Locally Advanced Head And Neck Squamous Cell Carcinoma Research Articles

Update and external validation of a multivariable prediction model for tube feeding dependency for at least four weeks during chemoradiotherapy for head and neck cancer.

6040 Background: Patients who receive chemoradiation or bioradiation (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often experience high toxicity rates, which may interfere with oral intake, leading to (temporary) tube feeding (TF) dependency. International guidelines recommend gastrostomy insertion when the expected use of TF exceeds four weeks. In this study we aimed to update and externally validate a prediction model to identify patients in need for TF for at least four weeks, meeting the international criteria for prophylactic gastrostomy insertion. Methods: This retrospective multicenter cohort study was performed in four tertiary referral head and neck cancer centers in the Netherlands. The prediction model was developed using data from the University Medical Center Utrecht and the Netherlands Cancer Institute. The model was externally validated in patients from the Maastricht University Medical Center and Radboud University Medical Center. The primary endpoint was TF, initiated during or within 30 days after completion of CRT/BRT, and administered for at least four weeks. Potential predictors were retrieved from patient medical records and radiotherapy dose-volume parameters were calculated. Results: The developmental and validation cohort included 409 and 334 patients respectively. Multivariable analysis showed significant predictive value (p < 0.05) for adjusted diet at start of CRT/BRT, percentage weight change prior to treatment initiation, WHO performance status, tumor-site, nodal stage, mean radiation dose to the contralateral parotid gland, and mean radiation dose to the oral cavity. The area under the receiver operating characteristics curve for the updated model was 0.73 and after external validation 0.64. Positive and negative predictive value at 90% cut off were 80.0% and 48.2% respectively. Conclusions: This externally validated prediction model to estimate TF-dependency for at least four weeks in LAHNSCC patients performs well. This model, which will be presented, can be used in clinical practice to guide personalized decision making on prophylactic gastrostomy insertion.

Induction Chemotherapy as a Prognostication Index and Guidance for Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: The Concept of Chemo-Selection (KCSG HN13-01).

PurposeCertain patient subgroups who do not respond to induction chemotherapy (IC) show inherent chemoresistance in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). This study aimed to assess the prognostic value of IC, and role of IC in guiding the selection of a definitive locoregional therapy.Materials and MethodsOut of the 445 patients in multi-institutional LA-HNSCC cohort, 158 (36%) receiving IC were enrolled. The study outcome was to assess overall survival (OS) through IC responsiveness and its role to select subsequent treatments.ResultsAmong 135 patients who completed subsequent treatment following IC, 74% responded to IC (complete response in 17% and partial response in 58%). IC-non-responders showed 4.5 times higher risk of mortality than IC-responders (hazard ratio, 4.52; 95% confidence interval, 2.32 to 8.81; p < 0.001). Among IC-responders, 84% subsequently received definitive concurrent chemoradiotherapy (CCRT) and OS was not differed by surgery or CCRT (p=0.960). Regarding IC-non-responders, 54% received CCRT and 46% underwent surgery, and OS was poor in CCRT (24-month survival rate of 38%) or surgery (24-month survival rate of 63%).ConclusionResponse to IC is a favorable prognostic factor. For IC-responders, either surgery or CCRT achieved similar survival probabilities. For IC-non-responder, multidisciplinary approach was warranted reflecting patients’ preference, morbidity, and prognosis.

A Prospective Randomised Comparative Study Between Weekly Cisplatin Versus Three Weekly Cisplatin with Radiotherapy in Unresectable Locally Advanced Head and Neck Cancer.

To compare the efficacy, compliance and the complications of weekly cisplatin 40mg/m2 against the three weekly cisplatin 100mg/m2 with EBRT(external beam radiotherapy) in unresectable locally advanced head and neck squamous cell carcinoma(LAHNSCC) Study design was Prospective randomized and comparative.85 Patients with histologically proven stage III-IVA LAHNSCC presenting from December 2017 to May 2019 were assigned to concurrent three weekly cisplatin 100mg/m2 (arm 1) and weekly cisplatin 40mg/m2 (arm 2) with EBRT. There were 41 patients were in arm 1 and 44 patients in arm 2. Statistical analysis was done using SPSS version 2.0. At 4week of completion of treatment, response was assessed using RECIST(1.1) criteria.In Arm 1,61% patients and in arm 2 55% patients achieved complete response but the difference was statistically non- significant (p = 0.756).Median follow up was 12months after which 49% patients in arm 1 and 38% in arm 2 had complete response whereas 12% patients in arm 1 and 15.5% patients in arm 2 had locoregional relapse. There was no statistically significant difference between the two arms in terms of mucositis, nausea,vomiting, dysphagia, acute skin reaction and ototoxicity. Leukopenia (p = 0.003),thrombocytopenia (p = 0.04) and acute renal toxicity (p = 0.004) was significantly more in three weekly arm. As compared to three weekly cisplatin, weekly cisplatin with radiotherapy is an acceptable approach in a limited resource setting due to good patient compliance where a large number of patients are treated on outpatient basis.

Valproic acid combined with cisplatin-based chemoradiation in locally advanced head and neck squamous cell carcinoma patients and associated biomarkers.

BackgroundCisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, however, relapses are frequent. Our goal was to evaluate if association of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, with CCRT improved response rate (RR) and associated biomarkers.MethodsThis phase II trial included patients with unresectable locally advanced (LA) oropharynx (OP) squamous cell carcinoma. CCRT began after 2 weeks of VPA (P1). Primary goal was RR at 8 weeks after chemoradiation (CRT)+VPA (P2). Biomarkers included microRNA (miR) polymerase chain reaction (PCR)-array profiling in plasma compared to healthy controls by two-sample t-test. Distribution of p-values was analysed by beta-uniform mixture. Findings were validated by real-time PCR quantitative polymerase chain reaction (qPCR) for selected miRs in plasma and saliva. p16, HDAC2 and RAD23 Homolog B, Nucleotide Excision Repair Protein (HR23B) tumour immunohistochemistry were evaluated.ResultsGiven significant toxicities, accrual was interrupted after inclusion of ten LA p16 negative OP patients. All were male, smokers/ex-smokers, aged 41–65 and with previous moderate/high alcohol intake. Nine evaluable patients yielded a RR of 88%. At false discovery rate of 5%, 169 miRs were differentially expressed between patients and controls, including lower expression of tumour suppressors (TSs) such as miR-31, -222, -let-7a/b/e and -145. miR-let-7a/e expression was validated by qPCR using saliva. A HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease-free survival.ConclusionsVPA and CRT offered high RR; however, with prohibitive toxicities, which led to early trial termination. Patients and controls had a distinct pattern of miR expression, mainly with low levels of TS miRs targeting Tumor protein P53 (TP53). miR-let-7a/e levels were lower in patients compared to controls, which reinforces the aggressive nature of such tumours (NCT01695122).

Early Loss of Fat Mass During Chemoradiotherapy Predicts Overall Survival in Locally Advanced Squamous Cell Carcinoma of the Lung, but Not in Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Background: Cancer cachexia is highly prevalent in advanced non-small cell lung cancer (NSCLC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC), and compromises treatment tolerance and overall survival (OS). NSCLC and LAHNSCC patients share similar risk factors, and receive comparable anti-cancer treatment regimens. The aim of this study was to determine the predictive value of body composition assessed by bioelectrical impedance analysis (BIA) and handgrip strength (HGS) (baseline and early changes during therapy) on OS in NSCLC and LAHNSCC patients treated with platinum-based chemoradiotherapy (CRT) or cetuximab-based bioradiotherapy (BRT). To elucidate potential underlying determinants of early changes in body composition and HGS, specific (fat and fat free) mass loss patterns of squamous NSCLC (sNSCLC) were compared to human papilloma virus negative (HPV–) LAHNSCC patients treated with CRT.Methods: Between 2013 and 2016, BIA and HGS were performed at baseline and after 3 weeks of CRT/BRT in LAHNSCC and NSCLC patients treated with curative intent.Results: Two hundred thirty-three patients were included for baseline measurements. Fat free mass index (FFMI) and HGS<10th percentile of reference values at baseline were both prognostic for poor OS in NSCLC and LAHNSCC [HR 1.64 [95%CI 1.13–2.39], p = 0.01 and HR 2.30 [95%CI 1.33–3.97], p = 0.003, respectively], independent of Charlson Comorbidity Index, cancer site, and gross tumor volume. Early fat mass (FM) loss during CRT was predictive for poor OS in sNSCLC (n = 64) [HR 3.80 [95%CI 1.79–8.06] p ≤ 0.001] but not in HPV– LAHNSCC (n = 61). In patients with significant weight loss (>2%) in the first 3 weeks of CRT (sNSCLC n = 24, HPV– LAHNSCC n = 23), the FM change was −1.4 ± 14.5% and −8.7 ± 9.0% in sNSCLC and HPV– LAHNSCC patients, respectively (p < 0.05). Fat fee mass change was −5.6 ± 6.3% and −4.0 ± 4.3% for sNSCLC and HPV– LAHNSCC, respectively (p = 0.31).Conclusion: FFMI and HGS<10th percentile at baseline are independent prognostic factors for poor OS in NSCLC and LAHNSCC patients treated with CRT/BRT. The specific composition of mass loss during first 3 weeks of CRT significantly differs between sNSCLC and HPV– LAHNSCC patients. Early FM loss was prognostic in sNSCLC only.

Efficacy and Safety of Aprepitant for the Prevention of Nausea and Emesis During Concurrent Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma (LA-HNSCC): A Phase 2 Trial

Few studies reported effective interventions for preventing nausea and emesis caused by concurrent chemoradiotherapy (CCRT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). This prospective phase II study was performed to assess the safety and efficacy of the neurokinin-1-receptor antagonist (NK1-RA) aprepitant in LA-HNSCC patients receiving CCRT with high-dose cisplatin. Treatment-naïve LA-HNSCC patients received intensity-modulated radiotherapy with concurrent cisplatin 100 mg/m2 in 6.5 weeks. Cisplatin was divided into 3 days on day 1-3 every 3 weeks, in company with the antiemesis regimen. All patients were given orally aprepitant 125 mg once on d1, then 80mg once on d2-5; ondansetron 8 mg once on d1; and dexamethasone 12 mg once on d1, then 8mg on d2-5. The primary endpoint was complete response (CR) in the overall phase, defined as no emesis and no use of rescue therapy in this period. Rescue medication was permitted for ≥ grade 2 nausea and emesis. Per the Simon two-stage design, 17 patients are enrolled in stage 1; if ≥ 13 patients are CR, 26 additional patients are enrolled in stage 2. If CR rate is ≥ 80%, the trial is deemed positive. The study was registered with ClinicalTrials.gov, number NCT03572829. Between Jan 2018 and Jan 2020, 44 LA-HNSCC patients were enrolled. The median age was 53 years old (range, 18-66), and 86.4% were male. All patients fulfilled the radiotherapy and the first cycle of cisplatin. Cisplatin dose changes were reported in 11 (28.9%) of 38 patients during the second cycle, while other 6 patients terminated chemotherapy owing to the hematotoxicities and hepatotoxicities. Sixteen of 17 patients were CR in stage 1 and 27 patients were enrolled in stage 2. The overall CR rates was 88.6% (39/44). The CR rates in cycles 1 and 2 were 90.9% (40/44) and 92.1% (35/38), respectively. The overall rates of no emesis and no nausea were 88.6% (39/44) and 61.4% (27/44). Grade 2 emesis occurred in 3 patients (1 patient was rescued) and grade 1 in 2 patients. The median score of nausea was 4 (range, 1-10). The rates of no emesis in cycle 1 and 2 were 90.9% and 92.1%, respectively. The corresponding rates of no nausea were 61.4% and 78.9%, respectively. There was no ≥ grade 3 antiemesis treatment related adverse event. The major toxicities were constipation (17 patients, 38.6%) and hiccough (7 patients, 15.9%). Aprepitant in addition to ondansetron and dexamethasone significantly improve control of emesis and nausea in patients with LA-HNSCC receiving concomitant high-dose cisplatin and radiotherapy. Randomized phase 3 studies are necessary to further define the potential role of NK1-RA in this setting.

LBA38 Pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC): Results of the GORTEC 2015-01 “PembroRad” randomized trial

Based on the hypothesis of a potential synergistic effect of the anti-PD1 pembrolizumab when combined with RT, this new combination was tested in a randomized trial against the well-established standard of care (SOC) cetuximab-RT in LA-HNSCC. In this phase II randomized trial, patients with non operated stage III-IVa-b SCC of oral cavity, oropharynx, hypopharynx and larynx and unfit for receiving high dose of cisplatin were enrolled. Patients received once-daily IMRT up to 69,96 Gy concomitant with cetuximab (Cetux-RT arm: 400 mg/m2 loading dose and 250 mg/m2 weekly) or pembrolizumab (Pembro-RT arm: 200 mg Q3W during RT). The primary endpoint was 15-month Loco-Regional Control (LRC) rate and secondary endpoints included Progression-free survival (PFS), Overall Survival (OS) and tolerance. To detect a difference between arms of 60% to 80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at 2-sided significance level of 0.20. Between May 2016 and October 2017, 131 patients were randomized and treated by 27 centers: 65 patients in Cetux-RT arm and 66 patients in Pembro-RT arm. The median age was 65 years, 92% were smokers, 60% of oropharynx (46% p16+), 41% of N2c-N3 with 25%, 56% and 19% of stage III, IVa and IVb respectively. Median follow-up was 25 months in both arms. Acute toxicity was lower in Pembro-RT arm than Cetux-RT arm: 74% vs 92% patients with at least one grade ≥ 3 acute adverse events (p=0.006), mainly due to dermatitis in radiation field, mucositis and cutaneous rash. LRC at 15 months were 59% in Cetux-RT arm and 60% in Pembro-RT arm, not significantly different: OR=1.05 (95%CI: 0.43-2.59, p=0.91). 2-year PFS rate was 40% in the Cetux-RT arm vs 42% in the Pembro-RT arm. There was no significant difference between arms for PFS: HR=0.83 (95%CI 0.53-1.29, p=0.41). 2-year OS rate was 55% in the Cetux-RT arm vs 62% in the Pembro-RT arm. OS was not significantly different between arms: HR=0.83 (95%CI: 0.49-1.40, p=0.49). Compared to the SOC cetuximab-RT, the anti-PD1 pembrolizumab concomitant with RT did not improve carcinologic outcomes but appeared less toxic.

Treatment strategy and outcomes in locally advanced head and neck squamous cell carcinoma: a nationwide retrospective cohort study (KCSG HN13\u201301)

BackgroundBy investigating treatment patterns and outcomes in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), we aimed at providing valuable insights into the optimal therapeutic strategy for physicians in real-world practice.MethodsThis is a multi-institutional study enrolled the patients with stage III to IVB LA-HNSCC, except for nasopharyngeal carcinoma, from 2004 to 2015 in thirteen referral hospitals capable of multidisciplinary care.ResultsA total of 445 LA-HNSCC patients were analyzed. The median age was 61 years (range, 24–89). The primary tumor location was the oropharynx in 191 (43%), oral cavity in 106 (24%), hypopharynx in 64 (14%), larynx in 57 (13%) and other sites in 27 (6%). The most common stage was T2 in 172 (39%), and N2 in 245 (55%). Based on treatment intents, 229 (52%) of the patients received definitive concurrent chemoradiotherapy (CCRT) and 187 (42%) underwent surgery. Approximately 158 (36%) of the study population received induction chemotherapy (IC). Taken together, 385 (87%) of the patients underwent combined therapeutic modalities. The regimen for definitive CCRT was weekly cisplatin in 58%, 3-weekly cisplatin in 28% and cetuximab in 3%. The preferred regimen for IC was docetaxel with cisplatin in 49%, and docetaxel, cisplatin plus fluorouracil in 27%. With a median follow-up of 39 months, one-year and two-year survival rates were 89 and 80%, respectively. Overall survival was not significantly different between CCRT and surgery group (p = 0.620).ConclusionsIn patients with LA-HNSCC, the majority of patients received combined therapeutic modalities. Definitive CCRT, IC then definitive CCRT, and surgery followed by adjuvant CCRT or radiotherapy are the preferred multidisciplinary strategies in real-world practice.

STAT3 as a predictive biomarker in head and neck cancer: A validation study

Locally advanced head and neck squamous cell carcinoma (LAHNSCC) treatment consists of radiotherapy (RT) alone or cisplatin-based concomitant chemoradiotherapy (CCRT). CCRT is accompanied by substantially more toxicity than RT alone. A previous retrospective cohort study found that LAHNSCC patients with tumors negative for nuclear expression of the signal transducer and activator of transcription 3 (STAT3) protein might not benefit from the addition of cisplatin to radiotherapy (RT) treatment. We set out to validate these results in a new cohort. We found that in patients with both STAT3 positive and negative tumors, disease-free survival (DFS) and overall survival (OS) did not differ significantly between treatment with cisplatin-based concomitant chemoradiotherapy (CCRT) and radiotherapy alone. Therefore, our validation study does not confirm that STAT3 is a potential biomarker to predict the effectiveness of the addition of cisplatin to RT in LAHNSCC patients.

Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial.

Our previous phase-3 study (TTCC 2503) failed to show overall survival advantage of 2 induction chemotherapy (IC) regimens followed by standard concurrent chemoradiotherapy (CRT) over CRT alone in patients with unresectable locally advanced head and neck squamous-cell carcinoma (LAHNSCC). This study described the long-term survival of those patients. Long-term follow-up study of patients with untreated LAHNSCC assigned to IC (three cycles), with either docetaxel, cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CRT, or CRT alone, included in the previous TTCC 2503 trial. In the intention-to-treat population (n = 439), the median OS times were 25.4 (95% CI, 16.8-34.4), 26.2 (95% CI, 18.2-36.6) and 25.4months (95% CI, 17.4-36.0) in the TPF-CRT, PF-CRT and CRT arms, respectively (log-rank p = 0.51). In the per-protocol population (n = 355), patients with larynx-hypopharynx primary tumors treated with IC (TPF or PF) followed by CRT had a longer median PFS than those who received CRT alone. Moreover, patients with ECOG 0 treated with IC (TPF or PF) followed by CRT had a better TTF than those with CRT alone. There were no statistically significant differences in terms of OS, PFS or TTF, according to the tumor load or affected nodes. After a long follow-up, the TTCC 2503 trial failed to show the benefit of IC-CRT in unresectable LAHNSCC regarding the primary end point. However, fit patients with ECOG 0 and primary larynx-hypopharyngeal tumors may benefit from the use of IC if administered by an experienced team. ClinicalTrials.gov identifier NCT00261703.

Abstract CT285: KEYNOTE-689: A phase 3 study of neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC)

Abstract Background: In phase 2 studies (NCT02296684 and NCT02641093), neoadjuvant and adjuvant pembrolizumab demonstrated a pathological response (PR) and acceptable safety in patients with high-risk, resectable, LA HNSCC. KEYNOTE-689 (NCT03765918) is a randomized, open-label, phase 3 trial that will evaluate efficacy and safety of neoadjuvant pembrolizumab and adjuvant pembrolizumab in combination with SOC in patients with previously untreated LA HNSCC. Methods: Key eligibility criteria include histologically confirmed, newly diagnosed, resectable, nonmetastatic SCC (stage III oropharyngeal p16-positive disease [T4 (N0-N2), M0]; stage III/IVA oropharyngeal p16 negative; or stage III/IVA larynx or hypopharynx or oral cavity, independent of p16 status), evaluable tumor burden (measurable and/or nonmeasurable tumor lesions), newly obtained core or excisional biopsy, and ECOG performance status 0 or 1. Patients will be randomly assigned 1:1 to arms A and B. Randomization will be stratified by primary tumor site (oropharynx/oral cavity vs larynx vs hypopharynx), tumor stage (III vs IVA), and PD-L1 status defined by tumor proportion score 50% (TPS ≥50% vs TPS &amp;lt;50%). In arm A, patients will receive 200 mg Q3W neoadjuvant pembrolizumab for 2 cycles, followed by surgical resection, then 200 mg Q3W adjuvant pembrolizumab for 15 cycles in combination with SOC. In arm B, patients will undergo surgical resection followed by adjuvant SOC without pembrolizumab. SOC is radiotherapy alone (patients at low risk) or radiotherapy plus concurrent 100 mg/m2 Q3W cisplatin for 3 cycles (patients at high risk). Radiotherapy is standard fractionation at 2 Gy/fraction for 30, 33, or 35 fractions (60 Gy, 66 Gy, or 70 Gy) for patients at low risk or high risk or with gross residual disease, respectively. Treatment will continue until disease progression that is radiographically documented and verified by blinded independent central review, unacceptable toxicity, or investigator or patient decision to withdraw. Co-primary end points are major PR (≤10% invasive SCC within resected primary tumor and sampled regional lymph nodes per blinded central pathology) and event-free survival per RECIST 1.1 to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Secondary end points include overall survival, pathological complete response, health-related quality of life, and safety. All end points except safety will be evaluated in patients whose tumors express PD-L1 combined positive score ≥1 and in all patients regardless of tumor PD-L1 status. The first radiologic imaging in arm A will occur after 2 cycles of pembrolizumab and before surgery. Postoperative imaging will occur in both arms 12 weeks after SOC, then every 3 months until year 3 and every 6 months thereafter. Recruitment is ongoing; planned enrollment is ~704 patients. Citation Format: Nancy Y. Lee, Ravindra Uppaluri, William Westra, Ezra E. Cohen, Robert I. Haddad, Stephane Temam, Christophe Le Tourneau, Rebecca Chernock, Sufia Safina, Arkadiy Klochikhin, Amichay Meirovitz, Irene Brana, Joy Yang Ge, Ramona F. Swaby, Cecilia Pinheiro, Douglas Adkins. KEYNOTE-689: A phase 3 study of neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT285.

Randomized Controlled Study Comparing Efficacy and Toxicity of Weekly vs. 3-Weekly Induction Chemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma.

Background: Head and Neck Cancer is a major public health problem in India, majority of which are lifestyle related, male predominant requiring dedicated infrastructure and human resource. The 5-year survival is 59% for all stages combined and only 45% in patients with locally advanced inoperable head and neck cancer using current chemoradiation schedules. Chemotherapy agents administered in the induction or concurrent setting comprise of taxanes (Docetaxel, paclitaxel), platinum compounds (Cisplatin, carboplatin) and fluorouracil (TPF). For patients with advanced Head and neck squamous cell carcinoma (HNSCC), 3-weekly TPF regimen is the established standard induction chemotherapy (ICT) option based on overall survival benefit. However, TPF regimen is known to be associated with significant dose limiting toxicities which may impair tolerance and effectiveness of therapy. In this study we assessed the efficacy and toxicity of weekly vs. 3-weekly Docetaxel, Cisplatin, and Fluoro-uracil (TPF) induction chemotherapy in locally advanced Head and neck squamous cell carcinoma (LA-HNSCC).Methods: This was an open labeled randomized two arm study with 41 patients in the 3-weekly TPF arm and 41 patients in the weekly arm. Patients were randomized using numbers from a randomization software, data recorded, and results were analyzed.Results: The weekly group achieved far greater symptom relief than 3-weekly group (72 vs. 64%). The overall response rates were similar in both arms (ORR 75.6 and 73.1% in the weekly and 3-weekly groups, respectively). Renal toxicity was significantly lower in the weekly group as compared to 3 weekly arm post three cycles of chemotherapy (CrCl 91.49 ml/min vs. 76.67 ml/min, respectively). The weekly group had predominantly grade I and II neutropenia (19.5 and 17.1%, respectively) as compared to 3-weekly group where grade III and IV neutropenia (31 and 12%, respectively) was more prominent (p-0.003). Among non-hematological toxicities, mucositis, nausea/vomiting, and diarrhea in the weekly group were significantly lower when compared to 3-weekly group. Progression free survival was slightly higher in the weekly group (18 months) when compared to 3-weekly group (15 months) which was not statistically significant.Conclusion: Weekly induction with TPF had lower toxicity and similar efficacy as compared to 3-weekly regimen in locally advanced HNSCC patients. Myelosuppression, which was the most serious and common complication of 3-weekly TPF regimens was notably low using the weekly regimen. Our results suggest that weekly TPF regimen may be a safer and effective alternative to 3-weekly TPF for treatment of LA-HNSCC. To our knowledge this is the first study reporting the efficacy of weekly TPF regimen in LA-HNSCC till date.

Induction chemotherapy for locally advanced laryngeal and hypopharyngeal cancer: Single institution experience.

The role of induction chemotherapy (IC) in locally-advanced head and neck squamous cell carcinoma (LAHNSCC) is unclear. A retrospective study of 104 patients with LAHNSCC of the larynx and hypopharynx, treated with IC or up-front chemoradiotherapy (CRT). Eighty patients received CRT and 24 IC followed by CRT; median follow up was 51.33 months. IC significantly improved median overall survival (OS) in the hypopharyngeal cancer group (64.7 vs 21 months, P = .003); with significant difference in the proportion of complete response at first imaging assessment post definitive CRT; no significant difference in disease free survival (DFS), loco-regional or distant failure in the hypopharyngeal cancer group; or OS and DFS in the laryngeal cancer group. Patients with laryngeal cancer had significantly better median OS than those with hypopharyngeal cancer. IC significantly improved complete response rates after CRT, and improved outcomes for patients with locally advanced hypopharyngeal, not laryngeal, cancers.

Decrease in treatment intensity predicts worse outcome in patients with locally advanced head and neck squamous cell carcinoma undergoing radiochemotherapy

PurposeRadiochemotherapy (RCT) is an effective standard therapy for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Nonetheless, toxicity is common, with patients often requiring dose modifications.MethodsTo investigate associations of RCT toxicities according to CTCAE version 5.0 and subsequent therapy modifications with short- and long-term treatment outcomes, we studied all 193 patients with HNSCC who received RCT (70 Gy + platinum agent) at an academic center between 03/2010 and 04/2018.ResultsDuring RCT, 77 (41%, 95% CI 34–49) patients developed at least one ≥ grade 3 toxicity, including seven grade 4 and 3 fatal grade 5 toxicities. The most frequent any-grade toxicities were xerostomia (n = 187), stomatitis (n = 181), dermatitis (n = 174), and leucopenia (n = 98). Eleven patients (6%) had their radiotherapy schedule modified (mean radiotherapy dose reduction = 12 Gy), and 120 patients (64%) had chemotherapy modifications (permanent discontinuation: n = 67, pause: n = 34, dose reduction: n = 7, change to other chemotherapy: n = 10). Objective response rates to RCT were 55% and 88% in patients with and without radiotherapy modifications (p = 0.003), and 84% and 88% in patients with and without chemotherapy modifications (p = 0.468), respectively. Five-year progression-free survival estimates were 20% and 50% in patients with and without radiotherapy modifications (p = < 0.001), and 53% and 40% in patients with and without chemotherapy modifications (p = 0.88), respectively.ConclusionsReductions of radiotherapy dose were associated with impaired long-term outcomes, whereas reductions in chemotherapy intensity were not. This suggests that toxicities during RCT should be primarily managed by modifying chemotherapy rather than radiotherapy.

Risk and impact of delayed renal impairment in patients with locally advanced head and neck squamous cell carcinoma receiving chemoradiotherapy with cisplatin.

An incidence of cisplatin-induced acute kidney injury (AKI) of 34% has been reported in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, delayed cisplatin-induced nephrotoxicity and long-term renal outcomes remain poorly studied. Patients with LA-HNSCC who underwent definitive or postoperative cisplatin-based chemoradiotherapy (CRT) were included. Acute kidney disease (AKD) was defined as newly developed estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2 for < 3months, ≥ 35% decrease in eGFR, or > 50% increase in serum creatinine for <3months from baseline. A total of 509 patients were analyzed. AKD and AKI occurred in 27.9% and 13.4% of patients, respectively. Most patients had primary prophylactic feeding tube (95%) and definitive CRT (83%). More AKD patients had an ECOG status of 0 (p = 0.017), diabetes (p = 0.044), and hypertension (p < 0.001). AKI, but not AKD, was significantly associated with cumulative cisplatin dose, delay, dose reduction, termination, and hospitalization during CRT. GFR percentage in patients with AKD declined significantly during CRT (- 36%), worsened at 3months (- 39%), and had not recovered to baseline at 12months after CRT (- 29%). Multivariate analysis identified ECOG status 0 and hypertension as significantly associated with the development of AKD. Almost one third of LA-HNSCC patients who underwent CRT with cisplatin developed AKD, and their eGFR did not recover to baseline even after 1year. ECOG 0 and hypertension were associated with AKD. These findings may have been due to the physician's awareness of AKD and underestimation of its potential complications in fit patients.

Comparison of Carboplatin With 5-Fluorouracil vs. Cisplatin as Concomitant Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma.

Background: Chemoradiotherapy (CRT) including three cycles of cisplatin is considered the standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, around one-third of the patients cannot complete cisplatin because of toxicity. Carboplatin plus 5-fluorouracil (carbo-5FU) is another accepted treatment option with a different toxicity profile. We compared tolerability and efficacy of concomitant carbo-5FU and cisplatin.Patients and Methods: We conducted a retrospective analysis of LA-HNSCC patients treated with CRT in two Dutch cancer centers between 2007 and 2016. All patients received intensity-modulated radiotherapy. One center routinely administered carboplatin 300–350 mg/m2 at day 1, 22, and 43 followed by 5FU 600 mg/m2/day for 96 h. The other center used cisplatin 100 mg/m2 at day 1, 22, and 43. The primary endpoint of this study was chemotherapy completion rate. Secondary endpoints included overall survival (OS), disease-free survival (DFS), locoregional control (LRC) and distant metastasis–free interval (DMFS), toxicity, and unplanned admissions.Results: In the carbo-5FU cohort (n = 211), 60.2% of the patients completed chemotherapy vs. 76.7% (p < 0.001) of the patients in the cisplatin cohort (n = 223). Univariate analysis showed a higher risk of death in the carbo-5FU cohort [hazard ratio (HR) 1.53, 95% CI, 1.09–2.14, p = 0.01] with a 3-year OS of 65.4 vs. 76.5% for cisplatin. OS was independently associated with T and N stage and p16 status, but not with chemotherapy regimen (HR 1.08, 95% CI, 0.76–1.55, p = 0.65). Three-year DFS was 70.0% for carbo-5FU vs. 78.6% for cisplatin (HR 1.37, 95% CI, 0.93–2.01, p = 0.05). A similar outcome was observed for both LRC (HR 1.27, 95% CI, 0.74–2.09, p = 0.4) and DMFS (HR 1.08, 95% CI 0.62–1.90, p = 0.77). The risk of discontinuation for chemotherapy-associated toxicity was higher in the carbo-5FU cohort than in the cisplatin cohort (relative risk = 1.69).Conclusion: LA-HNSCC patients treated with concomitant carbo-5FU completed chemotherapy less frequently than patients treated with cisplatin. Treatment regimen was not an independent prognostic factor for OS.

Quality of life in patients with locally advanced head and neck cancer undergoing chemoradiation with once-a-week versus once-every-three-weeks cisplatin.

12092 Background: This trial was conducted to compare the efficacy of low dose once-a-week cisplatin with once-every-3-weeks cisplatin with radiation in locally advanced head and neck squamous cell carcinoma (LAHNSCC). The current analysis focuses on the quality of life (QoL) of patients in this trial. Methods: In this phase III randomized trial, patients with stage III or IV non-metastatic LAHNSCC were randomized to receive cisplatin 30 mg/m2 once a week or cisplatin 100 mg/m2 once every 3 weeks concurrently with curative intent radiotherapy. The primary endpoint was locoregional control. QoL was a key secondary endpoint. QoL was assessed using the EORTC QLQ-C30 (v.3) and EORTC QLQ-H&amp;N35 (v.1). QoL data were assessed at baseline and days 22 and 43 during treatment; at the end of chemoradiation and at each follow-up. The linear mixed effects model was used for longitudinal analysis of QoL domains to determine the impact of treatment (arm) and time on QoL scores. Results: Three hundred patients were enrolled, 150 in each arm. QoL data from 283 patients with at least one assessable questionnaire were analyzed. The pretreatment QoL scores were similar in both the arms in all domains. There was no significant difference in the global health status/QoL with respect to the treatment arm ( P =0.608) or time ( P=0.0544 ). There was no significant difference in the longitudinal QoL scores between the two treatment arms in all domains except the physical function ( P= .0074), constipation ( P= .0326), trouble with social contact ( P= .0321) and sexuality ( P= .0004). There was a decline in the QoL scores in all domains in both arms during treatment. After completion of treatment, the QoL scores started improving steadily up to 1 year and plateaued thereafter in both arms. Conclusions: The use of once-every-three weeks cisplatin significantly improved the locoregional control without adversely impacting the quality of life as compared to once-a-week cisplatin in combination with radical radiotherapy in locally advanced HNSCC. Clinical trial information: CTRI/2012/10/ 003062. .

Randomized controlled trial to identify the optimal radiotherapy scheme for palliative treatment of incurable head and neck squamous cell carcinoma

BackgroundNo randomized controlled trials (RCT) have yet identified the optimal palliative radiotherapy scheme in patients with incurable head and neck squamous cell carcinoma (HNSCC). We conducted RCT to compare two radiation schemes in terms of efficacy, toxicity and quality-of-life (QoL). Materials and methodsPatients with locally-advanced HNSCC who were ineligible for radical treatment and those with limited metastatic disease were randomly assigned in 1:1 ratio to arm 1 (36 Gy in 6 fractions, twice a week) or arm 2 (50 Gy in 16 fractions, four times a week). ResultsThe trial was discontinued early because of slow accrual (34 patients enrolled). Objective response rates were 38.9% and 57.1% for arm 1 and 2 respectively (p = 0.476). The median time to loco-regional progression was not reached. The loco-regional control rates at 1 year was 57.4% and 69.3% in arm 1 and 2 (p = 0.450, HR = 0.56, 95%CI 0.12–2.58). One-year overall survival was 33.3% and 57.1%, with medians of 35.4 and 59.5 weeks, respectively (p = 0.215, HR = 0.55, 95%CI 0.21–1.43). Acute grade ≥3 toxicity was lower in arm 1 (16.7% versus 57.1%, p = 0.027), with the largest difference in grade 3 mucositis (5.6% versus 42.9%, p = 0.027). However, no significant deterioration in any of the patient-reported QoL-scales was found. ConclusionNo solid conclusion could be made on this incomplete study which is closed early. Long-course radiotherapy did not show significantly better oncologic outcomes, but was associated with more acute grade 3 mucositis. No meaningful differences in QoL-scores were found. Therefore, the shorter schedule might be carefully advocated. However, this recommendation should be interpreted with great caution because of the inadequate statistical power.

DAHANCA 28: A phase I/II feasibility study of hyperfractionated, accelerated radiotherapy with concomitant cisplatin and nimorazole (HART-CN) for patients with locally advanced, HPV/p16-negative squamous cell carcinoma of the oropharynx, hypopharynx, larynx and oral cavity

BackgroundA phase I–II study to evaluate the feasibility and efficacy of intensified, primary radiotherapy (RT) for Locally Advanced Head and Neck Squamous Cell Carcinoma (LAHNSCC) employing dose escalation by hyperfractionation, acceleration of treatment time, concomitant chemotherapy and hypoxic modification. MethodsPatients with HPV/p16- LAHNSCC receiving primary hyperfractionated, accelerated RT, 76 Gy/56 fx, 10 fx/week for 5½ weeks, concomitant weekly cisplatin (40 mg/m2) and nimorazole (HART-CN) were included. Primary endpoint was locoregional failure (LRF). Secondary endpoints were overall survival (OS) and toxicity. Results50 patients received HART-CN from 2013 to 2017. Median age was 60 years. Most patients had stage IV hypo- or oropharynx cancer with a heavy smoking history. All oropharyngeal cancers were HPV/p16-negative. Ninety-eight percent of patients completed RT, but compliance to cisplatin and nimorazole was lower. Median observation time was 44 months. LRF was diagnosed in 10 patients. All LRFs were in the high-dose CTV. The 3-year actuarial LRF was 21%, and OS was 74%. The peak incidence of acute toxicity showed that 67% of patients experienced severe dysphagia, 61% severe mucositis, and 78% were equipped with feeding tubes. Late severe morbidity was seen in 7 of 29 recurrence-free patients with at least 3 years of followup, who presented with either severe dysphagia (n = 2), severe xerostomia (n = 1), severe fibrosis of the neck (n = 3) or osteoradionecrosis (n = 1). Three were still tube dependent. ConclusionHART-CN is feasible in patients with HPV/p16- LAHNSCC in good health. Although acute toxicity was pronounced, the proportion of patients with late toxicity was acceptable and outcome at 3 years encouraging.

Treatment Related Risk Factors for Percutaneous Endoscopic Gastrostomy (PEG) Tube Placement in Locally Advanced Head and Neck Squamous Cell Carcinoma (LA-HNSCC)

Treatment Related Risk Factors for Percutaneous Endoscopic Gastrostomy (PEG) Tube Placement in Locally Advanced Head and Neck Squamous Cell Carcinoma (LA-HNSCC)