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Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity.

ABSTRACT: BACKGROUND AND PURPOSE:Esophageal cancer incidence is increasing and is rarely curable. Hypoxic tumor areas cause resistance to conventional therapies, making them susceptible for treatment with hypoxia-activated prodrugs (HAPs). We investigated in vivo whether the HAP evofosfamide (TH-302) could increase the therapeutic ratio by sensitizing esophageal carcinomas to radiotherapy without increasing normal tissue toxicity. MATERIALS AND METHODS:To assess therapeutic efficacy, growth of xenografted esophageal squamous cell (OE21) or adeno (OE19) carcinomas was monitored after treatment with TH-302 (50?mg/kg, QD5) and irradiation (sham or 10?Gy). Short- and long-term toxicity was assessed in a gut mucosa and lung fibrosis irradiation model, sensitive to acute and late radiation injury respectively. Mice were injected with TH-302 (50?mg/kg, QD5) and the abdominal area (sham, 8 or 10?Gy) or the upper part of the right lung (sham, 20?Gy) was irradiated. Damage to normal tissues was assessed 84 hours later by histology and blood plasma citrulline levels (gut) and for up to 1?year by non-invasive micro CT imaging (lung). RESULTS:The combination treatment of TH-302 with radiotherapy resulted in significant tumor growth delay in OE19 (P?=?0.02) and OE21 (P?=?0.03) carcinomas, compared to radiotherapy only. Irradiation resulted in a dose-dependent decrease of crypt survival (P?

SUBMITTER: Spiegelberg L

PROVIDER: S-EPMC6913516 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity.

Spiegelberg Linda L van Hoof Stefan J SJ Biemans Rianne R Lieuwes Natasja G NG Marcus Damiënne D Niemans Raymon R Theys Jan J Yaromina Ala A Lambin Philippe P Verhaegen Frank F Dubois Ludwig J LJ

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 20190817

<h4>Background and purpose</h4>Esophageal cancer incidence is increasing and is rarely curable. Hypoxic tumor areas cause resistance to conventional therapies, making them susceptible for treatment with hypoxia-activated prodrugs (HAPs). We investigated in vivo whether the HAP evofosfamide (TH-302) could increase the therapeutic ratio by sensitizing esophageal carcinomas to radiotherapy without increasing normal tissue toxicity.<h4>Materials and methods</h4>To assess therapeutic efficacy, growth ...[more]

PMID: 31431383

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Project description:The ectonucleoside triphosphate diphosphohydrolase (CD39)/5' ectonuclotidase (CD73)-dependent purinergic pathway emerges as promising cancer target. Yet, except for own previous work revealing a pathogenic role of CD73 and adenosine in radiation-induced lung fibrosis, the role of purinergic signaling for radiotherapy outcome remained elusive. Here we used C57BL/6 wild-type (WT), CD39 knockout (CD39-/-), and CD73 knockout (CD73-/-) mice and hind-leg tumors of syngeneic murine Lewis lung carcinoma cells (LLC1) to elucidate how host purinergic signaling shapes the growth of LLC1 tumors to a single high-dose irradiation with 10 Gy in vivo. In complementary in vitro experiments, we examined the radiation response of LLC1 cells in combination with exogenously added ATP or adenosine, the proinflammatory and anti-inflammatory arms of purinergic signaling. Finally, we analyzed the impact of genetic loss of CD39 on pathophysiologic lung changes associated with lung fibrosis induced by a single-dose whole-thorax irradiation (WTI) with 15 Gy. Loss of CD73 in the tumor host did neither significantly affect tumor growth nor the radiation response of the CD39/CD73-negative LLC1 tumors. In contrast, LLC1 tumors exhibited a tendency to grow faster in CD39-/- mice compared to WT mice. Even more important, tumors grown in the CD39-deficient background displayed a significantly reduced tumor growth delay upon irradiation when compared to irradiated tumors grown on WT mice. CD39 deficiency caused only subtle differences in the immune compartment of irradiated LLC1 tumors compared to WT mice. Instead, we could associate the tumor growth and radioresistance-promoting effects of host CD39 deficiency to alterations in the tumor endothelial compartment. Importantly, genetic deficiency of CD39 also augmented the expression level of fibrosis-associated osteopontin in irradiated normal lungs and exacerbated radiation-induced lung fibrosis at 25 weeks after irradiation. We conclude that genetic loss of host CD39 alters the tumor microenvironment, particularly the tumor microvasculature, and thereby promotes growth and radioresistance of murine LLC1 tumors. In the normal tissue loss of host, CD39 exacerbates radiation-induced adverse late effects. The suggested beneficial roles of host CD39 on the therapeutic ratio of radiotherapy suggest that therapeutic strategies targeting CD39 in combination with radiotherapy have to be considered with caution.

Project description:Purpose:Dose-volume histogram (DVH) toxicity relationships are poorly defined in men who receive radiation after radical prostatectomy (RP). We evaluated Radiation Therapy Oncology Group (RTOG) study 0534 and institutional intact normal-tissue sparing guidelines, as well as dose to bladder trigone, for ability to minimize late toxicity. Methods and materials:164 men received intensity modulated radiation therapy (RT) to a median prostate bed dose of 66.6?Gy at a median of 22 months after RP. 46% of men were prescribed androgen deprivation therapy and pelvic lymph node irradiation to a median dose of 50.4?Gy. DVH relationships for the rectum, bladder, trigone, and bladder excluding the clinical target volume (bladder-CTV) were analyzed against the Common Terminology Criteria for Adverse Events late grade 2?+?(G2+) gastrointestinal (GI) and genitourinary (GU) toxicity by log-rank test. RTOG 0534 (rectum V65, 40 Gy ?35, 55%, and bladder-CTV V65, 40 ?50, 70%) and intact prostate RT institutional guidelines (rectum V70, 65, 40 ?20, 40, 80% and bladder V70, 65, 40 ?30, 60, 80%, respectively) guidelines were evaluated. Results:With a median follow-up time of of 33 months, the 4-year freedom from G2?+?GI and GU toxicity were both 91%. G2?+?GI (n?=?12) and GU (n?=?15) toxicity included 4% diarrhea (n?=?6), 4% hemorrhage (n?=?6), 1% proctitis (n?=?1), and 4% urinary frequency (n?=?7), 1% obstructive (n?=?2), 2% cystitis (n?=?3), and 3% incontinence (n?=?5), respectively. RTOG 0534 rectum and bladder goals were not achieved in 65% and 41% of cases, while the institutional intact prostate goals were not achieved in 21% and 25% of cases, respectively. Neither dose to the bladder trigone nor any of the proposed normal tissue goals were associated with late toxicity (P?>?.1). In the univariate analysis, age, pelvic RT, RT dose, anticoagulation use, androgen deprivation therapy, time from RP to RT, and tobacco history were not associated with toxicity. Conclusions:More than 90% of men were free from late G2?+?toxicity 4 years after post-RP intensity modulated RT. No tested parameters were associated with late toxicity. In the absence of established normal-tissue DVH guidelines in the postoperative setting, the use of intact guidelines is reasonable.

Project description:PurposeIntensity-modulated radiation therapy (IMRT) has allowed optimization of three-dimensional spatial radiation dose distributions permitting target coverage while reducing normal tissue toxicity. However, radiation-induced normal tissue toxicity is a major contributor to patients' quality of life and often a dose-limiting factor in the definitive treatment of cancer with radiation therapy. We propose the next logical step in the evolution of IMRT using canonical radiobiological principles, optimizing the temporal dimension through which radiation therapy is delivered to further reduce radiation-induced toxicity by increased time for normal tissue recovery. We term this novel treatment planning strategy "temporally feathered radiation therapy" (TFRT).MethodsTemporally feathered radiotherapy plans were generated as a composite of five simulated treatment plans each with altered constraints on particular hypothetical organs at risk (OARs) to be delivered sequentially. For each of these TFRT plans, OARs chosen for feathering receive higher doses while the remaining OARs receive lower doses than the standard fractional dose delivered in a conventional fractionated IMRT plan. Each TFRT plan is delivered a specific weekday, which in effect leads to a higher dose once weekly followed by four lower fractional doses to each temporally feathered OAR. We compared normal tissue toxicity between TFRT and conventional fractionated IMRT plans by using a dynamical mathematical model to describe radiation-induced tissue damage and repair over time.ResultsModel-based simulations of TFRT demonstrated potential for reduced normal tissue toxicity compared to conventionally planned IMRT. The sequencing of high and low fractional doses delivered to OARs by TFRT plans suggested increased normal tissue recovery, and hence less overall radiation-induced toxicity, despite higher total doses delivered to OARs compared to conventional fractionated IMRT plans. The magnitude of toxicity reduction by TFRT planning was found to depend on the corresponding standard fractional dose of IMRT and organ-specific recovery rate of sublethal radiation-induced damage.ConclusionsTFRT is a novel technique for treatment planning and optimization of therapeutic radiotherapy that considers the nonlinear aspects of normal tissue repair to optimize toxicity profiles. Model-based simulations of TFRT to carefully conceptualized clinical cases have demonstrated potential for radiation-induced toxicity reduction in a previously described dynamical model of normal tissue complication probability (NTCP).

Project description:: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH-, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH- decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH- radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH-, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH- in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH- during the radiotherapy "beam on." Specifically, treatment with P-AscH- increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH--treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH- in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH- efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.

Project description:PurposeX-Ray Repair Cross Complementing 1 (XRCC1) functioning in the base excision repair pathway plays an important role in the repair of DNA single-strand breaks caused by ionizing radiation. The relationship between XRCC1 polymorphisms and the risk of radiation-induced side effects on normal tissues remains controversial. Therefore, we performed a comprehensive meta-analysis to elucidate these associations.Materials and methodsA systematic literature search was carried out in PubMed, Medline (Ovid), Embase, Web of Science, Cochrane database, and the references of relevant studies. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the strength of the association.ResultsA total of 40 studies including 6,682 patients were eventually identified in this meta-analysis. Pooled results suggested that rs25487 Arg399Gln polymorphism significantly increased the risk of acute radiation-induced side effects (OR=1.29, 95% CI: 1.10-1.52, P=0.002), especially acute mucositis (OR=1.91, 95% CI: 1.17-3.11, P=0.01) and acute gastrointestinal and genitourinary toxicity (OR=1.49, 95% CI: 1.04-2.11, P=0.03). Furthermore, patients who received head and neck irradiation with rs25487 Arg399Gln polymorphism were more likely to experience radiotherapy (RT)-induced side effects (OR=1.46, 95% CI: 1.12-1.90, P=0.005). However, no statistically significant correlations were identified between rs25487 polymorphism and any late side effects and other irradiation areas. Likewise, no significant associations were detected between rs25489, rs1799782, or rs3213245 polymorphism and RT-induced toxicity.ConclusionOur meta-analysis demonstrated that XRCC1 rs25487 Arg399Gln polymorphism had a significant predictive value and might predict a risk of severely acute RT-induced adverse effects, especially in acute mucositis and acute gastrointestinal and genitourinary toxicity, or in patients with head and neck irradiation. However, large-scale and well-designed studies are required to further evaluate the predictive value of XRCC1 variations on radiation-induced side effects in order to identify radiosensitive patients and predict radiotoxicity.

Dataset Information

Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity.

Publications

Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity.

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