P16INK4a Status and Response to Induction Low-Dose Fractionated Radiation in Advanced Head and Neck Cancer.
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ABSTRACT:
SUBMITTER: Silver NL
PROVIDER: S-EPMC5555599 | biostudies-other | 2015 Sep
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Phase 3 studies suggest that induction chemotherapy (ICT) of cisplatin and 5-fluorouracil plus docetaxel (TPF) is effective but toxic for patients with squamous-cell carcinoma of the head and neck (SCCHN). Dose-dense chemotherapy may yield favorable outcomes compared with standard-dose chemotherapy, yet the optimal induction regimen remains undefined. We assessed the efficacy and tolerability of biweekly dose-dense TPF ICT in patients with SCCHN. METHODS:In this prospective phase II study, We enrolled patients with stage III/IV (AJCC 7th edition) unresectable squamous cell carcinoma of head and neck cancer. Patients received dose-dense TPF (ddTPF) with cisplatin and docetaxel 50?mg/m2 on day 1, leucovorin 250?mg/m2 on day1, followed by 48-h continuous infusion of 2500?mg/m2 of 5-fluorouracil on day 1 and 2, every 2?weeks for 6?cycles followed by radiotherapy. The primary endpoint was the response rate (RR) after ICT. RESULTS:Fifty-eight patients were enrolled from June 2014 to September 2015. Overall RR after ICT was 89.6% [complete response (CR), 31%; partial response (PR), 58.6%]. Grade 3/4 neutropenia, mucositis, and diarrhea incidences were 25.9, 1.7, and 1.7%, respectively. 94.8% of patients completed all treatment courses of ICT without dose reduction. The 3-year overall survival (OS) was 54.3% (95%CI: 39.7 to 66.8%) and progression-free survival (PFS) was 34.3% (95%CI: 22.0 to 46.9%). Multivariate analysis showed that CR after ICT is an independent prognostic factor for OS and PFS. CONCLUSIONS:Six cycles of ddTPF is an active, well-tolerated induction regimen for patients with SCCHN. The presence of CR after ICT predicted long-term survival. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04397341 , May 21, 2020, retrospectively registered.
| S-EPMC7465725 | biostudies-literature
Project description:PurposeLow-dose fractionated radiation therapy (LDFRT) induces effective cell killing through hyperradiation sensitivity and potentiates effects of chemotherapy. We report our second investigation of LDFRT as a potentiator of the chemotherapeutic effect of induction carboplatin and paclitaxel in locally advanced squamous cell cancer of the head and neck (SCCHN).Experimental designTwo cycles of induction therapy were given every 21 days: paclitaxel (75 mg/m2) on days 1, 8, and 15; carboplatin (area under the curve 6) day 1; and LDFRT 50 cGy fractions (2 each on days 1, 2, 8, and 15). Objectives included primary site complete response rate; secondary included overall survival, progression-free survival (PFS), disease-specific survival, and toxicity.ResultsA total of 24 evaluable patients were enrolled. Primary sites included oropharynx (62.5%), larynx (20.8%), oral cavity (8.3%), and hypopharynx (8.3%). Grade 3/4 toxicities included neutropenia (20%), leukopenia (32%), dehydration/hypotension (8%), anemia (4%), infection (4%), pulmonary/allergic rhinitis (4%), and diarrhea (4%). Primary site response rate was 23/24 (95.8%): 15/24 (62.5%) complete response, 8/24 (33.3%) partial response, and 1/24 (4.2%) stable disease. With median follow-up of 7.75 years, 9-year rates for overall survival were 49.4% (95% confidence interval [CI], 30.5-79.9), PFS was 72.2% (CI, 55.3-94.3), and disease-specific survival was 65.4% (44.3-96.4).ConclusionChemopotentiating LDFRT combined with paclitaxel and carboplatin is effective in SCCHN and provided an excellent median overall survival of 107.2 months, with median PFS not yet reached in this locally advanced SCCHN cohort. This compares favorably to prior investigations and caused fewer grade 3 and 4 toxicities than more intensive, 3-drug induction regimens. This trial demonstrates the innovative use of LDFRT as a potentiator of chemotherapy.
| S-EPMC5514161 | biostudies-literature
Project description:BackgroundCompare adjuvant radiation dose trends and outcomes in head and neck squamous cell carcinoma (HNSCC).MethodsNonmetastatic HNSCCs treated between 2004 and 2014 with primary site surgery, lymph node dissection, and adjuvant radiation were identified in the National Cancer Database. Standard dose radiation (SD-RT) was defined as an equivalent dose in 2 Gy (EQD2) ≥56.64 and ≤60 Gy and high-dose radiation (HD-RT) as an EQD2 >60 and <70 Gy.ResultsHD-RT was given to 46% of the 15 836 HNSCC patients managed with adjuvant radiation. When adjusted for poor prognostic factors, HD-RT was associated with increased mortality (HR1.09; 95%CI 1.02-1.16). In nonoropharynx or human papillomavirus-negative oropharynx primary that had positive margins, ≥5 positive lymph nodes, and/or extranodal extension, HD-RT was still not associated with improved survival (HR 1.01, 95% CI 0.91-1.12).ConclusionsThere was no survival benefit from postoperative dose escalation above EQD2 60 Gy even in a high-risk cohort.
| S-EPMC7830814 | biostudies-literature
Project description:Transmission beam (TB) proton therapy (PT) uses single, high energy beams with Bragg-peak behind the target, sharp penumbras and simplified planning/delivery. TB facilitates ultra-high dose-rates (UHDRs, e.g., ≥40 Gy/s), which is a requirement for the FLASH-effect. We investigated (1) plan quality for conventionally-fractionated head-and-neck cancer treatment using spot-scanning proton TBs, intensity-modulated PT (IMPT) and photon volumetric-modulated arc therapy (VMAT); (2) UHDR-metrics. VMAT, 3-field IMPT and 10-field TB-plans, delivering 70/54.25 Gy in 35 fractions to boost/elective volumes, were compared (n = 10 patients). To increase spot peak dose-rates (SPDRs), TB-plans were split into three subplans, with varying spot monitor units and different gantry currents. Average TB-plan organs-at-risk (OAR) sparing was comparable to IMPT: mean oral cavity/body dose were 4.1/2.5 Gy higher (9.3/2.0 Gy lower than VMAT); most other OAR mean doses differed by <2 Gy. Average percentage of dose delivered at UHDRs was 46%/12% for split/non-split TB-plans and mean dose-averaged dose-rate 46/21 Gy/s. Average total beam-on irradiation time was 1.9/3.8 s for split/non-split plans and overall time including scanning 8.9/7.6 s. Conventionally-fractionated proton TB-plans achieved comparable OAR-sparing to IMPT and better than VMAT, with total beam-on irradiation times <10s. If a FLASH-effect can be demonstrated at conventional dose/fraction, this would further improve plan quality and TB-protons would be a suitable delivery system.
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Project description:Preclinical evidence suggests that high-dose hypofractionated ionizing radiation (IR) can enhance anti-tumor immunity and result in significant tumor control when combined with immune checkpoint blockade (ICB). However, low-dose daily fractioned IR used for many tumor types including head and neck squamous cell carcinoma results in lymphopenia and may be immunosuppressive. We compared immune correlates, primary tumor and abscopal tumor control rates following the addition of PD-1 mAb to either high-dose hypofractioned (8Gyx2) or low-dose daily fractionated (2Gyx10) IR in syngeneic models of cancer. When compared to 2Gyx10 IR, 8Gyx2 IR preserved peripheral and tumor-infiltrating CD8+ T-lymphocyte accumulation and activation and reduced peripheral and tumor gMDSC accumulation. Regulatory T-lymphocytes were largely unaltered. Type I and I IFN levels and expression of IFN-responsive MHC class I and PD-L1 was enhanced in tumors treated with 8Gyx2 compared to 2Gyx10 IR. Functionally, tumor-specific CD8+ T-lymphocyte IFN responses within tumor draining lymph nodes were enhanced following 8Gyx2 IR but suppressed following 2Gyx10 IR. When combined with PD-1 mAb, reversal of adaptive immune resistance and subsequent enhancement of CD8+ cell dependent primary and abscopal tumor control was observed following 8Gyx2 but not 2Gyx10 IR. These data strongly support that compared to daily fractionated low-dose IR, high-dose hypofractionated IR preserves or enhances anti-tumor immunity and, when combined with PD-1 mAb to reverse adaptive immune resistance, promotes anti-tumor immunity to control primary and distant tumors. These data critically inform the rational design of trials combining IR and ICB.
| S-EPMC5790397 | biostudies-literature
Project description:A systemic immune related response (SIME) of radiotherapy has been occasionally observed on metastatic tumors, but the clinical outcomes remain poor. Novel treatment approaches are therefore needed to improve SIME ratio. We used a combination of hypo-fractionated radiation therapy (H-RT) with low-dose total body irradiation (L-TBI) in a syngeneic mouse model of breast and colon carcinoma. The combination therapy of H-RT and L-TBI potentially enhanced SIME by infiltration of CD8+ T cell and altering the immunosuppressive microenvironment in non-irradiated subcutaneous tumor lesions. The frequency of IFN-γ, as a tumor-specific CD8+ T cells producing, significantly inhibited the secondary tumor growth of breast and colon. Our findings suggest that L-TBI could serve as a potential therapeutic agent for metastatic breast and colon cancer and, together with H-RT, their therapeutic potential is enhanced significantly.
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Project description:Patients with head and neck squamous cell carcinoma (HNC) related to human papillomavirus (HPV) represent a growing and distinct patient cohort with unique molecular and epidemiologic characteristics. These patients have markedly improved survival outcomes compared to those with traditional HNC, leading some to advocate for treatment dose reduction. In this article, we review ongoing clinical trials investigating several ways to reduce therapeutic intensity for patients with HPV-positive HNC, discuss the risks and benefits associated with these trials, and summarize the data underlying the advancement of dose reduction trials for patients with HPV-positive HNC.
| S-EPMC3986346 | biostudies-literature
Project description:Radiation treatment of head and neck cancer frequently causes severe collateral damage to normal tissues including mouth mucosa, salivary glands and skin. This toxicity limits the radiation dose that can be delivered and affects the patient's quality of life. Previous studies in mice and nonhuman primates showed that entolimod, a toll-like receptor 5 (TLR5) agonist derived from bacterial flagellin, effectively reduced radiation damage to hematopoietic and gastrointestinal tissues in both total-body and local irradiation scenarios, with no protection of tumors. Here, using a mouse model, we analyzed the efficacy of entolimod administered before or after irradiation in reducing damage to normal tissues. Animals received local fractionated radiation to the head and neck area, thus modeling radiotherapy of head and neck cancer. Tissue damage was evaluated through histomorphological examination of samples collected at different time points up to four weeks, mice were exposed locally to five daily fractions of 5, 6 or 7 Gy. A semiquantitative scoring system was used to assess the severity of observed pathomorphological changes. In this model, radiation damage was most severe in the lips, tongue and skin, moderate in the upper esophagus and minor in salivary glands. The kinetics of injury appearance and recovery of normal morphology varied among tissues, with maximal damage to the tongue, esophagus and salivary glands developing at earlier times (days 8-11 postirradiation) relative to that of lip and skin mucosa (days 11-15 postirradiation). While both tested regimens of entolimod significantly reduced the extent of radiation damage and accelerated restoration of normal structure in all tissues analyzed, administration of entolimod 1 h after each irradiation was more effective than treatment 30 min before irradiation. These results support the potential clinical use of entolimod as an adjuvant for improving the therapeutic index of head and neck cancer radiotherapy by reducing the radiation toxicity in normal tissues.
| S-EPMC5541767 | biostudies-literature
Project description:Cyclin D1 expression is precisely controlled during cell-cycle progression. However, repeated exposure to low-dose fractionated radiation (FR) abrogates cell cycle-dependent cyclin D1 degradation by constitutive activation of AKT survival signaling in normal human fibroblasts. The resulting abnormal nuclear cyclin D1 accumulation induces defects in DNA replication and resulting DNA double-strand breaks, and is associated with induction of genomic instability in low-dose irradiated cells. Here, we investigated the role of DNA damage signaling against such perturbed cell-cycle control of cyclin D1 expression. Nuclear cyclin D1 accumulation was induced within 7 days after low-dose FR (0.01 Gy or 0.05 Gy per fraction) in ATM-deficient cells (AT5BIVA), but appeared later in AT5BIVA cells harboring human ATM cDNA. Thus, ATM prevents abnormal nuclear cyclin D1 accumulation at early time points after low-dose FR. We further demonstrated that ATM-mediated downregulation of protein phosphatase 2A activity caused activation of the AKT/cyclin D1 pathway after long-term FR. Perturbation of cyclin D1 expression induced Rad51 foci that indicate homologous recombination repair (HRR) in control cells, while ATM- and NBS1-deficient cells (GM7166) failed to induce Rad51 foci after long-term low-dose FR. After 21 days of FR, NBS1- and ATM-deficient cells showed a decrease in nuclear cyclin D1-positive cells, and an increase in apoptotic cells. Similarly, inhibition of ATM with KU55933 abrogated nuclear cyclin D1 accumulation by induction of apoptosis in ATM-complemented cells exposed to low-dose FR. In conclusion, we here demonstrate that ATM is involved in controlling cyclin D1 levels after low-dose FR. DNA damage signaling mitigates the harmful effects of low-dose long-term FR by suppression of cell death induced by perturbation of cyclin D1 expression.
| S-EPMC4275562 | biostudies-literature
Project description:BackgroundThe rate of toxic deaths related to induction chemotherapy in the treatment of locally advanced head and neck cancers is unacceptable and calls into question this therapeutic strategy, which is however highly effective in terms of rate and speed of response. The purpose of the study was to investigate predictive factors of toxicity of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) in locally advanced head and neck cancers (LAHNC).MethodsBetween June 2009 and December 2017, 113 patients treated consecutively with TPF were included retrospectively. Patients were receiving induction chemotherapy for either an inoperable cancer or laryngeal preservation. For inoperable cancer, induction chemotherapy was proposed to patients presenting either a large tumor with strong symptoms (dyspnea, dysphagia, pain) or a tumor with rapid progression. Risk factors were chosen among the initial patient and tumour characteristics and chemotherapy modalities.ResultsEighty-nine patients (79%) were male; the median age was 58 years [32-71]. Sixty-nine (61%) patients were treated for inoperable cancer and 44 (39%) for laryngeal preservation. 45% had stage IVa cancer, 28% stage III and 25% stage IVb. Sixty percent of patients had a partial response after TPF, 22% had a complete response, 12% were stable, 5% were progressing, and 1% had a discordant response. Thirty-four patients (30%) received enteral feeding during induction chemotherapy with TPF. The possibility of oral feeding without a tube was predictive of a better response (p = 0.003). Seven (6%) patients died during TPF. There was an increased risk of death with preexisting liver dysfunction (liver dysmorphia on imaging or decrease prothrombin rate) (p = 0.032). There was an increased risk of grade ≥ 3 infection if an enteral feeding occurred during the period of induction chemotherapy (p = 0.03).ConclusionsTPF induction chemotherapy had an 82% objective response rate with 6% toxic deaths. Nutritional status and the presence of hepatic dysfunction are significant risk factors to be taken into account in therapeutic decisions.
| S-EPMC8025378 | biostudies-literature