU and weekly carboplatin/paclitaxel with selective radiation dose escalation yields promising results without surgery and adjuvant chemotherapy. The toxicities of therapy, while manageable, were significant.

Intensity-modulated radiotherapy for head-and-neck cancer in the community setting.

PURPOSE: To review outcomes with intensity-modulated radiation therapy (IMRT) in the community setting for the treatment of nasopharyngeal and oropharyngeal cancer. METHODS AND MATERIALS: Between April 2003 and April 2007, 69 patients with histologically confirmed cancer of the nasopharynx and oropharynx underwent IMRT in our practice. The primary sites included nasopharynx (11), base of tongue (18), and tonsil (40). The disease stage distribution was as follows: 2 Stage I, 11 Stage II, 16 Stage III, and 40 Stage IV. All were treated with a simultaneous integrated boost IMRT technique. The median prescribed doses were 70 Gy to the planning target volume, 59.4 Gy to the high-risk subclinical volume, and 54 Gy to the low-risk subclinical volume. Forty-five patients (65%) received concurrent chemotherapy. Toxicity was graded according to the Radiation Therapy Oncology Group toxicity criteria. Progression-free and overall survival rates were estimated with the Kaplan-Meier product-limit method. RESULTS: Median duration of follow-up was 18 months. The estimated 2-year local control, regional control, distant control, and overall survival rates were 98%, 100%, 98%, and 90%, respectively. The most common acute toxicities were dermatitis (32 Grade 1, 32 Grade 2, 5 Grade 3), mucositis (8 Grade 1, 33 Grade 2, 28 Grade 3), and xerostomia (0 Grade 1, 29 Grade 2, 40 Grade 3). CONCLUSIONS: Intensity-modulated radiotherapy in the community setting can be accomplished safely and effectively. Systematic internal review systems are recommended for quality control until sufficient experience develops.

Neoadjuvant chemoradiotherapy for esophageal cancer using weekly Paclitaxel and Carboplatin plus infusional 5-Fluorouracil.

PURPOSE: To evaluate neoadjuvant therapy with weekly paclitaxel/carboplatin plus 5-fluorouracil (5-FU) with conformal radiotherapy in a phase II trial in resectable esophageal carcinoma. METHODS: Twenty-four patients with T2-4N0-1M0-1a esophageal carcinoma were treated with paclitaxel 45 mg/m(2) intravenously over 1 hour and carboplatin at an area under the concentration-time curve (AUC) of 2 intravenously over 30 minutes on days 1, 8, 15, 22, and 29. 5-Fluorouracil 225 mg/m(2) was delivered as a continuous infusion on days 1-33. Concurrent conformal radiation was delivered to a dose of 45 Gy. Responders underwent surgical resection within 8 weeks of completing chemoradiotherapy. Kaplan-Meier survival analysis and log-rank test of survival dependent on pathologic response were performed. RESULTS: Progressive disease was discovered at surgery in three patients. Of the remaining 21 patients, pathologic complete response (pCR) was demonstrated in 12 (pCR rate of 57%) and partial response (PR) occurred in 9, including 4 with near complete response. Median follow-up in all patients was 23 months. Overall survival among all 24 patients was 48% at 3 years, with a median of 31 months. Disease-free survival was 57% at 3 years, with a median of 38 months. Differences in survival time based on pCR vs. PR showed a trend favoring pCR for disease-free survival (P = .12) but not overall survival (P > .20). Grade 3/4 toxicities included esophagitis in 33% of patients, hypotension in 29%, stomatitis in 25%, neutropenia in 13%, and anemia in 8%. CONCLUSION: This study demonstrates the activity of neoadjuvant paclitaxel, carboplatin, 5-FU, and conformal radiotherapy in the treatment of localized esophageal cancer. Evaluation with a larger number of patients and longer follow-up will be required to definitively assess the long-term efficacy of this regimen.