Adrenal insufficiency following nivolumab therapy in patients with recurrent or metastatic head and neck cancer

Nivolumab, an anti-programmed cell death-1 monoclonal antibody, is currently used to treat many types of advanced cancers including recurrent and metastatic head and neck cancer. However, there are increasing reports concerning immune-related adverse events related to nivolumab therapy. Here, we report three patients who presented with adrenal insufficiency following nivolumab therapy. Two were diagnosed as having isolated adrenocorticotropic hormone (ACTH) deficiency and one was diagnosed as having primary adrenal insufficiency. All three patients complained of progressive fatigue and appetite loss, so we measured their blood cortisol and ACTH levels and diagnosed them as having adrenal deficiency. Treatment with nivolumab was discontinued for all three patients, and replacement therapy using hydrocortisone was successful after a few days in all cases. Two patients subsequently resumed nivolumab therapy because their general condition had improved. Complaints of fatigue and appetite loss during cancer treatment are common and tend to be regarded as unimportant. Although adrenal insufficiency due to nivolumab is relatively rare, complaints of these symptoms could lead to the detection of adrenal insufficiency at an early stage. The present report highlights the importance of the early recognition of adrenal insufficiency.     

Outcome of chemotherapy following nivolumab treatment for recurrent and/or metastatic head and neck squamous cell carcinoma

ObjectiveAlthough nivolumab treatment is effective in extending the overall survival (OS) in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), only a few patients benefit from this treatment. Recent studies have reported that chemotherapy and cetuximab might be effective for R/M HNSCC after nivolumab treatment. In the present study, we aimed to elucidate the effectiveness of chemotherapy after nivolumab treatment in patients with R/M HNSCC.MethodsThis retrospective study included 10 patients with R/M HNSCC who were mainly treated with paclitaxel plus cetuximab (7/10, 70%) or S-1 (3/10, 30%) following nivolumab treatment. Chemotherapy was administered as a second-line or higher palliative treatment. The performance status of all patients ranged from 0 to 2. The progression-free survival (PFS) was analyzed using the Kaplan–Meier method.ResultsThe response rate (RR), clinical benefit rate, and median PFS were 60%, 90%, and 5.4 months, respectively. Regarding adverse effects, Grade 3 neutropenia and hypomagnesemia due to salvage chemotherapy administered after immunotherapy were observed in one patient. The treatment significantly increased the RR compared to that achieved with other palliative chemotherapies reported so far.ConclusionA higher RR and clinical benefit rate were observed for our strategy than for any first-line regimen, suggesting that our strategy might improve the PFS. Palliative chemotherapy with/without cetuximab after nivolumab treatment might be useful in patients with R/M HNSCC. Although the results of this retrospective study are limited, this strategy can be a good treatment option for patients with R/M HNSCC because of its strong clinical benefits and acceptable toxicity.     

PD-1/PD-L1 inhibitor monotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck: a meta-analysis

PurposeTo evaluate the efficacy and safety of programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy compared to the standard of care in the first-line setting for recurrent or metastatic head and neck squamous cell carcinoma.Materials and methodsThe PubMed, Embase, and Cochrane Library databases were searched for relevant randomized controlled trials. The clinical outcomes of overall survival, progression-free survival, objective response rates, and grade 3 or higher adverse events were analyzed using Stata SE 15 software with a significance level set to 0.05.ResultsWe identified four randomized controlled trials (1 nivolumab, 2 pembrolizumab, and 1 durvalumab), including a total of 2474 patients. The results of the meta-analysis showed pooled hazard ratios of overall and progression-free survival for programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy of 0.82 (95% CI: 0.73–0.91, p < 0.001) and 0.96 (95%CI: 0.84–1.07, p < 0.001) and pooled odds ratios of objective response rates and grade 3 or higher adverse events of 1.04 (95%CI: 0.46–2.37; p = 0.926) and 0.28 (95%CI: 0.22–0.35, p < 0.001), respectively. Subgroup analysis showed that inhibitors for both programmed cell death-1 (nivolumab and pembrolizumab) and programmed cell death-ligand 1 (durvalumab) were associated with significantly longer overall survival (HR = 0.80, 95% CI: 0.70–0.90, p < 0.001 and HR = 0.88, 95%CI: 0.70–1.06, p < 0.001, respectively).ConclusionsProgrammed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy showed more clinical benefit versus the standard of care in patients with recurrent or metastatic head and neck squamous cell carcinoma, with an acceptable safety profile.     

Real-world 2-year long-term outcomes and prognostic factors in patients receiving nivolumab therapy for recurrent or metastatic squamous cell carcinoma of the head and neck

ObjectiveReal-world outcomes and prognostic factors in Japanese patients receiving nivolumab therapy for recurrent or metastatic head and neck carcinoma (RMHNC) with an observation period of 1 year have been previously reported. The 1-year follow-up data have been subsequently accumulated, and the long-term real-world outcomes have been analyzed. This study aimed to investigate the 2-year long-term outcomes and prognostic factors associated with the response to nivolumab.MethodsThis was a multi-institutional retrospective study. In total, 88 RMHNC Japanese patients with squamous cell carcinoma who received nivolumab between May 2017 and May 2018 were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), and best overall response (BOR) were evaluated. Univariate and multivariable analyses were performed to identify the prognostic factors.ResultsThe median follow-up periods for monitoring OS and PFS were 73.1 and 48.1 weeks, respectively. The median OS was 74.1 weeks, and the 2-year survival rate was 33.4%. The median PFS was 18.5 weeks, and the 2-year PFS rate was 22.5%. The BOR rate was 10.2%, 19.3%, 25.0%, and 44.3% in patients who achieved complete response, partial response, stable disease, and progressive disease (PD), respectively. Among the 88 patients with RMHNC, a total of 40 immune-related adverse events (irAEs) were reported in 30 patients. Four patients continued nivolumab, while 84 patients discontinued nivolumab at the data cut-off date. The most common reason for discontinuation was PD in 61 patients, irAEs in 14 patients, and patients’ wishes in 7 patients. Of the 61 patients who discontinued nivolumab because of PD, 28 patients received subsequent treatment. Statistical analyses revealed radiotherapy history, performance status, platinum-refractory carcinoma, irAEs, age, and post-nivolumab treatment as the important prognostic factors associated with OS in patients with RMHNC, and the magnitude of BOR was significantly associated with OS. Additionally, patients with subsequent treatment, including molecular targeted therapy and/or chemotherapy, had significantly prolonged OS compared to patients without subsequent treatment in cases with nivolumab discontinuation because of PD.ConclusionThese findings could be a useful guide for future treatment strategies for head and neck carcinoma. Considering the limitations of our cohort, further larger-scale studies with long-term follow-up are needed to substantiate the results of this study.     

Prognostic factors of survival in head and neck cancer patients treated with surgery and postoperative radiation therapy

CONCLUSIONS: Given that radiation therapy (RT) is currently initiated as soon as possible after surgery, our results indicate that the main prognostic factors of survival are pT and pN stages in patients treated with surgery and postoperative RT for locally advanced head and neck squamous cell carcinoma (HNSCC). OBJECTIVES: To determine the prognostic factors for survival in patients treated with surgery and postoperative RT for locally advanced HNSCC. PATIENTS AND METHODS: A retrospective study was performed on 308 consecutive patients treated from 1990 to 1998 with surgery and postoperative RT. In addition to histological factors, time-related factors were considered. RESULTS: The median age of the whole cohort was 56 years (range 35-83). Median follow-up was 98 months. Median interval from surgery to the start of RT was 44 days (range 18-157), while median RT duration was 52 days (range 22-115). From univariate analysis of overall survival, statistically significant prognostic factors were pT stage (p<0.0001), pN stage (p=0.008), RT duration (p=0.01) and total treatment time (p=0.02). Perineural invasion, perivascular invasion, extranodal spread and positive resection margins did not appear to be related to survival. From multivariate analysis, the only statistically independent prognostic factors appeared to be pT and pN stages.     

Phase II study of weekly docetaxel and cisplatin in patients with advanced recurrent and metastatic head and neck cancer

OBJECTIVE: Response rates of presently used palliative chemotherapy for end-stage recurrent head and neck cancer are poor, but the regimes cause important toxicity. METHODS: A prospective phase II study was conducted to evaluate the activity and toxicity of a weekly combination of cisplatin and docetaxel in patients with recurrent head and neck cancer. From July 2003 to November 2004, 21 patients with metastatic neck disease were enrolled. Treatment consistent of 25 mg/m cisplatin and 35 mg/m docetaxel once a week for 3 weeks followed by 1 week without treatment for each cycle. The primary end point was median survival. Secondary end points were response rate (RECIST), time to progression, toxicity (NCI-CTC), and quality-of-life (EORTC QLQ-C30, QLQ-H&N35). RESULTS: Eight patients (42%) showed a partial response. Eight patients (42%) had stable disease. Progressive disease was seen in three patients (16%). The median follow-up time was 7.2 months (95% confidence interval [CI], 5.9-9.3 months). The median time to progression was 3.5 months (95% CI, 2.0-5.0 months). The median overall survival was 10.7 months (95% CI, 6.4-15.0 months). Grade 3 toxicities occurred in two patients (10%). A grade 4 adverse event was not recorded. Most global quality-of-life scores but not head and neck-specific scores are deteriorated after last chemotherapy. CONCLUSION: Weekly docetaxel and cisplatin is active in recurrent head and neck cancer and shows an excellent toxicity profile. Its influence on the stabilization of quality of life is less significant.     

Evaluation of survival of patients with locally advanced head and neck cancer treated in a single center

IntroductionEven with improved treatment outcomes with multimodality approaches, the question of what is the best initial treatment for locally advanced head and neck cancer still remains unanswered.ObjectiveTo review the overall survival of a large cohort of head and neck cancer, patients with locally advanced head and neck cancer treated in a single institution.Material and methodsWe studied a cohort of patients with locally advanced head and neck cancer treated in our institution in the last fifteen years. To gather a large sample of patients with adequate follow-up time, a cross-check between ours and Fundação Oncocentro de São Paulo databases were done. We included patients with head and neck cancer, clinical or pathological staging III or IV, treated with surgery followed by radiotherapy or surgery plus chemoradiation or radiotherapy alone or chemoradiation alone.Results796 patients with locally advanced head and neck cancer were included, 88% male, 44% age >60 years and 76% stage IV. The tumor location was the oral cavity (34%), oropharynx (27%), hypopharynx (17%) and larynx (17%). The treatment groups were chemoradiation alone (39.7%), surgery plus chemoradiation (26.3%), surgery followed by radiotherapy (18.5%) and radiotherapy alone (15.5%). Comparing the clinical variables between the treatment groups significant differences in age and clinical stage were observed. With a median follow up of 7.5 years (1–16 years), for the entire cohort, the overall survival at 5 and 10 years was 34.8% and 28%. The overall survival at 5 and 10 years was 16.7% and 12.2% for radiotherapy alone, 38.8% and 26.3% for surgery followed by radiotherapy, 28% and 16.6% for chemoradiation alone, and 37.3% and 23.2% for surgery plus chemoradiation. The staging IV (p = 0.03) and radiotherapy alone (p = 0.05), had a worst survival in multivariate analysis. Surgical groups vs. chemoradiation alone had no significant difference for overall survival.ConclusionThe present study is the largest cohort of locally advanced head and neck cancer of Brazilian patients to evaluate treatment outcomes. Although there were significant clinical differences between surgical and radiotherapy groups, surgery or chemoradiation alone as the initial treatment resulted in no significant difference in survival.     

Pituitary-adrenal dysfunction caused by nivolumab for head and neck cancer

Nivolumab exerts antitumor effects by inhibiting binding of PD-L1 to PD-1, and offers proven effectiveness in various disease areas, including cancers of the head and neck. The mechanisms of action lead nivolumab to induce immune-related adverse events (irAE). We report a case of pituitary-adrenal dysfunction to isolated adrenocorticotropic hormone (ACTH) deficiency as an irAE of nivolumab in a patient treated for head and neck cancer. This is the first report of an irAE of nivolumab in the field of head and neck squamous cell cancer. The patient was a man in his 50s with cancer of the tongue and hypopharynx that recurred after chemoradiotherapy, surgery and chemotherapy. After starting nivolumab, irAEs developed after 8 courses. The case was managed from the early stages in collaboration with the endocrinology department. Pituitary-adrenal hypofunction due to isolated ACTH deficiency was diagnosed on the basis of endocrine tests. The patient responded to hydrocortisone replacement therapy and has been able to continue treatment with nivolumab while continuing oral hydrocortisone. Although irAEs involving pituitary gland disorders are rare, these events can become life-threatening when severe. Early diagnosis and treatment are essential and require regular blood sampling and collaboration with specialists from an early stage.     

Improved survival in patients with head and neck cancer in the 1990s

It is generally felt amongst the medical profession and the lay public that cancer is being treated more successfully than in the past. This is certainly true for childhood malignancies and leukaemia but evidence that significantly improved survival is occurring in the common solid tumours is lacking. Since 1963 the University of Liverpool Department of Otolaryngology/Head and Neck Surgery has collected data on all patients with head and neck tumours presenting to the department. The present study investigates patients with histologically proven squamous cell carcinoma of the four main sites: larynx, hypopharynx, oral cavity and orophyarnx. From 1963 until the end of 1989, 2738 patients were seen by the department and from 1990 a further 717 patients have been seen. Since 1990 patients have tended to be in better general physical condition but, on the other hand, have tended to have more advanced disease at the primary site. The department has latterly tended to see fewer laryngeal cancers and more cancers of the oropharynx. Significantly fewer patients have presented with neck node metastases. Multiple logistic regression suggests that the most significant difference between the two groups is the great reduction in neck node recurrence rates in the group of patients seen since 1990 (P = 0.0001). The recurrence of tumours at the primary site since 1990 has been 35% compared with 41% before 1990, and recurrence in the neck nodes since 1990 has been 12%, compared with 15% before 1990. These differences are significant (P = 0.0141 and P = 0.0494, respectively). When studying survival in the 1960s, 1970s and 1980s, the 5-year cure rate was 50%, whereas since 1990 the figure has risen to 60% tumour-specific 5-year survival—a significant difference. A similar effect was noted in observed survival. This improvement in cure rate occurred for all four main sites. The results were confirmed by Cox’s proportional hazards model where year of treatment was highly significantly associated with improved survival (P = 0.0001). It has been demonstrated that locoregional recurrence has improved since 1990 and this is reflected in improved survival figures. Although there are differences in the parameters of tumours referred before 1990 and since 1990, multivariate analysis suggests that the improvement in neck node recurrence rates may be responsible for this improved survival rate. Multivariate analysis for survival also suggests that the improvement in cure rates is independent of compounding variables and dependent on the year of presentation of the tumour. This improved survival may be related to factors, such as the administration of radical postoperative radiotherapy.     

General health measures and long-term survival in patients with head and neck cancer

OBJECTIVE: To determine whether a self-reported, subjective general health assessment tool can provide prognostic information about survival in patients with head and neck cancer. DESIGN: Prospective observational cohort study. SETTING: Tertiary care center. PATIENTS: Five hundred seventy-one patients with squamous cell carcinoma of the upper aerodigestive tract who were enrolled in the institution's longitudinal Outcomes Assessment Project between January 1, 1995, and November 30, 2004. MAIN OUTCOME MEASURES: Actuarial 5-year observed and disease-specific survival. RESULTS: The physical component summary obtained from the SF-36 (Medical Outcomes Study 36-Item Short-Form Health Survey) was significantly associated with ACE-27 (Adult Comorbidity Evaluation-27) comorbidity ratings. The mental component summary was not associated with ACE-27 scores or survival. Although the comorbidity rating was an independent predictor of observed survival (P = .002) only, the physical component summary was independently predictive of both observed (P<.001) and disease-specific (P = .001) survival. These associations continued to be independently significant when site and stage were included in the analysis (P = .003, P<.001, and P = .004, respectively). CONCLUSION: The physical component summary generated by the SF-36, a self-reported, subjective measure of general physical health, is predictive of both observed and disease-specific survival.     

Trismus in patients with head and neck cancer and 5-year overall survival

Abstract

Background: Trismus is a common complication of radiotherapy for head and neck cancer but its impact on survival is unknown.

Aims/Objectives: This prospective study evaluates the incidence of trismus in patients with head and neck cancer receiving radiotherapy and the impact of trismus on 5-year overall survival.

Material and methods: Two hundred forty-four patients with head and neck cancer were included. All patients received instructions on jaw exercises and were evaluated before initiation of radiotherapy and at 2, 6, and 12 months after termination of radiotherapy.

Results: One year after treatment 25% had a reduced maximum interincisal opening (MIO) of 13?mm or more as compared to the pretreatment MIO. Trismus was most prevalent in patients with oral and oropharyngeal cancer. A trend towards worse 5-year overall survival was seen among patients with trismus.

Conclusions: The trismus rate was approximately 30% at 12 months. Jaw exercises should primarily be offered to patients with oral and oropharyngeal cancer who are most likely to benefit. Further studies are required to investigate the effect of trismus on survival.

Significance: This study identifies patients likely to benefit from jaw exercises and provides basis for further research on trismus and survival.     

Chemotherapy for unresectable recurrent or metastatic squamous cell carcinomas of the head and neck

The efficacy of chemotherapy for unresectable recurrent or metastatic squamous cell carcinomas of the head and neck can not be proved by survival periods. However, the efficacy of chemotherapy has been observed in some select patients. We investigated the effect of chemotherapy for unresectable recurrent squamous cell carcinomas of the head and neck. Four patients with a good performance status (PS) were treated with high-doses of leucovorin (LV), cisplatin (CDDP), and 5-fluorouracil (5-FU). The regimen consisted of 25 mg/m2 of CDDP on days 1-5; 600 mg/m2 of 5-FU of days 2-6; and 200 mg/m2 of LV on days 1-6. Patients received 3 cycles of this regimen at 28-day intervals. Ten patients with a poor PS were treated with low-doses of CDDP and tegafur.uracil upon admission. The regimen of seven poor PS patients consisted of 8 mg/m2 of CDDP on days 1-5 and 8-12, and 400 mg/body of tegafur.uracil administered orally on days 1-14. The other three patients received chemotherapy on an outpatient basis for ten weeks. The weekly regimen consisted of 7.5 mg/m2 of CDDP on days 3 and 6 and 400 mg/body of tegafur.uracil administered orally on days 1-7. With respect to the LV + CDDP and 5-FU treatment, complete remission was obtained in one patient. Two patients showed no change (NC), while one patient developed a progressive disease (PD). This regimen is highly toxic, has severe side effects including myelosuppression, oral mucositis, and diarrhea, and has a survival period of between 16 and 32 weeks. The low-dose CDDP + tegafur.uracil treatment produced a partial response in three patients, NC in three patients, and four patients developed a PD. This regimen doses not have any severe side effects and has a survival period of between 4 and 67 weeks.     

Management of recurrent head and neck cancer

The management of recurrent head and neck malignancy can be one of the most frustrating experiences faced by the head and neck surgeon. A recent study indicates that twice the number of patients succumb to distant metastasis from primary tumors than did 20 years ago. This article discusses the operative management of these patients and the role of radiotherapy and chemotherapy in their treatment.     

Quality of life in patients treated for head and neck cancer

In this paper we have studied the quality of life of patients that underwent treatment for an early laryngeal carcinoma in comparison to others with an advanced head and neck cancer. We have studied 62 patients (T1N0M0, T2N0M0) with laryngeal carcinoma diagnosed between 1990 and 1998. We have applied the European EORTC QOL C-30 questionnaire, and more specifically its head and neck module (H&N 35). The results were compared with a heterogeneous group of 48 patients with different degrees of head and neck cancers. The quality of life of our patients who were treated for an early glottic cancer was better in many functional scales of the EORTC and in many specific symptom scales of the H&N 35, but not in global cancer symptoms.     

Cachexia at diagnosis is associated with poor survival in head and neck cancer patients

Conclusions: One third of the patients had cachexia with an association of significantly shorter survival. These results suggest that combining HGS and MAMA seems to be a practical method to screen cachexia in patients with head and neck cancer and may also be used when assessing their prognosis.

Objectives: The aim of this study was to analyze the hypothesis that cachexia defined as both low mid-arm muscle area (MAMA) and handgrip strength (HGS) is associated with decreased survival in patients with head and neck squamous cell carcinoma (HNSCC).

Methods: Sixty-five consecutive patients with primary HNSCC were enrolled prior to cancer therapy. Cachexia was defined as low handgrip strength (HGS) and low mid-arm muscle area (MAMA). Nutritional status was assessed by patient-generated subjective global assessment (PG-SGA) and sarcopenia by low MAMA. Biochemical parameters reflecting nutritional status and S-25-OHD were measured.

Results: Cachexia was seen in 31% and sarcopenia in 46% of patients. Altogether, 34% of patients were malnourished. Disease-free survival was 13 months (3–62) in cachectic patients, compared with 66 months (31–78) in non-cachectic patients (p?=?0.009). S-25-OHD was 28?nmol/l in cachectic patients, compared with 46?nmol/l in non-cachectic patients (p?=?0.009) and prealbumin 187?mg/l and 269?mg/l, respectively (p?相似文献   

Sarcopenia with inflammation as a predictor of survival in patients with head and neck cancer

ObjectiveAlthough both sarcopenia and systemic inflammation affect the outcomes of head and neck cancer (HNC) patients, the association between sarcopenia and systemic inflammation and the combined prognostic effect of these factors in HNC patients remain unknown. This study aimed to evaluate the effect of sarcopenia with systemic inflammation on survival and disease control in HNC patients.MethodsWe retrospectively reviewed medical records of HNC patients treated between 2009 and 2016. The skeletal muscle area was measured using a single computed tomography image slice at the level of the third cervical vertebra. A prognostic score (SPLR) was developed based on sarcopenia and the platelet-lymphocyte ratio (PLR), and its prognostic value was evaluated.ResultsOverall, 164 patients were enrolled. In the multivariate analysis, sarcopenia was significantly associated with poor overall survival (OS) (p < 0.01). However, neither sarcopenia nor a high PLR was an independent prognostic factor for disease-free survival (DFS) or locoregional recurrence-free survival (LRFS). A high PLR was an independent predictor for sarcopenia (p < 0.01). A high SPLR was associated with older age, lower serum hemoglobin, and lower body mass index (all p < 0.05). Multivariate analysis revealed that SPLR was a significant independent predictor of OS, DFS, and LRFS (all p < 0.05).ConclusionsSystemic inflammation is significantly associated with sarcopenia. The survival and oncological effects of sarcopenia were enhanced when PLR was high. Thus, the combination of these two parameters may be useful for identifying HNC patients at a risk of poor survival outcomes.