Publications by authors named "Makoto Tahara"

167 Publications

Real-world safety and effectiveness of nivolumab for recurrent or metastatic head and neck cancer in Japan: a post-marketing surveillance.

Int J Clin Oncol 2021 Jun 10. Epub 2021 Jun 10.

Department of Head and Neck Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

Background: On the basis of phase III CheckMate 141 results, nivolumab was approved for recurrent or metastatic head and neck cancer after undergoing platinum-containing chemotherapy in Japan. This post-marketing surveillance aimed to evaluate the safety and effectiveness of nivolumab for head and neck cancer in the real-world setting.

Methods: All patients with head and neck cancer who planned to receive nivolumab were centrally registered. This study monitored 607 patients for 6 months to assess nivolumab's safety, especially treatment-related adverse events (TRAEs) of special interest, and effectiveness.

Results: TRAEs occurred in 36.1% patients, with no new safety signals. The most common TRAEs with grade ≥ 3 were interstitial lung disease (1.2%), diarrhea (0.8%), and hepatic function abnormal (0.7%). Meanwhile, thyroid dysfunction (10.2%), hepatic dysfunction (5.3%), and interstitial lung disease (4.1%) were the most common TRAE categories of special interest. Although the median time to the onset of each TRAE category of special interest was mostly 1-2 months, most of them occurred throughout the observation period; nonetheless, the majority of patients recovered or remitted. The 6-month survival rate was 55.9%.

Conclusion: Japanese patients with head and neck cancer treated with nivolumab in the real-world setting manifested no new safety signals.

Clinical Trial Registration: clinicaltrials.jp: JapicCTI-184071.
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http://dx.doi.org/10.1007/s10147-021-01949-1DOI Listing
June 2021

Cholangioscopic finding of severe hemorrhagic cholangitis associated with immune-related adverse events.

Gastrointest Endosc 2021 Jun 1. Epub 2021 Jun 1.

Department of Head and Neck Medical oncology, National Cancer Center Hospital East.

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http://dx.doi.org/10.1016/j.gie.2021.05.038DOI Listing
June 2021

Electrochemotherapy in the Treatment of Head and Neck Cancer: Current Conditions and Future Directions.

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan.

Despite recent advances in the development of chemotherapeutic drug, treatment for advanced cancer of the head and neck cancer (HNC) is still challenging. Options are limited by multiple factors, such as a prior history of irradiation to the tumor site as well as functional limitations. Against this background, electrochemotherapy (ECT) is a new modality which combines administration of an antineoplastic agent with locally applied electric pulses. These pulses allow the chemotherapeutic drug to penetrate the intracellular space of the tumor cells and thereby increase its cytotoxicity. ECT has shown encouraging efficacy and a tolerable safety profile in many clinical studies, including in heavily pre-treated HNC patients, and is considered a promising strategy. Efforts to improve its efficacy and broaden its application are now ongoing. Moreover, the combination of ECT with recently developed novel therapies, including immunotherapy, represented by immune checkpoint inhibitor (ICI)s, has attracted attention for its potent theoretical rationale. More extensive, well-organized clinical studies and timely updating of consensus guidelines will bring this hopeful treatment to HNC patients under challenging situations.
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http://dx.doi.org/10.3390/cancers13061418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003720PMC
March 2021

Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

Lancet Oncol 2021 04;22(4):450-462

Moores Cancer Center, UC San Diego Health, La Jolla, CA, USA.

Background: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population.

Methods: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued.

Findings: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure).

Interpretation: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT.

Funding: Pfizer and Merck KGaA, Darmstadt, Germany.
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http://dx.doi.org/10.1016/S1470-2045(20)30737-3DOI Listing
April 2021

Hematological immune related adverse events after treatment with immune checkpoint inhibitors.

Eur J Cancer 2021 Apr 9;147:170-181. Epub 2021 Mar 9.

Department of Dermatology, University Hospital Kiel, Kiel, Germany.

Introduction: With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes.

Patients And Methods: Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres.

Results: In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis).

Conclusion: Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection.
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http://dx.doi.org/10.1016/j.ejca.2021.01.013DOI Listing
April 2021

Correlation of Performance Status and Neutrophil-Lymphocyte Ratio with Efficacy in Radioiodine-Refractory Differentiated Thyroid Cancer Treated with Lenvatinib.

Thyroid 2021 Apr 29. Epub 2021 Apr 29.

Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

Radioiodine-refractory differentiated thyroid cancer (RR-DTC) has a low 10-year patient-survival rate and is challenging to treat. Lenvatinib is a multikinase inhibitor approved for the treatment of RR-DTC. This study aims to assess Eastern Cooperative Oncology Group performance status (ECOG PS) and neutrophil-to-lymphocyte ratio (NLR) as prognostic markers for patients with RR-DTC treated with lenvatinib. In this retrospective analysis of the tudy of (7080) nvatinib in Differentiated ancer of the hyroid (SELECT), patients randomly assigned to receive lenvatinib were classified according to baseline ECOG PS (0 or 1) or baseline NLR (≤3 or >3). The effects of baseline ECOG PS and NLR on progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were evaluated. In addition, the effects of baseline ECOG PS on the change in diameter of target lesions and correlations between baseline NLR and the sums of the diameters of target lesions were calculated. Among patients who received lenvatinib, patients with a baseline ECOG PS of 0 had statistically improved PFS (hazard ratio [HR] 0.52; 95% confidence interval [CI 0.35-0.77];  = 0.001), OS (HR 0.42 [CI 0.26-0.69];  = 0.0004), and ORR (odds ratio [OR] 3.51 [CI 2.02-6.10];  < 0.0001) compared with patients with a baseline ECOG PS of 1. Patients who received lenvatinib with a baseline NLR ≤3 also had improved PFS (HR 0.43 [CI 0.29-0.65];  < 0.0001) and OS (HR 0.48 [CI 0.29-0.78];  = 0.0029) versus patients with a baseline NLR >3. Moreover, patients with a baseline NLR ≤3 had a trend toward increased ORR (OR 1.57 [CI 0.94-2.64];  = 0.08) compared with patients with a baseline NLR >3. Treatment-emergent adverse events were generally similar among patients who received lenvatinib, irrespective of patients' ECOG PS at baseline. Lower ECOG PS and NLR may provide prognostic value for improved efficacy in patients with RR-DTC. ClinicalTrials.gov no. NCT01321554.
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http://dx.doi.org/10.1089/thy.2020.0779DOI Listing
April 2021

Impact of lung metastases on overall survival in the phase 3 SELECT study of lenvatinib in patients with radioiodine-refractory differentiated thyroid cancer.

Eur J Cancer 2021 Apr 19;147:51-57. Epub 2021 Feb 19.

Massachusetts General Hospital Cancer Center, Boston, MA, USA.

Background: Lung metastases may worsen overall survival (OS) in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). We investigated (post hoc) the impact of lung metastases on survival in SELECT (a phase 3 study).

Patients And Methods: 392 patients with RR-DTC were randomised 2:1 to lenvatinib 24 mg daily (n = 261) or placebo (n = 131). Placebo-treated patients could crossover to open-label lenvatinib following progression. Patients were grouped by size of baseline lung metastases. Safety/efficacy outcomes, collated by these lung-metastases subgroups, were generated.

Results: Lenvatinib-treated population distributions per baseline lung metastases subgroup were any lung metastases (target/nontarget lesions; n = 226), and by maximum size of target lung lesions ≥1.0 cm (n = 199), ≥1.5 cm (n = 150), ≥2.0 cm (n = 94) and <2.0 cm (n = 105). In patients with any lung metastases, no statistically significant difference in OS was observed between treatment arms (HR: 0.76; 95% CI: 0.57-1.01; P = 0.0549). Median OS for lung metastases of ≥1.0 cm was 44.7 months (lenvatinib) versus 33.1 months (placebo) (HR: 0.63; 95% CI: 0.47-0.85; P = 0.0025). OS was significantly prolonged with lenvatinib versus placebo among patients with lung metastases of ≥1.0 cm, ≥1.5 cm, ≥2.0 cm and <2.0 cm; median OS was shorter in the ≥2.0 cm subgroup (lenvatinib: 34.7 months) versus other subgroups (lenvatinib: 44.1-49.2 months). Multivariate analysis demonstrated lenvatinib significantly prolonged OS in patients with lung metastases of ≥1.0 cm after adjustment for baseline characteristics.

Conclusions: Lenvatinib treatment resulted in longer OS in patients with lung metastases of ≥1.0 cm versus placebo (even with the 89% crossover rate). Early initiation of lenvatinib may improve outcomes in patients with RR-DTC and lung metastases of ≥1.0 cm.

Source Study Registration: ClinicalTrials.Gov Identifier: NCT01321554.
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http://dx.doi.org/10.1016/j.ejca.2020.12.032DOI Listing
April 2021

Palbociclib and cetuximab compared with placebo and cetuximab in platinum-resistant, cetuximab-naïve, human papillomavirus-unrelated recurrent or metastatic head and neck squamous cell carcinoma: A double-blind, randomized, phase 2 trial.

Oral Oncol 2021 04 8;115:105192. Epub 2021 Feb 8.

Head and Neck Oncology Division, Japanese National Cancer Center, Chiba, Japan.

Objectives: This study examined whether palbociclib and cetuximab prolonged overall survival (OS) versus placebo and cetuximab.

Materials And Methods: In this double-blind, randomized, phase 2 trial (PALATINUS), patients with platinum-resistant, cetuximab-naïve, human papillomavirus-unrelated recurrent/metastatic head and neck squamous-cell carcinoma received cetuximab and either palbociclib (arm A) or placebo (arm B). The primary endpoint was OS; 120 patients were required to have ≥80% power to detect a hazard ratio (HR) of 0.6 (median OS of 10 months in arm A and 6 months in arm B) using a one-sided, log-rank test (P = 0.10).

Results: 125 patients were randomized (arm A: 65, arm B: 60). Median follow-up was 15.9 months (IQR, 11.3-22.7). Median OS was 9.7 months in arm A and 7.8 months in arm B (HR, 0.82; 95% CI, 0.54-1.25; P = 0.18). Median progression-free survival was 3.9 months in arm A and 4.6 months in arm B (HR, 1.00; 95% CI, 0.67-1.5; P = 0.50). The most common treatment-related adverse events in arm A were rash (39 patients, 60.9%) and neutropenia (26, 40.6%; three febrile) and in arm B was rash (32, 53.3%).

Conclusion: There was no significant difference in median OS with palbociclib and cetuximab versus placebo and cetuximab.

Funding: Pfizer Inc (NCT02499120).
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http://dx.doi.org/10.1016/j.oraloncology.2021.105192DOI Listing
April 2021

Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck.

Jpn J Clin Oncol 2021 Feb;51(2):173-179

Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

In order to maximize the benefit of induction chemotherapy, practice based on a comprehensive interpretation of a large number of clinical trials, as in this review, is essential. The standard treatment for locally advanced squamous cell carcinoma of the head and neck is surgery or chemoradiation. However, induction chemotherapy followed by (chemo) radiotherapy may be used in some circumstances. Although many clinical trials of induction chemotherapy have been conducted, a rationale other than to preserve the larynx is still controversial. Selection of this modality should therefore be made with care. The current standard regimen for induction chemotherapy is docetaxel, cisplatin and 5-FU, but concerns remain about toxicity, cost and the duration of treatment. Regarding treatment after induction chemotherapy, it is also unclear whether radiation alone or chemoradiation is the better option. Furthermore, there is no answer as to what drugs should be used in combination with radiation therapy after induction chemotherapy. Several new induction chemotherapy treatment developments are currently underway, and future developments are expected. This review article summarizes the current position of induction chemotherapy for head and neck squamous cell carcinoma, based on the evidence produced to date, and discusses the future prospects for this treatment.
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http://dx.doi.org/10.1093/jjco/hyaa220DOI Listing
February 2021

Multi-institutional Survey of Squamous Cell Carcinoma of the External Auditory Canal in Japan.

Laryngoscope 2021 03 30;131(3):E870-E874. Epub 2020 Jul 30.

Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Japan.

Objectives: This study aimed to evaluate the efficacy of chemoradiotherapy (CRT) for patients with advanced cancer of the external auditory canal (EAC) by analyzing the outcome of the patients.

Methods: This is a multi-institutional retrospective survey, and we reviewed the medical records of the subjects. A total of 181 patients with tumor (T)3 or T4 tumor in 17 institutions were enrolled. Further analysis was performed for 74 patients who underwent CRT under curative intent.

Results: Overall 5-year survival rates of the patients who underwent CRT (n = 74) were 54.6%. Those of the patients who underwent CRT with modified TPF (docetaxel, cisplatin [CDDP], and 5-fluorouracil) regimen (n = 50) and CRT with CDDP regimens (n = 24) were 64.4% and 36.7%, respectively. Significant differences were observed between these two groups.

Conclusion: Given the tendency that head and neck surgeons prefer CRT for advanced larger cancer of the EAC, CRT for advanced EAC cancer using the modified TPF regimen showed good clinical outcomes.

Level Of Evidence: 4 Laryngoscope, 131:E870-E874, 2021.
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http://dx.doi.org/10.1002/lary.28936DOI Listing
March 2021

A management of neutropenia using granulocyte colony stimulating factor support for chemotherapy consisted of docetaxel, cisplatin and 5-fluorouracil in patients with oesophageal squamous cell carcinoma.

Jpn J Clin Oncol 2021 Feb;51(2):199-204

Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan.

Background: An exploratory study was designed to evaluate the efficacy of granulocyte colony stimulating factor support for chemotherapy consisting of docetaxel, cisplatin and 5-fluorouracil chemotherapy in patients with oesophageal cancer.

Methods: The inclusion criteria were as follows: (1) oesophageal squamous cell carcinoma, (2) a schedule to receive three courses of induction chemotherapy (docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, 5-fluorouracil 750 mg/m2 days 1-5, every 3 weeks), (3) stage IB-III, (4) 20-75 years old, (5) 0-1 performance status, (6) preserved organ functions and (7) written informed consent. The endpoints were to evaluate the efficacy of granulocyte colony stimulating factor support including secondary prophylactic usage for docetaxel, cisplatin and 5-fluorouracil chemotherapy. Patients who previously had 'febrile neutropenia', or 'Grade 3 or 4 infection accompanied by grade 3 or 4 neutropenia' prophylactically received granulocyte colony stimulating factor support from day 7.

Results: A total of 91 patients were included in the analysis. Granulocyte colony stimulating factor support was given to 81.3%. The incidence of grade 4 neutropenia and febrile neutropenia were 81.3 and 32.9%, respectively. The dose of anticancer agents was reduced in 48.4%. There were no treatment-related deaths. The relative dose intensity of docetaxel, cisplatin and 5-fluorouracil were 92.7 ± 9.8%, 86.0 ± 15.6% and 91.8 ± 10.0%, respectively. In the secondary prophylactic granulocyte colony stimulating factor support group, the neutrophil count significantly increased between day 7 and day 13 as compared with the non-prophylactic granulocyte colony stimulating factor support group (P < 0.05 for each day).

Conclusions: Granulocyte colony stimulating factor support including secondary prophylactic usage may be feasible for maintaining the intensity of docetaxel, cisplatin and 5-fluorouracil chemotherapy in patients with oesophageal cancer.
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http://dx.doi.org/10.1093/jjco/hyaa190DOI Listing
February 2021

Combination Treatment With Paclitaxel, Carboplatin, and Cetuximab (PCE) as First-Line Treatment in Patients With Recurrent and/or Metastatic Nasopharyngeal Carcinoma.

Front Oncol 2020 7;10:571304. Epub 2020 Oct 7.

Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Platinum-containing doublet chemotherapy regimens are generally considered the standard first-line systemic therapy for recurrent or metastatic (R/M) nasopharyngeal cancer (NPC). Gemcitabine (GEM) plus cisplatin (CDDP) has become a standard therapy based on a phase 3 study in several countries, yet this regimen sometimes affects quality of life due to nausea or appetite loss. Here, we present the manageable toxicity and promising activity of paclitaxel + carboplatin + cetuximab (PCE) therapy for R/M NPC. We conducted a retrospective review of patients with R/M NPC who were treated with PCE from 2013 to 2019 at the National Cancer Center East, Kashiwa, Japan. PCE consisted of PTX 100 mg/m on days 1 and 8; CBDCA area under the blood concentration-time curve (AUC) 2.5 on days 1 and 8, repeated every 3 weeks; and cetuximab at an initial dose of 400 mg/m, followed by 250 mg/m weekly, as reported in the paper. Fourteen patients were identified, consisting of 10 males and 4 females with a median age 59.6 years (range, 43-74). Among the 12 of 14 patients assessed for efficacy, overall response rate was 58.3%, with 2 complete responses and 5 partial responses. On median follow-up of 23.8 months, median overall survival was not reached with observed death events of 2. Median PFS was 4.1 months (95% CI, 2.6-5.6 months). Two patients experienced disease progression during cetuximab maintenance and restarted PCE treatment, then achieved partial response again. The most common grade 3 or 4 adverse events were neutropenia (21.4%) and skin reaction (14.3%). No treatment-related death was observed. Although the number of study population was small, our results suggest that PCE is feasible and potentially effective for R/M NPC, with a 58.3% response rate and 4.1-month PFS. Further prospective evaluation is warranted.
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http://dx.doi.org/10.3389/fonc.2020.571304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575747PMC
October 2020

Immunotherapy for squamous cell carcinoma of the head and neck.

Jpn J Clin Oncol 2020 Sep;50(10):1089-1096

Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Japan.

Squamous cell carcinoma of the head and neck is characterized by an immunosuppressive environment and evades immune responses through multiple resistance mechanisms. A breakthrough in cancer immunotherapy employing immune checkpoint inhibitors has evolved into a number of clinical trials with antibodies against programmed cell death 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for patients with squamous cell carcinoma of the head and neck. CheckMate141 and KEYNOTE-048 were practice-changing randomized phase 3 trials for patients with platinum-refractory and platinum-sensitive recurrent or metastatic squamous cell carcinoma of the head and neck, respectively. Furthermore, many combination therapies using anti-CTLA-4 inhibitors, tyrosine kinase inhibitors and immune accelerators are currently under investigation. Thus, the treatment strategy of recurrent or metastatic squamous cell carcinoma of the head and neck is becoming more heterogeneous and complicated in the new era of individualized medicine. Ongoing trials are investigating immunotherapeutic approaches in the curative setting for locoregionally advanced disease. This review article summarizes knowledge of the role of the immune system in the development and progression of squamous cell carcinoma of the head and neck, and provides a comprehensive overview on the development of immunotherapeutic approaches in both recurrent/metastatic and locoregionally advanced diseases.
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http://dx.doi.org/10.1093/jjco/hyaa139DOI Listing
September 2020

Re-challenge of Platinum-based Chemotherapy for Platinum-refractory Patients with Recurrent or Metastatic Head and Neck Cancer: Claims Data Analysis in Japan.

J Health Econ Outcomes Res 2020 20;7(1):43-51. Epub 2020 May 20.

Bristol-Myers Squibb K.K., Tokyo, Japan.

Background: The role of platinum rechallenge in head and neck cancer (HNC) has not yet been fully evaluated.

Objectives: It is our goal to assess the real-world treatment patterns and usefulness of platinum rechallenge in patients with platinum-refractory recurrent or metastatic HNC receiving platinum rechallenge.

Methods: This is a retrospective study using data from a Japanese hospital claims database stored in electronic hospital information systems. Patients with HNC or undefined histology with an HNC diagnosis using the disease code, between January 1, 2013 and September 30, 2016, were included. Patients diagnosed with other malignancies on or before the initial diagnosis of HNC and those without cancer stage information in the database were excluded from the study.

Results: A total of 43 994 patients were identified from the database as HNC patients. Of those, in patients who had cancer progression within 6 months after platinum-based chemotherapy administered for primary or recurrent disease (N=842), the median treatment duration of platinum rechallenge for platinum refractory patients was only 1 cycle. The second-line treatment continuation rate at 6 months was 20.1% for patients who received platinum rechallenges and 32.8% for those who received non-platinum-based regimens.

Conclusions: The findings from this study of data from routine clinical practice suggest that the benefit of platinum rechallenge in a platinum-refractory setting would be limited.
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http://dx.doi.org/10.36469/jheor.2020.12853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299445PMC
May 2020

Safety and Effectiveness of Lenvatinib in 594 Patients with Unresectable Thyroid Cancer in an All-Case Post-Marketing Observational Study in Japan.

Adv Ther 2020 09 16;37(9):3850-3862. Epub 2020 Jul 16.

Kanagawa Health Service Association, Nihon-odori bldg. 58 Nihon-odori, Naka-ku, Yokohama, 231-0021, Japan.

Introduction: Lenvatinib is approved in Japan for treating patients with all histological subtypes of unresectable thyroid cancer, including differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC), and anaplastic thyroid cancer (ATC). However, safety and effectiveness data are limited in Japanese patients. Therefore, this prospective, post-marketing observational study evaluated, in daily clinical practice, the safety and effectiveness of lenvatinib in Japanese patients with unresectable thyroid cancer.

Methods: All patients with unresectable thyroid cancer first treated with lenvatinib between May and November 2015 were registered. Patients were orally administered lenvatinib and followed up for 12 months. The endpoints included adverse drug reactions (ADRs), overall survival (OS), overall response rate (ORR), and time-to-treatment failure. Post hoc Cox multivariate analyses were performed to assess prognostic factors associated with the 12-month OS rate.

Results: Of 629 registered patients, 594 were included in the analysis. A total of 442 patients (74.4%) had DTC, 28 (4.7%) had MTC, and 124 (20.9%) had ATC. Hypertension, proteinuria, and palmar-plantar erythrodysesthesia syndrome were the most frequently reported ADRs across all histological subtypes. The median OS was 101.0 days in patients with ATC which was not reached in patients with DTC and patients with MTC, with 12-month OS rates of 15.6%, 75.7%, and 83.0%, respectively. The ORRs were 59.2%, 45.0%, and 43.8% among 368 patients with DTC, 20 with MTC, and 105 with ATC, respectively. Multivariate analyses revealed that Eastern Cooperative Oncology Group performance status (ECOG PS), tumor size, the presence of tumor invasion, and body weight were baseline prognostic factors affecting OS in patients with DTC, while ECOG PS and the presence of liver metastasis were prognostic factors in patients with ATC.

Conclusion: Lenvatinib demonstrated an acceptable safety profile for patients with thyroid cancer in a real-world setting in Japan. The safety profile and effectiveness findings for lenvatinib in this study were consistent with those from previous clinical trials, irrespective of histological subtype.
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http://dx.doi.org/10.1007/s12325-020-01433-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444395PMC
September 2020

Impact of outpatient pharmacy interventions on management of thyroid patients receiving lenvatinib.

SAGE Open Med 2020 12;8:2050312120930906. Epub 2020 Jun 12.

Department of Pharmacy, National Cancer Center Hospital East, National Research and Development Agency, Kashiwa, Japan.

Objectives: Medical oncologists and pharmacists at our institution established an integrated support program aimed at preventing unnecessary treatment interruption or dose reduction during oral targeted therapy with lenvatinib. Here, we evaluated the benefits of this program in managing patients with thyroid cancer receiving lenvatinib.

Methods: We retrospectively evaluated thyroid cancer patients who received lenvatinib between May 2015 and March 2017. This descriptive study collected records in which pharmacists contributed to changing doctors' prescriptions and categorized the interventions.

Results: During the study period, 24 thyroid cancer patients were treated with lenvatinib. Among patients, the incidence of temporary interruption and dose reduction of lenvatinib due to adverse drug reactions was 100% (n = 24) and 83.3% (n = 20), respectively. There were 193 temporary interruptions of lenvatinib due to adverse drug reactions. A total of 501 outpatient pharmacy services were conducted by pharmacists in collaboration with oncologists, of which 125 were interventions (24.9%). In addition, pharmacists conducted 156 telephone follow-up services; 18 (11.5%) of these were to consult an oncologist about a patient's confirmed problems and resulted in the decision to continue observation with no medical intervention while 41 (26.2%) resulted in the oncologist deciding to temporarily interrupt lenvatinib treatment after the report of an adverse drug reaction from the pharmacist.

Conclusion: Pharmacist interventions in collaboration with medical oncologists improved lenvatinib therapy. Interventions for outpatients were conducted not only in outpatient clinics but also by telephone follow-up, clarifying the importance of continuous management for patients at risk of adverse reactions and misuse of oral medicine.
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http://dx.doi.org/10.1177/2050312120930906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294491PMC
June 2020

Two-year follow-up of a randomized phase III clinical trial of nivolumab vs. the investigator's choice of therapy in the Asian population for recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141).

Head Neck 2020 10 24;42(10):2852-2862. Epub 2020 Jun 24.

Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Background: The present study evaluated the 2-year survival of the Asian population in the CheckMate 141 trial.

Methods: The CheckMate 141 trial included patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). In the present study, 34 Asian patients (nivolumab group: 23 patients; investigator's choice of therapy [IC] group: 11 patients) were analyzed.

Results: The median overall survival (OS) was 12.1 and 6.2 months for the nivolumab and IC groups, respectively. The estimated 2-year OS rates were 22.7% and 0% for the nivolumab and IC groups, respectively. In the nivolumab group, the patients with any treatment-related adverse events (TRAEs), including skin-related disorders, showed better OS than the patients without any TRAEs.

Conclusions: Nivolumab demonstrated prolonged OS benefits in the Asian population with platinum-refractory R/M SCCHN and a favorable safety profile. TRAEs, including skin-related disorders, may be favorable prognostic factors for nivolumab efficacy.

Clinical Trial Registration: NCT02105636.
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http://dx.doi.org/10.1002/hed.26331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540331PMC
October 2020

DNA markers based on retrotransposon insertion polymorphisms can detect short DNA fragments for strawberry cultivar identification.

Breed Sci 2020 Apr 26;70(2):231-240. Epub 2020 Feb 26.

Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.

In this study, DNA markers were developed for discrimination of strawberry ( × L.) cultivars based on retrotransposon insertion polymorphisms. We performed a comprehensive genomic search to identify retrotransposon insertion sites and subsequently selected one retrotransposon family, designated CL3, which provided reliable discrimination among strawberry cultivars. Through analyses of 75 strawberry cultivars, we developed eight cultivar-specific markers based on CL3 retrotransposon insertion sites. Used in combination with 10 additional polymorphic markers, we differentiated 35 strawberry cultivars commonly cultivated in Japan. In addition, we demonstrated that the retrotransposon-based markers were effective for PCR detection of DNA extracted from processed food materials, whereas a SSR marker was ineffective. These results indicated that the retrotransposon-based markers are useful for cultivar discrimination for processed food products, such as jams, in which DNA may be fragmented or degraded.
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http://dx.doi.org/10.1270/jsbbs.19116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272250PMC
April 2020

De-Escalation After DE-ESCALATE and RTOG 1016: A Head and Neck Cancer InterGroup Framework for Future De-Escalation Studies.

J Clin Oncol 2020 08 4;38(22):2552-2557. Epub 2020 Jun 4.

University of Queensland, and Princess Alexandra Hospital, Brisbane, Queensland, Australia.

Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is increasing rapidly. The younger age, significantly improved prognosis, and relative morbidity of the standard-of-care cisplatin and radiotherapy in this population have led to the popularization of the concept of treatment de-escalation. The recent results of the first 3 randomized de-escalation trials, however, have shown a clear detriment in survival when cisplatin is omitted or substituted. In view of these results, the Head and Neck Cancer International Group identified the need to issue guidance regarding future de-escalation studies for patients with HPV-positive head and neck cancer to avoid the possibility of patients being harmed. We review the current state of the literature regarding HPV de-escalation trials and present a framework and guidance on future and existing clinical trials for treatment de-escalation of HPV-positive OPC. De-escalation paradigms of HPV-positive OPC should be evaluated in phase II studies, and results should be awaited before proceeding to phase III studies. Implementation into clinical practice before high-level evidence is available should be undertaken in this context. Finally, harm-minimization techniques should also be evaluated as an alternative to de-escalation of treatment in these patient groups.
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http://dx.doi.org/10.1200/JCO.20.00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392745PMC
August 2020

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412.

Future Oncol 2020 Jun 3;16(18):1235-1243. Epub 2020 Jun 3.

Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.

Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0184DOI Listing
June 2020

Salvage Reconstructive Surgery During Nivolumab Therapy for a Patient With Hypopharyngeal Cancer.

Clin Med Insights Case Rep 2020 18;13:1179547620908854. Epub 2020 Apr 18.

Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Japan.

Objectives: Nivolumab, a fully IgG4-programmed death-1 inhibitor antibody, led to improved overall survival compared with single-agent therapy in patients with platinum-refractory recurrent head and neck cancers. In general, nivolumab is used in inoperable patients. To the best of our knowledge, there have been no reports of salvage surgery during nivolumab therapy for patients with head and neck cancer. We report the case of a woman treated with salvage reconstructive surgery during nivolumab therapy.

Method: Case report and literature review.

Results: The patient underwent nivolumab therapy for recurrent primary and neck disease after induction chemotherapy, followed by concurrent chemoradiation therapy. The neck disease shrunk, whereas the primary disease temporarily shrunk but later progressed again. Recurrent primary disease led to a narrowing of her airway, and she required airway management. We performed total pharyngolaryngectomy with free jejunal reconstruction, and her quality of life improved. The surgery was performed without complications and the postoperative course was uneventful. She was discharged postoperative day 18 with oral intake function and a safer airway.

Conclusion: As far as we know, this is the first report of salvage surgery during nivolumab therapy for patients with head and neck cancer. The salvage reconstructive surgery in this case proceeded uneventfully.
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http://dx.doi.org/10.1177/1179547620908854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169354PMC
April 2020

Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.

Lancet Oncol 2020 04 24;21(4):531-540. Epub 2020 Feb 24.

Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address:

Background: The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.

Methods: Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).

Findings: Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred.

Interpretation: These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible.

Funding: Bayer and Loxo Oncology.
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http://dx.doi.org/10.1016/S1470-2045(19)30856-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497841PMC
April 2020

Efficacy and safety of accelerated fractionated radiotherapy without elective nodal irradiation for T3N0 glottic cancer without vocal cord fixation.

Head Neck 2020 08 7;42(8):1775-1782. Epub 2020 Feb 7.

Department of Radiation Oncology, National Cancer Center Hospital East, Chiba, Japan.

Background: The purpose of this study was to evaluate accelerated fractionated radiotherapy (AFRT) without elective nodal irradiation (ENI) for T3N0 glottic cancer (GC) without vocal cord fixation, especially in comparison with chemoradiotherapy (CRT) and hyperfractionated radiotherapy (HFRT) both of which included ENI.

Methods: The medical charts of patients with T3N0GC without cord fixation received definitive radiotherapy between June 2005 and March 2018 were reviewed.

Results: A total of 74 patients were analyzed. After a median follow-up time of 46 months (range, 12-141), 3-year local failure in AFRT/CRT/HFRT (n = 41/10/23) was 10%/20%/26%, 3-year regional failure 6%/0%/9%, 3-year progression-free survival 71%/69%/74%, and 3-year overall survival 77%/100%/87%. There were no significant differences among three groups in recurrence or survival. Grade 3 adverse events (AEs) were noted in 5/2/8 patients (12%/20%/35%) in AFRT/CRT/HFRT, respectively. There were no Grade 4/5 AEs.

Conclusions: AFRT without ENI is an effective and feasible treatment for T3N0GC without cord fixation.
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http://dx.doi.org/10.1002/hed.26092DOI Listing
August 2020

A multicenter phase II trial of paclitaxel, carboplatin, and cetuximab followed by chemoradiotherapy in patients with unresectable locally advanced squamous cell carcinoma of the head and neck.

Cancer Med 2020 03 13;9(5):1671-1682. Epub 2020 Jan 13.

Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.

Background: Induction chemotherapy (IC) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) often compromises compliance with subsequent chemoradiotherapy (CRT), which negatively affects outcomes. Here, we assessed the combination of paclitaxel (PTX), carboplatin (CBDCA), and cetuximab (Cmab) as IC for unresectable LA-SCCHN.

Methods: Induction chemotherapy consisted of weekly CBDCA area under the plasma concentration-time curve = 1.5, PTX 80 mg/m and Cmab with an initial dose of 400 mg/m followed by 250 mg/m for 8 weeks. Following IC, CDDP (20 mg/m , 4 days × 3 cycles) and concurrent radiotherapy (70 Gy/35 fr) were started. Primary endpoint was the proportion of CRT completion (%CRT completion). PCE was planned to be deemed effective if the Bayesian posterior probability (PP), defined as the probability that %CRT completion was larger than the threshold value of 65%, exceeded 84%.

Results: Thirty-five patients were enrolled. Cases were hypopharynx/oropharynx/larynx in 17/17/1 patients, all at Stage IV. Of 35 patients, 34 (97%) completed IC and 32 received CRT and met the criteria of full analysis set (FAS). In FAS, the %CRT completion was 96.9%, and PP was 99.9%, exceeding the prespecified boundary of 84%. Mean cumulative dose and relative to dose intensity of CDDP in CRT was 232.5 mg/m and 100%, respectively. Response rate was 88.6% by IC and 93.8% in the CRT phase. Three year overall survival was 83.5%. Main grade 3 toxicities included neutropenia (11.4%) and skin rash (5.7%) during IC; and oral mucositis (31.3%) and neutropenia (12.5%) during CRT. No grade 4 toxicity or treatment-related death was seen.

Conclusions: PCE as IC was feasible, with promising efficacy and no effect on compliance with subsequent CRT in unresectable LA-SCCHN.
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http://dx.doi.org/10.1002/cam4.2852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050099PMC
March 2020

Comparison of salvage surgery for recurrent or residual head and neck squamous cell carcinoma.

Jpn J Clin Oncol 2020 Mar;50(3):288-295

Departments of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Japan.

Objective: Concomitant chemoradiation therapy is a standard treatment for head and neck cancer. Thus, salvage surgery has become a necessary treatment. The aim of the study was to evaluate the results of salvage surgery by each site of the head and neck, especially the oropharynx, hypopharynx and larynx.

Methods: This was a retrospective, single-institute study. The primary endpoint was overall survival. Secondary endpoints were disease-free survival, the locoregional control rate after salvage surgery, the indication rate for salvage surgery, the reasons for contraindications to salvage surgery, the post-operative complication rate and the predictors of survival.

Results: Three-year overall survival after salvage surgery was 58.8% in the salvage surgery group and 8.59% in the other treatment group (P < 0.0001). Regarding overall survival and disease-free survival after salvage surgery, there was no difference among sites. Regarding locoregional control rate among sites, there was no significant difference. The oropharyngeal cancer group had the lowest rate of salvage primary resection. Surgical margin and local and regional recurrence or residual disease were predictors on univariate and multivariate analyses.

Conclusions: Salvage surgery is effective for recurrent or residual cases after concomitant chemoradiation therapy. For oropharyngeal cancer, local control is important, and for oropharyngeal cancer and hypopharyngeal cancer, distant metastasis is important.
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http://dx.doi.org/10.1093/jjco/hyz176DOI Listing
March 2020

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study.

Lancet 2019 11 1;394(10212):1915-1928. Epub 2019 Nov 1.

Peter MacCallum Cancer Centre, Melbourne, VIC, Austrialia; University of Melbourne, Melbourne, VIC, Australia.

Background: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.

Methods: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.

Findings: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group.

Interpretation: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S0140-6736(19)32591-7DOI Listing
November 2019

Nutritional support dependence after curative chemoradiotherapy in head and neck cancer: supplementary analysis of a phase II trial (JCOG0706S1).

Jpn J Clin Oncol 2019 Dec;49(11):1009-1015

Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Objectives: To explore the risk factors of laryngo-esophageal dysfunction-free survival and nutritional support dependence over 12 months in patients with unresectable locally advanced head and neck carcinomas who received chemoradiotherapy in a phase II trial of JCOG0706 (UMIN000001272).

Methods: Forty-five patients received radiation therapy for a total of 70 Gy/35fr concurrently with S-1 and cisplatin. Risk factors of laryngo-esophageal dysfunction-free survival and nutritional support dependence over 12 months were analyzed using Cox regression models and logistic regression models, respectively, with consideration to patient laboratory data just before chemoradiotherapy. Radiation fields were reviewed to analyze the relationship between the extent of the irradiated field and functional outcome.

Results: With a median follow-up period of 3.5 years, 3-year laryngo-esophageal dysfunction-free survival was 48.9%. For laryngo-esophageal dysfunction-free survival, hazards ratio of 2.35 in patients with nutritional support at registration (vs. without nutritional support; 95% confidence interval 0.96-5.76). For nutritional support dependence over 12 months, odds ratio was 6.77 in patients with hemoglobin less than the median of 13.4 g/dl (vs. higher than or equal to the median; 95% confidence interval 1.24-36.85) and was 6.00 in patients with albumin less than the median of 3.9 g/dl (vs. higher than or equal to the median; 95% confidence interval 1.11-32.54). Primary sites in disease-free patients with nutritional support dependence over 12 months were the oropharynx (N = 2) or hypopharynx (N = 1), and all pharyngeal constrictor muscles were included in irradiated fields with a curative dose.

Conclusions: This supplementary analysis showed that pretreatment severe dysphagia requiring nutritional support, anemia and hypoalbuminemia might have a negative prognostic impact on long-term functional outcomes after curative chemoradiotherapy in head and neck cancer.
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http://dx.doi.org/10.1093/jjco/hyz121DOI Listing
December 2019

The Evolving Role of Taxanes in Combination With Cetuximab for the Treatment of Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck: Evidence, Advantages, and Future Directions.

Front Oncol 2019 21;9:668. Epub 2019 Aug 21.

Medical Oncology Department, Catalan Institute of Oncology, B-ARGO Group-Badalona, Barcelona, Spain.

The addition of cetuximab to platinum-based chemotherapy (cisplatin or carboplatin plus 5-fluorouracil [5-FU]), followed by maintenance cetuximab until disease progression (EXTREME), resulted in the first regimen to yield significantly improved survival outcomes in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in over 30 years. Currently, the EXTREME regimen is a guideline-recommended treatment in the first-line R/M setting, and, therefore, it is used as a control arm in all new first-line, phase 3 immunotherapy trials. More recently, new checkpoint inhibitor approaches have emerged and are changing the treatment landscape for PD-L1-positive patients with R/M SCCHN. Additionally, alternative chemotherapy backbones in R/M SCCHN are continually investigated. Replacing 5-FU with a taxane in the EXTREME regimen seeks to take advantage of the potential immunogenic and proapoptotic synergy between cetuximab and docetaxel or paclitaxel. These cetuximab-, platinum-, and taxane-based treatments have demonstrated promising survival results and cytoreductive properties in single-arm studies. Thus, these combination treatments may be of importance to patients with high tumor burden and dangerous site involvements (e.g., causing bleeding, suffocation, dysphagia, or ulceration), in whom symptom relief is a key treatment goal. TPExtreme is the first large, randomized trial comparing a cetuximab, platinum, and taxane combination regimen with EXTREME. Currently, the substitution of 5-FU with a taxane is a feasible and clinically beneficial option for patients with contraindications to 5-FU. The TPEx regimen appears to be a new option in first-line R/M SCCHN, with a shorter time on CT and significantly lower toxicity than the EXTREME regimen. For patients with R/M disease in whom further cisplatin- or carboplatin-based treatment is unsuitable, or whose disease has already progressed on first-line R/M therapy, treatment options such as cetuximab plus a taxane, which capitalize on the combinative ability of the 2 agents, can be considered. Notably, it is as of yet unknown what second-line treatments may be suitable to follow a checkpoint inhibitor-based first-line therapy.
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http://dx.doi.org/10.3389/fonc.2019.00668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712586PMC
August 2019

Afatinib as second-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: Subgroup analyses of treatment adherence, safety and mode of afatinib administration in the LUX-Head and Neck 1 trial.

Oral Oncol 2019 10 23;97:82-91. Epub 2019 Aug 23.

Department of Medicine, West German Cancer Center, University Hospital Essen of the University Duisburg-Essen, Essen, Germany.

Objectives: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis).

Methods: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m/week).

Results: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83-92% and 76-92% (of patients with data available) across all subgroups took ≥80% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70-91%), rash/acne (72-84%), stomatitis (34-73%) with afatinib; and included stomatitis (39-100%), fatigue (22-50%), nausea (19-36%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took ≥80% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72-1.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%).

Conclusion: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration.
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http://dx.doi.org/10.1016/j.oraloncology.2019.08.004DOI Listing
October 2019

Development of molecular markers associated with resistance to Meloidogyne incognita by performing quantitative trait locus analysis and genome-wide association study in sweetpotato.

DNA Res 2019 Oct;26(5):399-409

Graduate School of Environmental and Life Science, Okayama University, Okayama, Okayama, Japan.

The southern root-knot nematode, Meloidogyne incognita, is a pest that decreases yield and the quality of sweetpotato [Ipomoea batatas (L.) Lam.]. There is a demand to produce resistant cultivars and develop DNA markers to select this trait. However, sweetpotato is hexaploid, highly heterozygous, and has an enormous genome (∼3 Gb), which makes genetic linkage analysis difficult. In this study, a high-density linkage map was constructed based on retrotransposon insertion polymorphism, simple sequence repeat, and single nucleotide polymorphism markers. The markers were developed using F1 progeny between J-Red, which exhibits resistance to multiple races of M. incognita, and Choshu, which is susceptible to multiple races of such pest. Quantitative trait locus (QTL) analysis and a genome-wide association study detected highly effective QTLs for resistance against three races, namely, SP1, SP4, and SP6-1, in the Ib01-6 J-Red linkage group. A polymerase chain reaction marker that can identify genotypes based on single nucleotide polymorphisms located in this QTL region can discriminate resistance from susceptibility in the F1 progeny at a rate of 70%. Thus, this marker could be helpful in selecting sweetpotato cultivars that are resistant to multiple races of M. incognita.
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http://dx.doi.org/10.1093/dnares/dsz018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796513PMC
October 2019