A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902.

PURPOSE: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). METHODS AND MATERIALS: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. RESULTS: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). CONCLUSIONS: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa

Adjuvant and neoadjuvant therapy for gastric cancer using epirubicin/cisplatin/5-fluorouracil (ECF) and alternative regimens before and after chemoradiation

Chemoradiation is now used more commonly for gastric cancer following publication of the US Intergroup trial results that demonstrate an advantage to adjuvant postoperative chemoradiotherapy. However, there remain concerns regarding the toxicity of this treatment, the optimal chemotherapy regimen and the optimal method of radiotherapy delivery. In this prospective study, we evaluated the toxicity and feasibility of an alternative chemoradiation regimen to that used in the Intergroup trial. A total of 26 patients with adenocarcinoma of the stomach were treated with 3D-conformal radiation therapy to a dose of 45 Gy in 25 fractions with concurrent continuous infusional 5-fluorouracil (5-FU). The majority of patients received epirubicin, cisplatin and 5-FU (ECF) as the systemic component given before and after concurrent chemoradiation. The overall rates of observed grade 3 and 4 toxicities were 38 and 15%, respectively. GIT grade 3 toxicity was observed in 19% of patients, while haematologic grade 3 and 4 toxicities were observed in 23%. Our results suggest that this adjuvant regimen can be delivered safely and with acceptable toxicity. This regimen forms the basis of several new studies being developed for postoperative adjuvant therapy of gastric cancer

Cetuximab Augments Cytotoxicity with Poly (ADP-Ribose) Polymerase Inhibition in Head and Neck Cancer

Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing tumors with defective DNA repair. In this study, we demonstrate that C225 enhances cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. The mechanism of increased susceptibility to C225 and PARPi involves C225-mediated reduction of non-homologous end-joining (NHEJ)- and homologous recombination (HR)-mediated DNA double strand break (DSB) repair, the subsequent persistence of DNA damage, and activation of the intrinsic apoptotic pathway. By generating a DSB repair deficiency, C225 can render head and neck tumor cells susceptible to PARP inhibition. The combination of C225 and the PARPi ABT-888 can thus be an innovative treatment strategy to potentially improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers

Clinical Study Hypofractionated Prostate Radiotherapy with or without Conventionally Fractionated Nodal Irradiation: Clinical Toxicity Observations and Retrospective Daily Dosimetry

properly cited. Purpose. To evaluate toxicity associated with the addition of elective nodal irradiation (ENI) to a hypofractionated regimen for the treatment of prostate cancer. Methods and Materials. Fifty-seven patients received pelvic image-guided IMRT to 50.4 Gy in 28 fractions with a hypofractionated simultaneous boost to the prostate to 70 Gy. Thirty-one patients received prostate-only treatment to 70 Gy in 28 fractions. Results. Median followup was 41.1 months. Early grade ≥2 urinary toxicity rates were 49% (28 of 57) for patients receiving ENI and 58% (18 of 31) for those not (P = 0.61). Early grade ≥2 rectal toxicity rates were 40% (23 of 57) and 23% (7 of 31), respectively (P = 0.09). The addition of ENI resulted in a 21% actuarial rate of late grade ≥2 rectal toxicity at 4 years, compared to 0% for patients treated to the prostate only (P = 0.02). Retrospective daily dosimetry of patients experiencing late rectal toxicity revealed an average increase of 2.67% of the rectal volume receiving 70 Gy compared to the original plan. Conclusions. The addition of ENI resulted in an increased risk of late rectal toxicity. Grade ≥2 late rectal toxicity was associated with worse daily rectal dosimetry compared to the treatment plan

Cetuximab (C225) enhances cytotoxicity with the PARP inhibitor ABT-888 in head and neck cancer cells.

<p>(A) Combination C225 and ABT-888 reduces the viability of UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. Cells were treated with either vehicle or 2.5 µg/mL C225 for 16 hours and subsequently exposed to vehicle or 10 µM ABT-888. Twenty-four hours following ABT-888, cell viability was assayed with the ATPlite system (Perkin Elmer). Shown is the representative data of at least 3 independent experiments of the cell viability following various treatments as measured by relative ATP levels (mean +/− SEM, *p<0.01, **p<0.001 compared to vehicle control). (B–D) Combination C225 and ABT-888 reduces the colony forming ability of (B) UM-SCC1, (C) UM-SCC6, and (D) FaDu head and neck cancer cells. Cells were treated with either vehicle or 2.5 µg/mL C225 for 16 hours. Following the treatment period, cells were seeded for colony formation assays and subjected to various doses of ABT-888. Shown is the mean survival fraction (+/− SEM) from at least 3 independent colony formation assay experiments following treatment (**p<0.001).</p

Cetuximab (C225) increases DNA damage by inhibiting DNA double strand break (DSB) repair in head and neck cancer cells.

<p>(A) C225 increases the number of cells with DSBs as evidenced by γ-H2AX foci, a commonly used marker for DSBs. Shown is the representative data of 3 independent experiments the % of cells (mean +/− SEM) with >10 foci (*p<0.05, **p<0.01 compared to vehicle control). (B) C225 increases γ-H2AX protein levels in treated cells. UM-SCC1, UM-SCC6, and FaDu cells were treated with vehicle, 2.5 µg/mL C225, or 5.0 µg/mL C225 for 16 hours. Following the treatment period, cells were processed for (A) immunofluorescence staining for γ-H2AX foci or (B) western blot analysis for γ-H2AX levels. Shown is the representative Western blot of 3 independent experiments.</p

Cetuximab (C225) attenuates non-homologous end-joining (NHEJ) repair.

<p>C225 attenuates irradiation (IR)-induced DNA-Pk Thr2609 foci, well established markers of non-homologous end joining (NHEJ)-mediated DNA DSB repair in (A) UM-SCC1, (B) UM-SCC6, and (C) FaDu head and neck cancer cells. Cells were treated with vehicle, 2.5 µg/mL C225, or 5.0 µg/mL C225 for 16 hours and subsequently subjected to mock or 4 Gy IR. At the indicated time following IR, cells were processed for immunofluorescence staining for DNA-Pk Thr2609 foci. Shown is the representative data of 3 independent experiments the % of cells (mean +/− SEM) with >10 foci (*p<0.05, **p<0.01 compared to cells not exposed to C225). (D) C225 reduces phospho-Thr2609 DNA-Pk levels in UM-SCC6 head and neck cancer cells. Cells were treated with vehicle or 2.5 µg/mL C225 for 16 hours and subsequently subjected to mock or 4 Gy IR. One hour following IR, cells were processed for Western blot analysis for phospho-Thr2609 DNA Pk levels. Total DNA Pk was also analyzed and tubulin was used as loading control.</p

Cetuximab (C225) attenuates homologous recombination (HR) repair.

<p>C225 attenuates IR-induced Rad51 foci, well characterized markers of homologous recombination (HR)-mediated DNA DSB repair in (A) UM-SCC1, (B) UM-SCC6, and (C) FaDu cells. Cells were treated with vehicle, 2.5 µg/mL C225, or 5.0 µg/mL C225 for 16 hours and subsequently subjected to mock or 4 Gy irradiation (IR). At the indicated times following IR, cells were processed for immunofluorescence staining for Rad51 foci. Shown is the representative data of 3 independent experiments the % of cells (mean +/− SEM) with >10 foci (*p<0.05, **p<0.01 compared to vehicle at each respective time point). The inset in (A) is a representative image of UM-SCC1 cells exhibiting Rad51 foci following IR.</p