ALLIANCE A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer.

Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. Methods: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (+/- 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 296 evaluable patients (148 per arm) will provide statistical power of 90.5% to detect an 17% increase in cCR rate, at a one-sided alpha=0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse effects. Biospecimens including archival tumor tissue, plasma and buffy coat in EDTA tubes, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and has a current accrual of 312. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Discussion: Building off of data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed the current trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. Trial Registration: Clinicaltrials.gov ID: NCT05610163 ; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

Microstructural, Tribology and Corrosion Properties of Optimized Fe3O4-SiC Reinforced Aluminum Matrix Hybrid Nano Filler Composite Fabricated through Powder Metallurgy Method.

Hybrid reinforcement's novel composite (Al-Fe3O4-SiC) via powder metallurgy method was successfully fabricated. In this study, the aim was to define the influence of SiC-Fe3O4 nanoparticles on microstructure, mechanical, tribology, and corrosion properties of the composite. Various researchers confirmed that aluminum matrix composite (AMC) is an excellent multifunctional lightweight material with remarkable properties. However, to improve the wear resistance in high-performance tribological application, hardening and developing corrosion resistance was needed; thus, an optimized hybrid reinforcement of particulates (SiC-Fe3O4) into an aluminum matrix was explored. Based on obtained results, the density and hardness were 2.69 g/cm3, 91 HV for Al-30Fe3O4-20SiC, after the sintering process. Coefficient of friction (COF) was decreased after adding Fe3O4 and SiC hybrid composite in tribology behaviors, and the lowest COF was 0.412 for Al-30Fe3O4-20SiC. The corrosion protection efficiency increased from 88.07%, 90.91%, and 99.83% for Al-30Fe3O4, Al-15Fe3O4-30SiC, and Al-30Fe3O4-20SiC samples, respectively. Hence, the addition of this reinforcement (Al-Fe3O4-SiC) to the composite shows a positive outcome toward corrosion resistance (lower corrosion rate), in order to increase the durability and life span of material during operation. The accomplished results indicated that, by increasing the weight percentage of SiC-Fe3O4, it had improved the mechanical properties, tribology, and corrosion resistance in aluminum matrix. After comparing all samples, we then selected Al-30Fe3O4-20SiC as an optimized composite.

A retrospective comparison of neoadjuvant chemoradiotherapy regimens for locally advanced esophageal cancer.

Preoperative chemoradiotherapy (CRT) with carboplatin/paclitaxel has been shown to increase survival in patients with esophageal cancer, including gastroesophageal junction (GE) junction cancer, over surgery alone; however, there have been no studies comparing the different neoadjuvant CRT regimens. We retrospectively evaluated the long-term results of trimodality therapy for patients with locally advanced esophageal cancer treated on several chemotherapy regimens. Between 1999 and 2014, 215 patients with locally advanced esophageal cancer underwent neoadjuvant CRT followed by surgical resection. The median age was 62 years (range 21-84), 80.5% were men and 86% had adenocarcinoma. The following chemotherapy regimens were administered: cisplatin/5FU (14.9%), cisplatin/irinotecan (35.8%), carboplatin/paclitaxel (35.8%), and other (9.7%). The majority of patients (92.1%) received a radiation dose of 50.4 Gy. Predictors of toxicities and surgical complications were assessed using logistic regression. Overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method and proportional hazards regression was used to model time-to-event outcomes. The median follow-up among surviving patients was 4.1 years (range 0.4,13). The median OS was 3.0 years from time of diagnosis and OS was 36.8% at 5 years. RFS was 34.9% at 5 years. After neoadjuvant CRT, 34.7% of patients achieved a pathologic complete response including 60.7% of squamous cell carcinoma patients and 18.4% of adenocarcinoma patients (P < 0.001) and 66% were downstaged. Of the variables examined, pathologic stage, preoperative baseline cardiac comorbidity, postoperative cardiac or pulmonary complications, and chemotherapy regimen were associated with OS. Using cisplatin and 5FU as the reference regimen, patients treated with carboplatin/paclitaxel had significantly improved OS (HR = 0.47, P = 0.017 after adjusting for surgery type, radiation modality, baseline cardiac comorbidity, and preoperative stage) with 5-year OS rate of 66%. The most common surgical complications were cardiac in 61 patients (28.5%) and pulmonary in 52 patients (24.3%). Cardiac complications were associated with age (OR 1.05, P = 0.007) and cardiac comorbidity (OR 2.6, P = 0.02) and pulmonary complications with female gender (OR 3.98, P < 0.001). Forty-four patients (20.5%) required readmission within 30 days of discharge, and readmission was associated with cardiac comorbidity (OR 2.7, P = 0.017). Three patients died within 30 days of surgery. We observed an association between neoadjuvant carboplatin/paclitaxel and improved overall survival that requires confirmation in a prospective randomized trial.

The Impact of Pathologic Complete Response in Patients with Neoadjuvantly Treated Locally Advanced Rectal Cancer-a Large Single-Center Experience.

Small cohort studies demonstrated better oncologic outcomes for patients with pathologic complete response (PathCR) after neoadjuvant treatment for locally advanced rectal cancer. This study reviews long-term outcomes of a large cohort of clinically stage II/III rectal cancer patients who received neoadjuvant chemoradiation and surgery. This is a retrospective analysis of a single-center cohort, including all clinical stage II/III rectal cancer patients who received neoadjuvant chemoradiation and surgery between 2004 and 2014 (n = 271). Cox regressions were done to assess the influence of PathCR on recurrence-free survival (RFS) and overall survival (OS), adjusting for postoperative chemotherapy, clinical AJCC staging, comorbidity, and age where appropriate. PathCR patients had significantly lower distant recurrence rates (4 vs. 15.8%; P = 0.028) and lower disease-specific mortality rates (0 vs. 8.1%; P = 0.052), compared to patients with residual disease. PathCR was associated with longer RFS (HR, 5.6 [95% CI 1.3-23.1] P = 0.018) and longer OS (HR, 3.4 [1.31-10.0] P = 0.014) compared to having pathological residual disease. This large single-center study shows that patients with PathCR have significant longer RFS and OS than patients with residual disease on pathology after neoadjuvant chemoradiation.

Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer.

BACKGROUND: To determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab and safety and efficacy of this combination in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Patients with Magnetic resonance imaging (MRI) or ultrasound defined T3 or T4 adenocarcinoma of the rectum and without evidence of metastatic disease were enrolled. Patients received infusional 5-FU 225 mg/M2/day continuously, along with bevacizumab 5 mg/kg days 14, 1, 15 and 29. Standard radiotherapy was administered to 50.4 Gy in 28 fractions. Erlotinib started at a dose of 50 mg orally daily and advanced by 50 mg increments in the subsequent cohort. Open total mesorectal excision was carried out 6-9 weeks following the completion of chemoradiation. RESULTS: Thirty-two patients received one of three dose levels of erlotinib. Erlotinib dose level of 100 mg was determined to be the maximally tolerated dose. Thirty-one patients underwent resection of the primary tumor, one refused resection. Twenty-seven patients completed study therapy, all of whom underwent resection. At least one grade 3-4 toxicity occurred in 46.9% of patients. Grade 3-4 diarrhea occurred in 18.8%. The pathologic complete response (pCR) for all patients completing study therapy was 33%. With a median follow-up of 2.9 years, there are no documented local recurrences. Disease-free survival at 3 years is 75.5% (confidence interval: 55.1-87.6%). CONCLUSIONS: Erlotinib added to infusional 5-FU, bevacizumab and radiation in patients with locally advanced rectal cancer is relatively well tolerated and associated with an encouraging pCR.

Toxicity and outcomes after chemoradiation for esophageal cancer in patients age 75 or older.

Randomized trials of chemoradiation for esophageal cancer have included very few patients age > or = 75. In this retrospective study, we describe the outcomes and toxicity of full-dose chemoradiation in elderly patients with esophageal cancer. Patients, age > or = 75, treated with full-dose chemoradiation for esophageal carcinoma from 2002 to 2008 were retrospectively reviewed. Thirty-four patients were identified with a median age of 79.5 (range 75-89). The median Eastern Cooperative Oncology Group performance status was 1 (range 0-3) and the median Adult Comorbidity Evaluation-27 score was 1 (range 0-3). Twenty-eight patients received definitive and six received neoadjuvant chemoradiation. The median radiation dose delivered was 50.4 Gray (range 3.6-68.4 Gray). Platinum-based chemotherapy was used in 79.4% of patients. Fifty percent of the patients completed all planned radiation therapy (RT) and chemotherapy; 85.3% completed RT. Acute toxicity > or = grade 4 occurred in 38.2% of patients, and 70.6% of the patients required hospitalization, emergency department visit, and/or RT break. Median follow-up was 14.5 months among 7 survivors, and median survival was 12.0 months (95% confidence interval [CI]: 9.7 to 24.1 months). The actuarial overall survival at 2 years was 29.7% (95% CI: 16.6 to 52.6%). There were four treatment-related deaths. The median time to any recurrence was 10.4 months. Nineteen patients had a local and/or distant recurrence. In conclusion, elderly patients experienced substantial morbidity from chemoradiation, and long-term survival was low. Future efforts to improve treatment tolerability in the elderly are needed.

Intensity-modulated radiation therapy: emerging cancer treatment technology.

The use of intensity-modulated radiation therapy (IMRT) is rapidly advancing in the field of radiation oncology. Intensity-modulated radiation therapy allows for improved dose conformality, thereby affording the potential to decrease the spectrum of normal tissue toxicities associated with IMRT. Preliminary results with IMRT are quite promising; however, the clinical data is relatively immature and overall patient numbers remain small. High-quality IMRT requires intensive physics support and detailed knowledge of three-dimensional anatomy and patterns of tumour spread. This review focuses on basic principles, and highlights the clinical implementation of IMRT in head and neck and prostate cancer.

Microinjection of human sperm into perivitelline space of hamster eggs: comparison with zona-free hamster egg penetration of human sperm.

Micromanipulation of human sperm and oocyte has been utilized to facilitate fertilization of those patients with male factor due to oligoasthenospermia or those patients with repeated fertilization failure in an in vitro fertilization (IVF) program. Before manipulating human gametes, one needs experience with animal models. Our objective was to perform subzonal insertion of human sperm into hamster eggs and to compare the result with that of sperm penetration assay (SPA) using zona-free hamster eggs. Semen samples were obtained from 15 fertile donors with normal semen analysis and the motile sperm were collected by swim-up procedure. Microinjection was performed by injecting a varied number of sperm into the perivitelline space of 222 hamster eggs pretreated with sucrose solution (0.1 M). The rate of damage of eggs during microinjection was 7.2% (16/222). The rates of penetration in the microinjection group were 5.1% (4/79) for 1-5 sperm injected, 10.9% (11/101) for 6-10 sperm injected, and 11.5% (3/26) for 11-15 sperm injected. The average rate of penetration per egg was 8.7% (18/206), and the polyspermic rate was 11.1% (2/18). Simultaneously SPA was performed in each sample of semen as a positive control, and the average rate of penetration of SPA was 51.4% (108/210). The rate of penetration in the microinjection group was significantly smaller (p < .05) than that in the SPA group. Whether the penetration rate and polyspermic rate in a hamster model reflect similar results in human oocyte requires further investigation. However, the hamster egg provides an ideal model to develop a micromanipulation technique for human beings.