Concurrent Radiation Therapy In Patients Research Articles

Nivolumab and Ipilimumab Combined with Definitive Radiation Therapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: In-field Toxicity Analysis of a Phase I Clinical Trial

Cisplatin added to radiation therapy (RT) for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is associated with a modest improvement in survival at the cost of increased toxicity, highlighting the need for newer agents. Immune checkpoint inhibitors (ICI) have a favorable safety profile and are the standard of care in recurrent/metastatic SCCHN, but their role in the definitive setting with RT remains to be determined. We conducted a single institution clinical trial assessing the safety of combined nivolumab (Nivo), a PD-1 inhibitor, and ipilimumab (Ipi), a CTLA-4 inhibitor, with concurrent RT in patients with high risk LA-SCCHN. Newly diagnosed, chemotherapy eligible patients (pts) with stage IVA-IVB p16(-) SCC of the oral cavity, oropharynx, larynx, and hypopharynx, or T4, N2c, or N3 p16(+) SCC of the oropharynx (AJCC 7th edition) were enrolled. Nivo (3 mg/kg Q2 weeks IV x17 doses) and Ipi (1 mg/kg Q6 weeks IV x6 doses) were administered 2 weeks prior to the start of RT. RT (70 Gy in 2 Gy daily fractions) was delivered to the primary tumor using VMAT and daily cone-beam CT IGRT. The primary objective was safety of combined ICI and RT. Between July 2017 and July 2019, 24 pts were enrolled with a median follow-up of 15 months (range 7-31); median age 60 (range 48-77); 20 male; 16 oropharynx (14 HPV+), 6 larynx, and 2 hypopharynx. All pts completed RT with no treatment delays. Seventeen out of twenty-four pts (71%) experienced grade 3 acute in-field adverse events (AE) consisting of mucositis (9), dysphagia (6), dermatitis (5), odynophagia (4), and dysphonia (1) during concurrent ICI-RT; there were no grade 4/5 AEs during ICI-RT. Five pts (22%) developed soft tissue ulcers (STU) at the primary tumor site during the ICI maintenance phase, one of which was not treated and led to a fatal carotid rupture. All STUs developed at a median of 91 (range 50-107) days post RT and were negative for viable tumor. Four primary site STUs were managed with either hyperbaric oxygen (HBO) (2), lingual artery embolization (1), or surgical debridement (1). One pt treated with HBO healed after 189 days while the pt who underwent debridement healed after 285 days. Two additional pts developed areas of necrosis at adjacent sites not involved by tumor, underwent surgical debridement, and healed after an average of 18.5 days. Two other pts experienced osteoradionecrosis (ORN) at sites of prior teeth extractions and were treated with HBO. Two pts experienced persistent inflammation without ulceration (PI). Six out of eleven pts (55%) with STU, necrosis, ORN, or PI discontinued maintenance ICI. Locoregional PFS is 100%. Combined PD-1 and CTLA-4 blockade with concurrent RT is associated with excellent locoregional control in high risk LA-SCCHN, albeit at the cost of in-field complications. Patients treated with such an approach should be closely monitored for soft tissue ulceration.

Phase I Trial of MK-3475 and Concurrent Radiation for the Elimination of Extensive-Stage Small Cell Lung Cancer

We present toxicity and efficacy findings from a phase I trial that combines MK-3475 with concurrent radiation therapy in patients with extensive stage small-cell lung cancer (ES-SCLC). Eligible patients with ES-SCLC after completion of standard chemotherapy were enrolled in a nonrandomized fashion to receive consolidation radiation therapy. Maximum tolerated dose (MTD) of MK-3475 was determined with a 3 + 3 dose escalation design, starting at 100 mg and either decreased to 70 mg or increased to 150 mg, then 200 mg. MK-3475 q3w) for up to 16 cycles. Radiation therapy was delivered to the chest 45 Gy in 15 fractions (3 Gy /fraction given daily. Toxicity was scored per the Common Terminology Criteria for Adverse Events version 4.0 and was evaluated by radiation and medical oncologists. Disease response was scored per immunotherapy related response criteria by a radiologist. Kaplan-Meier method and log-rank test were used to assess progression-free survival (PFS) and overall survival (OS). Thirty-five patients were enrolled; of these, one was not financially cleared, one failed screening, another was non-compliant and two were removed due to toxicity. In all, 25 patients completed radiation therapy. MK-3475 was tolerated and dose was escalated up to MTD of 200 mg. The median number of MK-3475 cycles was 4 (range 1-16). One patient completed all 16 cycles of MK-3475. Four patients received prophylactic cranial irradiation (PCI). To date, 22 patients were taken off the trial; 2 due to toxicity, 1 due to non-adherence, and 19 due to disease progression. Median follow-up was 7.2 months (range 1.1-12.7 months). No treatment related grade 4 toxicities were observed; there were three grade 3 events in 1 (3%) patient possibly related to treatment (paresthesia and myasthenia) and one grade 3 event probably or definitely related to treatment (rash). None of these adverse events were in the field of radiation. Of the 24 patients with evaluable imaging data, 1 (4%) had CR, 1 (4%) had PR, 8 (33%) had SD, and 13 (54%) had PD as best responses. Median follow-up was 6 months (range 1-12 months) at the time this abstract was written. Median PFS and OS were 4.6 and 8.4 months, respectively. These data suggest that the addition of concurrent and radiation therapy have acceptable toxicity profiles for ES-SCLC. Our short-term outcomes are comparable to historic controls using only consolidative RT in ES-SCLC. Further follow-up is needed to assess long-term outcomes.

Comparison of the short-term efficacy between docetaxel plus carboplatin and 5-fluorouracil plus carboplatin in locoregionally advanced nasopharyngeal carcinoma.

ObjectivePlatinum-based chemotherapy in combination with radiotherapy is a standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma (NPC). This study aimed to investigate the long-term efficacy and tolerability of inductive chemotherapy with docetaxel plus carboplatin (TC) or 5-fluorouracil plus carboplatin (FC) followed by concurrent radiation therapy in patients with NPC.MethodsPatients (N=88) were randomized to receive TC or FC as inductive therapy followed by concurrent radiotherapy (60–70 Gy) with two cycles of carboplatin (area under the curve =5 mg·h/L). Patients were followed up for 8 years. Primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), toxicity, tumor response, distant metastasis-free survival, and local recurrence-free survival.ResultsAt the end of the follow-up period, 31 patients died, 32 had disease progression, eleven had cancer recurrence, and 25 had distant metastasis. Overall, there was no difference between treatment groups with regard to response or survival. We found that following induction and concurrent chemoradiotherapy, the majority of patients showed a complete response (~96%–98% for induction therapy and 82%–84% for comprehensive therapy) to both therapies. PFS and OS were also similar between groups. The rate of PFS was 63.6% for both FC and TC and that of OS was 65.9% and 63.5%, respectively. The overall incidence of grade 3–4 adverse events in the TC group (20.5%) was higher than in the FC group (10.7%). Neutropenia and leukopenia were the most common grade 3–4 adverse events in the TC group, and mucositis was the most common in the FC group.ConclusionThese data indicate that TC and FC therapies have similar efficacy in treating locally advanced NPC and both are well tolerated.

A Multicenter Phase II Trial of S-1 With Concurrent Radiation Therapy for Locally Advanced Pancreatic Cancer

The aim of this trial was to evaluate the efficacy and toxicity of S-1 and concurrent radiation therapy for locally advanced pancreatic cancer (PC). Locally advanced PC patients with histologically or cytologically confirmed adenocarcinoma or adenosquamous carcinoma, who had no previous therapy were enrolled. Radiation therapy was delivered through 3 or more fields at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. S-1 was administered orally at a dose of 80 mg/m2 twice daily on the day of irradiation during radiation therapy. After a 2- to 8-week break, patients received a maintenance dose of S-1 (80 mg/m2/day for 28 consecutive days, followed by a 14-day rest period) was then administered until the appearance of disease progression or unacceptable toxicity. The primary efficacy endpoint was survival, and the secondary efficacy endpoints were progression-free survival, response rate, and serum carbohydrate antigen 19-9 (CA19-9) response; the safety endpoint was toxicity. Of the 60 evaluable patients, 16 patients achieved a partial response (27%; 95% confidence interval [CI], 16%-40%). The median progression-free survival period, overall survival period, and 1-year survival rate of the evaluable patients were 9.7 months (95% CI, 6.9-11.6 months), 16.2 months (95% CI, 13.5-21.3 months), and 72% (95%CI, 59%-82%), respectively. Of the 42 patients with a pretreatment serum CA19-9 level of ≥100 U/ml, 34 (81%) patients showed a decrease of greater than 50%. Leukopenia (6 patients, 10%) and anorexia (4 patients, 7%) were the major grade 3-4 toxicities with chemoradiation therapy. The effect of S-1 with concurrent radiation therapy in patients with locally advanced PC was found to be very favorable, with only mild toxicity.

Phase I Trial of Gemcitabine Dose Escalation with Concurrent Radiotherapy for Patients with Locally Advanced Pancreatic Cancer

Aim: The safety and efficacy, and the dose-limiting toxicity (DLT) of the chemotherapeutic agent gemcitabine administered in conjunction with radiotherapy in patients with locally advanced pancreatic cancer are not yet established. Here, we evaluated the safety and efficacy, DLT, and maximum tolerated dose of gemcitabine with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Tumor response and time to progression were also assessed. Patients and Methods: Patients with previously untreated pancreatic cancer (n = 12) received gemcitabine intravenously on days 1, 8, and 15. Concurrent radiation therapy was initiated on day 1 (40 Gy in 2 Gy/day × 20 fractions, days 1–5, 8–12, 15–19, 22–26). Patients received limited-field irradiation with three-dimensional radiotherapy. Dose escalation included dose levels 1–3 (gemcitabine 400, 600, and 800 mg/m2). Results: No patient developed DLT in this study. Of the 12 patients, there were 11 sustained responses, 0 partial responses, and 1 progressive disease. Two patients with a sustained response underwent surgery after re-evaluation. The median progression-free survival was 8 months, not including the patients that underwent surgery. Conclusion: Weekly gemcitabine at a dose of 800 mg/m2 with concurrent radiation therapy in patients with locally advanced pancreatic cancer was well tolerated.

Full-Dose Gemcitabine With Concurrent Radiation Therapy in Patients With Nonmetastatic Pancreatic Cancer: A Multicenter Phase II Trial

Gemcitabine is effective in the treatment of pancreatic cancer and is a potent radiosensitizer. This study assessed safety and efficacy of full-dose gemcitabine administered before and during concurrent three-dimensional conformal radiation (3D-CRT) in patients with nonmetastatic pancreatic cancer. During cycles 1 and 3, patients received gemcitabine at 1,000 mg/m(2) on days 1 and 8 of each 21-day cycle. Cycle 2 included the same dose of gemcitabine on days 1, 8, and 15 of a 28-day cycle with concurrent 3D-CRT at 36 Gy, administered in 15 fractions of 2.4 Gy, over 3 weeks. Resectable patients underwent surgery 4 to 6 weeks after treatment. The primary objective was evaluation of toxicity. Tumor response, CA 19-9, and 1-year survival were also assessed. Forty-one patients enrolled at six institutions between April 2002 and October 2003. Among the 39 treated patients, the most common toxicities were grade 3 neutropenia (12.8%), grade 3 nausea (10.3%), and grade 3 vomiting (10.3%). The response rate was 5.1% and disease control rate was 84.6%. Mean post-treatment CA 19-9 levels (228 +/- 347 U/mL) were significantly (P = .006) reduced compared with pretreatment levels (1,241 +/- 2,124 U/mL). Thirteen (81%) of 16 patients initially judged resectable, three (33%) of nine borderline-resectable patients, and one (7%) of 14 unresectable patients underwent resection after therapy. One-year survival rates were 73% for all patients, 94% for resectable patients, 76% for borderline-resectable patients, and 47% for unresectable patients. Full-dose gemcitabine with concurrent radiotherapy was well tolerated and active. Evaluation of this regimen in a larger, randomized trial for patients with resectable or borderline-resectable disease may be warranted.

A phase I study of oxaliplatin, full-dose gemcitabine and concurrent radiation therapy in patients with pancreatic cancer

4107 Background: We previously demonstrated safety and efficacy of full dose gemcitabine (GEM) and radiation therapy (RT) in patients (pts) with pancreatic cancer (PC). Our preclinical studies have shown that GEM with oxaliplatin (OX) preserves radiosensitization with synergistic cytotoxicity. To enhance local and systemic treatment effects, we initiated a study of OX and GEM with concurrent RT. Methods: Pts with untreated PC received up to 4 cycles of GEM day 1, 8, 15 and OX days 1, 15 repeated at 28 day intervals. RT (27 Gy in 1.8 Gy fractions to gross tumor volume with 1 cm margin) was given during cycle 1 and repeated in cycle 4. Surgery occurred after cycle 2 in resectable pts. Dose escalation was guided using time-to-event continuous reassessment method (TITE-CRM). Dose levels 1–4 GEM 1 g/m2 IV over 30 min and OX 40, 55, 70, 85 mg/m2 IV over 90 min; dose level 5, 6 OX dose remained 85 mg/m2 but infusion time for GEM 1 g/m2 was increased to 65, 100 min, respectively. Trial objective is to determine dose level associated with DLT thru cycle 2 in ≤ 20% of pts; planned accrual is 40 pts evaluable for DLT. Results: 40 pts have been enrolled (median age 63, men/women 26/14) with resectable (10), unresectable (27), and metastatic (3) PC. 29 pts have completed 2 cycles and 11 pts 4 cycles. After 2 cycles CA19–9 decreased > 50% in 14 of 24 evaluable pts (58%). Six of 8 explored pts underwent margin negative resection with 1 path CR and 2 with small residual microscopic foci only. Per RECIST, CT response of the primary lesion after 2 cycles included 3 PR, 23 SD and 1 PD. Two additional PR were seen after cycle 4. Thirty pts are presently evaluable for DLT; 7 pts have suffered DLT including grade 4 platelets (4), decline in PS (2), GI bleed (1) and grade 3 weight loss (1). Current estimated probability of DLT is 21% (95% CI 11%,34%) for dose level 3 and 24% (95% CI 13%,37%) for dose level 4. Conclusions: The addition of OX 70–85 mg/m2 days 1, 15 to full dose GEM based RT is tolerable and efficacious. A neoadjuvant phase II study in resectable PC using the MTD defined in this phase I study is planned. Supported by Sanofi-Aventis. [Table: see text]

Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers

To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated. Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography. Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1-2 micromol/kg occurred between 4 and 6 h after MGd infusion. Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.

Phase II trial of erlotinib with temozolomide and concurrent radiation therapy in patients with newly-diagnosed glioblastoma multiforme

1567 Background: Approximately 40 - 50% of GBM tumors overexpress EGFR, which activates tyrosine kinase to promote GBM cell infiltration in vitro. Radioresistance of some GBMs has been correlated with EGFR overexpression. Erlotinib is a specific and potent EGFR tyrosine kinase inhibitor (TKI) with activity against refractory GBM. Furthermore, the occurrence of erlotinib-induced rash of ≥ grade 2 has been correlated with improved survival in non-small cell lung cancer. A phase 2 trial of erlotinib with concurrent RT-temozolomide (RT-tmz) was therefore initiated with pharmacodynamic dosing of erlotinib. Methods: Eligible patients (pts) have newly diagnosed GBM; age ≥ 18; KPS ≥ 60; no cytochrome P-450 enzyme-inducing anticonvulsants; no prior temozolomide (tmz), TKI or cranial RT. Pts receive RT 60 Gy in 30 fractions with concurrent tmz (75 mg/m2/day × 7 days/week). Four weeks after RT-tmz pts receive tmz 150 mg/m2/day × 5 days, every 28 days for 12 cycles. Pts receive erlotinib daily from day 1 of RT until disease progression. Erlotinib dosing starts at 50mg/day with escalation every 2 weeks by 50mg/day until the occurrence of grade 2 rash or 150 mg/day. All tumors have FISH assay for EGFR amplification. Results: To date 11 patients have enrolled with a median follow up of 11 weeks (range 9–22); 2 did not start therapy and 4 remain on study. The median age is 47 (18–65); KPS 90 (70–100). Two pts had gross total resection. Seven pts are EGFR negative. Maximum dose of erlotinib reached before grade (G) 2 rash: 50 mg/d (1 pt), 100 mg/d (1 pt), and 150 mg/day (2pts). Three pts reached 150 with G0 or 1 rash and 2 pts are still on escalating doses of erlotinib. Of 9 pts evaluable for response, best response has been stable disease (3 pts) of 10.5, 7 and 3.5+ months duration; progression (3), and too early (3). No pt has had G4 toxicity. G3 toxicity has included neutropenia (1 pt) and lymphopenia (2). Additional events unrelated to therapy have included wound infection, spontaneous pneumothorax, and rectus sheath hematoma. Conclusions: The combination of erlotinib with RT-tmz is feasible and overall has been well tolerated. Dose escalation to a pharmacodynamic endpoint is feasible in GBM. Accrual continues. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech

Comparison of Temporary and Permanent Stent Placement with Concurrent Radiation Therapy in Patients with Esophageal Carcinoma

To assess the clinical effectiveness of temporary metallic stent placement with concurrent radiation therapy in patients with esophageal carcinoma by comparing it with permanent stent placement with concurrent radiation therapy. Covered retrievable expandable nitinol stents were placed in 47 patients with esophageal carcinoma 1 week before starting radiation therapy; the stents were electively removed 4 weeks after placement in 24 patients (group A), while not electively removed in the other 23 patients (group B). In cases of complications, the stents were also removed from patients in groups A and B. The dysphagia score, complications (severe pain, granulation tissue formation, stent migration, esophagorespiratory fistula, and hematemesis), tumor overgrowth/regrowth, reintervention rates, and dysphagia-progression-free and overall survival rates were compared in the two groups. Stent placement or removal was technically successful and well tolerated in all patients. The dysphagia score was significantly improved in both groups after stent placement (P < .01). Each of the stent-related complications was less in group A than in group B but there was no significant difference. However, the total number of patients with one or more than one complications and who needed related reinterventions was significantly less in group A than in group B (P = .042 and .030, respectively). Tumor overgrowth/regrowth and the total number of patients who required related reinterventions was not significantly different (P = 1.00 and .517, respectively). Dysphagia-progression-free and overall survival rates were significantly longer in group A than in group B (P = .005 and .001, respectively). Temporary placement of a covered retrievable expandable metallic stent with concurrent radiation therapy for patients with esophageal carcinoma is beneficial for reducing complications and related reinterventions and for increasing resultant survival rates compared with permanent esophageal stent placement.

Bortezomib with concurrent radiation therapy in head and neck squamous cell carcinoma

Problem: Head and neck squamous cell carcinomas (HNSCCs) exhibit constitutive activation of nuclear factor-kappa B (NF-kB), a transcription factor which regulates genes important in tumor progression. Bortezomib, a potent proteasome inhibitor shown to inhibit NF-kB activation in vitro, has not been studied in HNSCC patients. Methods: We initiated a phase I trial of bortezomib with concurrent radiation therapy in patients with recurrent/metastatic HNSCC. Patient biopsy specimens were stained for apoptotic cells and serum cytokines were measured pre- and posttreatment. To investigate the possible basis for differences in clinical response, we conducted real-time RT-PCR to examine gene expression in HNSCC cell lines treated with bortezomib. Results: Two of the 6 patients treated with 0.6 mg/m2/dose bortezomib with radiation at 1.8 Gy daily fractions to 60–72 Gy showed tumor reductions of more than 50%. Significant apoptosis was demonstrated by TUNEL in 1 patient who had a 50% tumor reduction by 3 weeks, whereas less apoptosis was observed in another patient clinically less responsive. A second patient, who experienced a 90% tumor reduction, had a greater than 90% decrease in levels of NF-kB-dependent serum cytokines IL-6, IL-8, VEGF, GRO-1. Patients not demonstrating marked tumor reductions did not show a significant decrease. In vitro studies revealed significant cell death and suppressed cyclin D1 and IAP-1 gene expression in UMSCC-11A and -11B lines treated with 10-7M bortezomib. Conclusion: In patients with clinically responsive tumors, bortezomib induces apoptotic effects and reductions in NF-kB-regulated cytokines in serum as early as 24 hours posttreatment. Suppression of IAP-1 and cyclin D1 gene expression in HNSCC cells may contribute to the antiproliferative and apoptotic effects of bortezomib. Significance: Further investigation of antiapoptotic and cell cycle genes in patient tissue with real-time RT-PCR is in progress to study the molecular mechanism of differential sensitivity of tumors in HNSCC patients to bortezomib. Understanding this mechanism may significantly improve the efficacy of this drug in HNSCC patients. Support: Intramural Project DC-00016 and NIH Clinical Research Training Program

896 Poster Encouraging survival without increased toxicity in a phase II trial of induction chemotherapy followed by RSR 13 and concurrent radiation therapy in patients with locally advanced unresectable non-small cell lung cancer

896 Poster Encouraging survival without increased toxicity in a phase II trial of induction chemotherapy followed by RSR 13 and concurrent radiation therapy in patients with locally advanced unresectable non-small cell lung cancer