Paired phase II trials evaluating cetuximab and radiotherapy for low risk HPV associated oropharyngeal cancer and locoregionally advanced squamous cell carcinoma of the head and neck in patients not eligible for cisplatin.
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ABSTRACT: Background
Alternative therapeutic strategies are needed for localized oropharyngeal carcinoma. Cetuximab represents a potential option for those ineligible for cisplatin or, until recently, an agent for de-escalation in low risk HPV+ oropharyngeal carcinoma (OPSCC). Our objective was to define the toxicity and efficacy of cetuximab-radiotherapy.Methods
We conducted paired phase II trials evaluating cetuximab-radiotherapy in two cohorts (a) low risk HPV+ OPSCC and (b) cisplatin ineligible. The mean follow-up was 48 months.Results
Forty-two patients were enrolled in cohort A with a 2-year disease free survival (DFS) of 81%. Twenty-one patients were enrolled in cohort B prior to closure due to adverse outcomes with a 2-year DFS of 37%. Severe toxicities were seen in 60% of patients, 30% required enteral nutrition.Conclusion
Among cisplatin ineligible patients, cetuximab treatment engendered poor outcomes. Rates of severe toxicities were on par with platinum-based regimens suggesting that cetuximab is not a benign treatment.
SUBMITTER: Swiecicki PL
PROVIDER: S-EPMC7404812 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceClinicians frequently use radiotherapy with cetuximab over radiotherapy only or radiotherapy with cisplatin because of a perceived survival and tolerability advantage, but scant data are available to support this perception.ObjectiveTo measure the 3 aspects of value (quality, outcomes, and cost) in older patients receiving radiotherapy only, radiotherapy with cisplatin, or radiotherapy with cetuximab for locoregionally advanced head and neck cancer.Design, setting, and participantsFor this cohort study, patient records were obtained from the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare outcomes and claims database from January 1, 2004, to December 31, 2014. Participants were 65 years or older; received a diagnosis between 2006 and 2013 of stages III to IVB head and neck cancer; had only 1 cancer on record; and did not undergo surgical intervention. Data analysis was conducted from February 5, 2018, to March 27, 2019.ExposuresPatients were divided into exposure arms on the basis of their first-line therapy or identified chemoradiotherapy and radiotherapy regimen.Main outcomes and measuresOverall survival was analyzed by propensity score matching Cox proportional hazards regression models, quality by measuring 90-day emergency department (ED) visit and inpatient admission rates, and costs by assessing 90-day total Medicare spending.ResultsThe overall cohort included 1091 patients, of whom 815 (74.7%) were male; the mean (SD) age was 73.9 (6.6) years. Patients receiving radiotherapy with cisplatin had higher overall survival compared with those receiving radiotherapy only (adjusted hazard ratio [HR], 0.64; 95% CI, 0.47-0.87). This finding was not seen in patients receiving radiotherapy with cetuximab (adjusted HR, 0.95; 95% CI, 0.75-1.20), compared with the radiotherapy only group, and it persisted after stratifying patients by age. The ED visit (adjusted incidence rate ratio [IRR], 1.72; 95% CI, 1.30-2.30) and inpatient admission (adjusted IRR, 1.48; 95% CI, 1.12-1.98) rates in the 90 days after treatment start were higher in patients receiving radiotherapy with cisplatin compared with those treated with radiotherapy only. Patients receiving radiotherapy with cetuximab had a higher rate of ED visits (adjusted IRR, 1.38; 95% CI, 1.05-1.82) compared with those in the radiotherapy only group. The 90-day after-treatment spending for patients receiving radiotherapy with cetuximab was $48 620 (95% CI, $46 466-$50 775) compared with $33 009 (95% CI, $31 499-$34 519) for radiotherapy with cisplatin and $27 622 (95% CI, $25 118-$30 126) for radiotherapy only.Conclusions and relevanceIn this cohort study, no survival difference, a higher rate of ED visits but not of inpatient admissions, and higher spending were observed in patients receiving radiotherapy with cetuximab compared with patients receiving radiotherapy only. The findings suggest that radiotherapy alone should be maintained as a treatment arm in evaluation of novel therapeutics for locoregionally advanced head and neck cancer in older and sicker patients.
| S-EPMC6802372 | biostudies-literature
Project description:BackgroundThe De-ESCALaTE HPV trial confirmed the dominance of cisplatin over cetuximab for tumour control in patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). Here, we present the analysis of health-related quality of life (HRQoL), resource use, and health care costs in the trial, as well as complete 2-year survival and recurrence.Materials and methodsResource use and HRQoL data were collected at intervals from the baseline to 24 months post treatment (PT). Health care costs were estimated using UK-based unit costs. Missing data were imputed. Differences in mean EQ-5D-5L utility index and adjusted cumulative quality-adjusted life years (QALYs) were compared using the Wilcoxon signed-rank test and linear regression, respectively. Mean resource usage and costs were compared through two-sample t-tests.Results334 patients were randomised to cisplatin (n = 166) or cetuximab (n = 168). Two-year overall survival (97·5% vs 90·0%, HR: 3.268 [95% CI 1·451 to 7·359], p = 0·0251) and recurrence rates (6·4% vs 16·0%, HR: 2·67 [1·38 to 5·15]; p = 0·0024) favoured cisplatin. No significant differences in EQ-5D-5L utility scores were detected at any time point. At 24 months PT, mean difference was 0·107 QALYs in favour of cisplatin (95% CI: 0·186 to 0·029, p = 0·007) driven by the mortality difference. Health care costs were similar across all categories except the procurement cost and delivery of the systemic agent, with cetuximab significantly more expensive than cisplatin (£7779 [P < 0.001]). Consequently, total costs at 24 months PT averaged £13517 (SE: £345) per patient for cisplatin and £21064 (SE: £400) for cetuximab (mean difference £7547 [95% CI: £6512 to £8582]).ConclusionsCisplatin chemoradiotherapy provided more QALYs and was less costly than cetuximab bioradiotherapy, remaining standard of care for nonsurgical treatment of HPV-positive OPSCC.
| S-EPMC6947474 | biostudies-literature
Project description:PurposeWe incorporated cetuximab, a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR), into the induction therapy and subsequent chemoradiotherapy of head and neck cancer (HNC).Patients and methodsPatients with locally advanced HNC, including squamous and undifferentiated histologies, were treated with docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, and cetuximab 250 mg/m2 days 1, 8, and 15 (after an initial loading dose of 400 mg/m2), termed TPE, repeated every 21 days for three cycles, followed by radiotherapy with concurrent cisplatin 30 mg/m2 and cetuximab weekly (XPE), and maintenance cetuximab for 6 months. Quality of life (QOL) was assessed using Functional Assessment of Cancer Therapy-Head and Neck. In situ hybridization (ISH) for human papillomavirus (HPV), immunohistochemistry for p16, and fluorescence ISH for EGFR gene copy number were performed on tissue microarrays.ResultsOf 39 enrolled patients, 36 had stage IV disease and 23 an oropharyngeal primary. Acute toxicities during TPE included neutropenic fever (10%) and during XPE, grade 3 or 4 oral mucositis (54%) and hypomagnesemia (39%). With a median follow-up of 36 months, 3-year progression-free survival and overall survival were 70% and 74%, respectively. Eight patients progressed in locoregional sites, three in distant, and one in both. HPV positivity was not associated with treatment efficacy. No progression-free patient remained G-tube dependent. The H&N subscale QOL scores showed a significant decrement at 3 months after XPE, which normalized at 1 year.ConclusionThis cetuximab-containing regimen resulted in excellent long-term survival and safety, and warrants further evaluation in both HPV-positive and -negative HNC.
| S-EPMC3018361 | biostudies-literature
Project description:BackgroundThe incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy.MethodsWe did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080.FindingsBetween Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007).InterpretationCompared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin.FundingCancer Research UK.
| S-EPMC6319250 | biostudies-literature
Project description:BACKGROUND:Addition of nimotuzumab to weekly cisplatin and radiation improves outcomes in head and neck cancer. HPV negative oropharyngeal cancer has unsatisfactory treatment outcomes and is a candidate for escalation of treatment. We wanted to determine whether the addition of nimotuzumab to cisplatin-radiation could improve outcomes in these poor-risk tumors. METHODS:This was a subgroup analysis of a phase 3 randomized study. In this study, locally advanced head and neck cancer patients undergoing definitive chemoradiation were randomly allocated to weekly cisplatin (30 mg/m2 IV)- radiation (66-70 Gy) {CRT arm} or nimotuzumab (200 mg weekly) -weekly cisplatin (30 mg/m2)-radiation (66-70 Gy) {NCRT arm}. The data of HPV negative oropharyngeal cancer was extracted from the database of this study for the analysis. HPV testing was done with p16 immunohistochemistry (IHC) staining and reported according to the CAP criteria. The outcomes assessed were progression-free survival (PFS), disease-free survival (DFS), locoregional control, and overall survival (OS). Interaction test was performed between the study arms and HPV status prior to doing any HPV specific analysis for each of the studied outcomes. Kaplan Meier estimates for 2 year OS with 95%CI was calculated. The hazard ratio was obtained using COX regression analysis. RESULTS:We had 187 HPV negative oropharyngeal cancers, 91 in the CRT arm and 96 in NCRT arm. The interaction test was significant for PFS (p = 0.000), locoregional control (p = 0.007) and overall survival (p = 0.002) but not for DFS (p = 0.072). The 2- year PFS was 31.5% (95%CI 21.5-42) in CRT arm versus 57.2% (95%CI 45.8-67.1) in NCRT arm (HR -0.54; 95%CI 0.36-0.79, p = 0.002). The 2-year LRC was 41.4% (95%CI 29.8-52.6) in the CRT arm versus in 60.4% (95%CI 48.7-70.2) in the NCRT arm (HR -0.61; 95%CI 0.4-0.94, p = 0.024). The addition of nimotuzumab also lead to an improvement in 2-year OS from 39.0% (95%CI 28.4-49.6) to 57.6% (95%CI 46.3-67.4) (HR-0.63, 95%CI 0.43-0.92, p = 0.018). CONCLUSIONS:The addition of nimotuzumab to weekly cisplatin-radiation improves outcomes inclusive of OS in HPV negative oropharyngeal cancers.
| S-EPMC6996911 | biostudies-literature
Project description: Not available
| S-EPMC6541928 | biostudies-literature
Project description:PurposeWe performed an open-label randomized controlled phase III study comparing treatment outcome and toxicity between radiotherapy (RT) with concomitant cisplatin versus concomitant cetuximab in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC; stage III-IV according to the Union for International Cancer Control TNM classification, 7th edition).Materials and methodsEligible patients were randomly assigned 1:1 to receive either intravenous cetuximab 400 mg/m2 1 week before start of RT followed by 250 mg/m2/wk, or weekly intravenous cisplatin 40 mg/m2, during RT. RT was conventionally fractionated. Patients with T3-T4 tumors underwent a second random assignment 1:1 between standard RT dose 68.0 Gy to the primary tumor or dose escalation to 73.1 Gy. Primary end point was overall survival (OS) evaluated using adjusted Cox regression analysis. Secondary end points were locoregional control, local control with dose-escalated RT, pattern of failure, and adverse effects.ResultsStudy inclusion was prematurely closed after an unplanned interim analysis when 298 patients had been randomly assigned. At 3 years, OS was 88% (95% CI, 83% to 94%) and 78% (95% CI, 71% to 85%) in the cisplatin and cetuximab groups, respectively (adjusted hazard ratio, 1.63; 95% CI, 0.93 to 2.86; P = .086). The cumulative incidence of locoregional failures at 3 years was 23% (95% CI, 16% to 31%) compared with 9% (95% CI, 4% to 14%) in the cetuximab versus the cisplatin group (Gray's test P = .0036). The cumulative incidence of distant failures did not differ between the treatment groups. Dose escalation in T3-T4 tumors did not increase local control.ConclusionCetuximab is inferior to cisplatin regarding locoregional control for concomitant treatment with RT in patients with locoregionally advanced HNSCC. Additional studies are needed to identify possible subgroups that still may benefit from concomitant cetuximab treatment.
| S-EPMC7771720 | biostudies-literature
Project description:PurposeThis study aimed to compare the outcomes of primary radiotherapy (RT) versus surgery in early-stage human papilloma virus-positive oropharyngeal squamous cell carcinoma (hpv+OPC), and investigate the preoperative clinical factors that can predict the requirement for postoperative adjuvant treatment.Materials and methodsThis multicenter study included 166 patients with American Joint Committee on Cancer 8th edition-Stages I-II hpv+OPC. Sixty (36.1%) and 106 (63.9%) patients underwent primary (concurrent chemo)radiotherapy [(CC)RT] and surgery, respectively. Seventy-eight patients (73.6%) in the surgery group received postoperative (CC)RT.ResultsWith a median follow-up of 45.6 months for survivors, the 2-year overall survival (OS), progression-free survival (PFS), and locoregional control (LC) for RT/surgery were 97.8%/96.4%, 91.1%/92.0%, and 92.9%/93.3%, respectively. In multivariate analyses, patients with synchronous radiologic extranodal extension and conglomeration (ENEcong) of metastatic lymph nodes (LNs) showed significantly poorer OS (p=0.047), PFS (p=0.001), and LC (p=0.003). In patients undergoing primary surgery, two or more clinically positive LN metastases (odds ratio [OR], 5.15; p=0.004) and LN metastases with ENEcong (OR, 3.75; p=0.009) were predictors of postoperative chemoradiotherapy. No patient in the primary RT group demonstrated late severe toxicity whereas three (2.8%), one (0.9%), and one (0.9%) patient in the surgery group showed grade 3 dysphagia, grade 3 xerostomia, and fatal oral cavity bleeding.ConclusionWe found no differences in OS, PFS, and LC between upfront RT and surgery in stage I-II hpv+OPC which warrants comparison through a prospective trial in the treatment de-escalation era. However, most early-stage hpv+OPC patients undergoing surgery received adjuvant (CC)RT. Pretreatment LN findings were prognostic and predictive for adjuvant treatment.
| S-EPMC9016308 | biostudies-literature
Project description:BackgroundConcurrent cisplatin with radiotherapy (CRT) or concurrent cetuximab with radiotherapy (BRT) improves outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC) compared with radiotherapy alone. Nevertheless, a detailed comparison between CRT and BRT in locally advanced HNSCC is required due to inconclusive results.MethodsA comprehensive literature search was conducted on PubMed, Web of Science, Cochrane databases, and EMBASE. Studies that evaluated CRT vs BRT in locally advanced HNSCC were included. The primary outcome that was overall survival (OS), whereas the secondary outcomes were progression-free survival (PFS), locoregional control (LRC), and distant metastasis-free survival (DMFS). Pooled hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to evaluate prognosis. All the analyses were performed using Stata Statistical Software 12.0.ResultsTwenty-three studies, with a total of 8701 patients, were considered eligible and included in this meta-analysis. Our results revealed that patients treated with CRT had longer OS (HR = 0.51, 95%CI, 0.41-0.64, P < .001), PFS (HR = 0.37, 95%CI, 0.23-0.60, P < .001), LRC (HR = 0.46, 95%CI, 0.37-0.57, P < .001), and DMFS (HR = 0.56, 95%CI, 0.40-0.77, P < .001) than those treated with BRT. Furthermore, the results of the subgroup analyses were consistent with the primary analysis.ConclusionsCRT has a better OS, PFS, LRC, and DMFS than BRT in locally advanced HNSCC, and should be the preferred treatment for patients with the disease.
| S-EPMC7478598 | biostudies-literature
Project description:BackgroundThe addition of cisplatin or cetuximab to radiation therapy (RT) improves outcomes in comparison with RT alone in the nonoperative management of head and neck squamous cell carcinoma (HNSCC), but limited data exist for comparing these approaches. Using Veterans Health Affairs data, this study compared the outcomes of patients treated with RT plus cisplatin or cetuximab.MethodsPatients with stage III to IVb HNSCC who had been treated nonsurgically with RT and cisplatin or cetuximab from 2000 to 2016 within the Veterans Health Affairs system were identified. Patients were analyzed by the drug used in the first treatment cycle (intent to treat). Overall survival (OS) was compared by treatment group with Cox regression models, and propensity score (PS) methods were used to account for a treatment allocation bias. The risk of toxicities was determined, with logistic regression models fit into propensity-matched cohorts.ResultsA total of 4520 patients were included in the analysis with a median follow-up of 3 years: 83% received cisplatin. Cisplatin patients were younger (P < .001) and had fewer comorbidities (P < .001). In an unmatched analysis, cetuximab was associated with inferior OS (P < .001). After PS matching, cetuximab treatment remained statistically significantly associated with inferior OS (1.7 vs 4.1 years; hazard ratio, 1.61; 95% confidence interval, 1.44-1.79; P < .001). These differences remained significant across all primary HNSCC subsites and in comparison with low- and high-dose cisplatin.ConclusionsCetuximab with RT yields inferior OS in comparison with cisplatin for the nonoperative management of stage III to IVb HNSCC. According to this study, cisplatin may be the most appropriate partner for RT in this setting.
| S-EPMC6886128 | biostudies-literature