Dataset Information

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.

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 | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

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.

Swiecicki Paul L PL Li Pin P Bellile Emily E Stucken Chaz C Malloy Kelly K Shuman Andrew A Spector Matthew E ME Chinn Steven S Casper Keith K McLean Scott S Moyer Jeffery J Chepeha Douglas D Wolf Gregory T GT Prince Mark M Bradford Carol C Nyati Mukesh M Eisbruch Avraham A Worden Francis P FP Jolly Shruti S Mierzwa Michelle M

Head & neck 20200127 8

<h4>Background</h4>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.<h4>Methods</h4>We conducted paired phase II trials evaluating cetuximab-radiotherapy in two cohorts (a) low risk HPV+ OPSCC and (b) cisplatin i ...[more]

PMID: 31989702

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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.

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.

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.

Project description:ObjectivesInduction chemotherapy (ICT) followed by definitive treatment is an accepted non-surgical approach for locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, ICT remains a challenge for cisplatin-unfit patients. We evaluated paclitaxel and cetuximab (P-C) as ICT in a cohort of LA-HNSCC patients unfit for cisplatin.Materials and methodsThis is a retrospective analysis of patients with newly diagnosed LA-HNSCC considered unfit for cisplatin-based chemotherapy (age >70 and/or ECOG≥2 and/or comorbidities) treated with weekly P-C followed by definitive radiotherapy and cetuximab (RT-C) between 2010 and 2017. Toxicity and objective response rate (ORR) to ICT and RT-C were collected. Median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Cox regression analysis was performed to determine baseline predictors of OS and PFS.ResultsA total of 57 patients were included. Grade 3-4 toxicity rate to ICT was 54.4%, and there was a death deemed treatment-related (G5). P-C achieved an ORR of 66.7%, including 12.3% of complete responses (CR). After P-C, 45 patients (78.9%) continued with concomitant RT-C. Twenty-six patients (45.6%) achieved a CR after definitive treatment. With a median follow-up of 21.7 months (range 1.2-94.6), median OS and PFS were 22.9 months and 10.7 months, respectively. The estimated 2-year OS and PFS rates were 48.9% and 33.7%, respectively. Disease stage had a negative impact on OS (stage IVb vs. III-IVa: HR = 2.55 [1.08-6.04], p = 0.03), with a trend towards worse PFS (HR = 1.92 [0.91-4.05], p = 0.09). Primary tumor in the larynx was associated with improved PFS but not OS (HR = 0.45 [0.22-0.92], p = 0.03, and HR = 0.69 [0.32-1.54], p = 0.37, respectively).ConclusionP-C was a well-tolerated and active ICT regimen in this cohort of LA-HNSCC patients unfit for cisplatin-based chemotherapy. P-C might represent a valid ICT option for unfit patients and may aid patient selection for definitive treatment.

Project description:BackgroundManagement of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) when cisplatin is contraindicated is controversial. We aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared with radiotherapy with cetuximab.MethodsNRG-HN004 was designed as an open-label, multicentre, parallel-group, randomised, phase 2/3 trial with safety lead-in conducted at 89 academic and community medical centres in North America. Eligible patients were aged 18 years or older with American Joint Committee on Cancer 8th edition stage III-IVB p16-negative HNSCC or unfavourable stage I-III p16-positive oropharyngeal or unknown primary carcinoma, who had a contraindication to cisplatin (Eastern Cooperative Oncology Group [ECOG] performance status 2, renal or hearing impairment, peripheral neuropathy, aged at least 70 years with moderate or severe comorbidity, or aged younger than 70 years with severe comorbidity). Patients were randomly assigned (2:1) by permuted block randomisation (multiples of 6) to intravenous durvalumab 1500 mg starting 2 weeks before radiotherapy then every 4 weeks starting week 2 of radiotherapy (seven cycles) or intravenous cetuximab 400 mg/m2 1 week before radiotherapy then 250 mg/m2 weekly beginning week 1 of radiotherapy (eight cycles), with intensity-modulated radiotherapy (70 Gy in 35 fractions over 7 weeks). Stratification factors were tumour and nodal stage, ECOG performance status and comorbidity, and primary site and p16 status. The phase 2 primary endpoint was progression-free survival in the intention-to-treat population. There was one prespecified interim futility analysis at 50% of progression-free survival information. If the observed hazard ratio was 1·0 or more, favouring cetuximab, early stopping would be considered. Extended follow-up analysis was post hoc. This trial is registered with ClinicalTrials.gov, NCT03258554, and is closed to enrolment.FindingsFollowing a ten-patient safety lead-in, the phase 2 trial enrolled 190 patients from March 12, 2019, to July 30, 2021, 186 of whom were randomly assigned (123 to durvalumab and 63 to cetuximab). Median age was 72 years (IQR 64-77), 30 (16%) patients were women and 156 (84%) were men. Phase 2 accrual was suspended in July 30, 2021, following an interim futility analysis, and permanently closed in Sept 1, 2022. The phase 3 part of the trial was not conducted. At a median follow-up of 2·3 years (IQR 1·9-3·1) for the extended follow-up (data cutoff July 31, 2023; post-hoc analysis), 2-year progression-free survival was 50·6% (95% CI 41·5-59·8) in the durvalumab group versus 63·7% (51·3-76·1) in the cetuximab group (hazard ratio 1·33 [95% CI 0·84-2·12]; p=0·89). Adverse events were similar in both groups. The most common grade 3-4 adverse events were dysphagia (26 [22%] of 119 patients in the durvalumab group vs 18 [30%] of 61 patients in the cetuximab group), lymphopenia (33 [28%] vs 20 [33%]), and oral mucositis (13 [11%] vs 11 [18%]). Four (3%) patients in the durvalumab group and one (2%) in the cetuximab group died from treatment-related adverse events (death not otherwise specified, laryngeal oedema, lung infection, and respiratory failure in the durvalumab group and sudden death not otherwise specified in the cetuximab group).InterpretationOur findings suggest that durvalumab did not improve outcomes compared with cetuximab in patients with HNSCC with contraindications to cisplatin. Further trials are needed to define the standard of care for this population.FundingUS National Cancer Institute and AstraZeneca.

Dataset Information

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.

Background

Methods

Results

Conclusion

Publications

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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