Anti­epidermal growth factor receptor monoclonal antibody therapy in locally advanced head and neck cancer: A systematic review of phase III clinical trials.

The present systematic review evaluated the effectiveness of anti-EGFR therapy in combination with radiotherapy (RT) or with chemoradiation compared with the existing standard of care for the treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC). The PubMed, SCOPUS, EMBASE and COCHRANE databases were searched and 12 phase III randomized controlled trials were included. The effectiveness of the anti-EGFR monoclonal antibody cetuximab was evaluated in nine trials. Nimotuzumab (one trial), zalutumumab (one trial) and panitumumab (one trial) were the monoclonal antibodies evaluated in the remaining three trials. One study tested the effectiveness of adding cetuximab to radical RT and found that patients with LAHNSCC exhibited improvement in locoregional control (LRC), overall survival (OS) and progression-free survival (PFS) compared with those of patients treated with RT alone. A total of three studies tested the effectiveness of adding an anti-EGFR agent to chemoradiation. Of these, a single institution study in which patients received cisplatin at 30 mg/m2 weekly, instead of the standard doses of 100 mg/m2 every 3 weeks or 40 mg/m2 every week, reported significant improvement in PFS with the addition of nimotuzumab to chemoradiotherapy without an improvement in overall survival. However, the other two studies indicated that, when added to standard chemoradiation, the anti-EGFR monoclonal antibodies cetuximab or zalutumumab did not improve survival outcomes. Two phase III trials evaluated RT plus an anti-EGFR agent compared with chemoradiation alone. Of these, one study reported inferior outcomes with cetuximab-RT in terms of OS and LRC, whereas the other study with panitumumab plus RT failed to prove the non-inferiority. Two trials evaluated induction chemotherapy followed by cetuximab-RT compared with chemoradiotherapy and reported no benefits in terms of OS or PFS. Furthermore, one study evaluated induction chemotherapy followed by cetuximab-RT compared with induction chemotherapy followed by chemoradiotherapy and found no improvement in OS or PFS. Finally, three phase III trials tested the effectiveness of cetuximab plus RT in the treatment of human papillomavirus-positive oropharyngeal carcinoma, and found it to be inferior compared with cisplatin-RT in terms of OS, PFS and failure-free survival. Based on the aforementioned findings, it is difficult to conclude that anti-EGFR therapy in any form has an advantage over conventional chemoradiation in the treatment of LAHNSCC.

Immune checkpoint inhibitors in head and neck squamous cell carcinoma: A systematic review of phase-3 clinical trials.

BACKGROUND: The outcomes of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal. A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors (ICIs). The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field. AIM: To evaluate the evidence on the effectiveness of ICIs in HNSCC, based on published phase-3 clinical trials. METHODS: We searched PubMed, Cochrane Library, Embase, and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC (R/M HNSCC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC). We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, immune checkpoint inhibitors, monoclonal antibodies, programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte associated protein-4 (CTLA-4), and phase-3 clinical trial. A sensitive search filter was used to limit our results to randomized controlled trials. RESULTS: Five phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far: Four in R/M HNSCC and one in LAHNSCC. In patients with R/M HNSCC, anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care (standard single-agent systemic therapy). While the net gain in overall survival (OS) with nivolumab was 2.4 mo [hazard ratio (HR) = 0.69, P = 0.01], that with pembrolizumab was 1.5 mo (HR = 0.80 nominal P = 0.0161). The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes. In the first-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME. In LAHNSCC, immunotherapy using avelumab (an anti-PD-L1 agent) along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy. CONCLUSION: Anti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings, with acceptable toxicity profiles compared to standard therapy. There is no proven efficacy in the curative setting to date.

Induction chemotherapy in nasopharyngeal carcinoma- A systematic review of phase III clinical trials.

BACKGROUND: Induction Chemotherapy (IC) has the potential advantage of resulting in early eradication of micro metastasis thereby reducing distant failure in Nasopharyngeal Carcinoma (NPC). This study is to evaluate the effectiveness of induction chemotherapy in NPC based on published phase III Randomized Controlled Trials (RCT) METHODS: : We searched PubMed, SCOPUS, EMBASE and COCHRANE databases for phase III trials evaluating the role of IC in NPC using the following key words: nasopharyngeal carcinoma, locally advanced, locoregionally advanced, induction chemotherapy, and concurrent chemoradiation. We included phase 3 RCTs of NPC in which intervention patients received induction chemotherapy plus concurrent chemoradiation (CCRT) and the control patients received CCRT alone. RESULTS: Six phase III RCTs have reported the data on effectiveness of IC in NPC so far. All except one study found statistically significant improvement in the primary outcome. One study demonstrated improved relapse free survival (RFS) with IC (stratified HR for recurrence or death 0.51; p=0.0001). Two studies reported improvement in disease free survival (DFS) with IC [adjusted HR 0.739 (p=0.0264) in one study; HR for 3-year and stratified HR for 5-year DFS 0.67 (p=0.028) and 0.66 (p=007) respectively in the other study]. One study demonstrated improvement in failure free survival (FFS) with IC [HR for 3-year and 5-year FFS 0.68 (p=0.034) and 0.67 (p=0.019) respectively] and another study reported improved progression free survival (PFS) [HR 0.44; p=0.042)]. Grade 3-4 acute adverse events were higher among patients who received IC. CONCLUSION: IC followed by CCRT showed superior clinical outcomes in NPC compared to CCRT alone. Conflicting results were found with regard to overall survival.

Association between referral-to-death interval and location of death of patients referred to a hospital-based specialist palliative care service.

CONTEXT: The time interval between palliative care referral and death may play a role in determining the last place of care and location of death of patients referred to palliative care teams. OBJECTIVES: To examine the association between the referral-to-death interval and location of death of patients referred to a hospital-based palliative care service in Singapore. METHODS: A retrospective analysis of data from a palliative care service's administrative database was performed. Individual patient's referral-to-death interval was calculated using the date of first contact with the service and date of death. Multinomial regression analysis was done to determine the influence of referral-to-death interval in predicting death at home and in an inpatient hospice facility compared with death in hospital, separately by gender. RESULTS: Of 842 patients, 52% were female and 56% were aged 65 years or older. Terminal cancer was the diagnosis for most patients (86%). Three hundred ninety patients (46%) died outside the hospital setting. A referral-to-death interval of ≥30 days (as opposed to <30 days) was associated with an increased likelihood of dying at home (odds ratio [OR] 2.21, 95% CI 1.34-3.67 for males and OR 3.33, 95% CI 2.07-5.35 for females) or in an inpatient hospice facility (OR 2.02, 95% CI 1.13-3.60 for males and OR 2.69, 95% CI 1.55-4.66 for females) compared with death in hospital. Male patients' age, ethnicity, and marital status were found to be the contributing factors in predicting death at home. CONCLUSION: Longer referral-to-death interval was associated with death outside the hospital for patients enrolled in a hospital-based service. The study highlights the importance of early referral in predicting the last place of care and location of death of palliative care patients.

Place of death and its determinants for patients with cancer in Singapore: an analysis of data from the Singapore Cancer Registry, 2000-2009.

AIMS: To describe the place of death for patients with cancer in Singapore from 2000 to 2009, and determinants of death at home and in in-patient hospice compared to death in hospital. METHOD: Cross-sectional analysis of all patients registered with the Singapore Cancer Registry who had died in the study period (N=52120). Places of death were grouped as homes, in-patient hospices, hospitals and others. For determinants of death at home and in in-patient hospice, covariates adjusted for in logistic regression analyses were age group, gender, ethnic group, primary tumour site, stage at diagnosis, duration and cause of death. RESULTS: In the 10-year period, 52.9% of patients with cancer had died in the hospital, 30.3% died at home and 10.7% in in-patient hospice. Determinants of death at home were older age, female (odds ratio OR 1.23, 95% confidence interval, CI 1.17-1.29), Malay (OR 2.28, 95% CI 2.13-2.44), cancers of the colo-rectum, liver, stomach, pancreas and nasopharynx (compared to lung cancer), duration of illness of 1-5 years (OR 1.40, 95% CI 1.34-1.48), primary cause of death being 'neoplasms' (OR 2.97, 95% CI 2.79-3.17). Determinants of death in in-patient hospice were older age, distant metastasis (OR 1.35, 95% CI 1.21-1.50) and primary cause of death being 'neoplasms' (OR 20.07, 95% CI 16.05-25.09). CONCLUSION: Knowledge about place of death and its determinants will facilitate the planning of healthcare services to enable patients with terminal cancer to die at home and in in-patient hospices, thereby avoiding inappropriate hospitalization at the end of life.

Opioid use amongst cancer patients at the end of life.

INTRODUCTION: Concerns about the life shortening effect of opioids is a well known fact in the medical world when considering administration of these drugs for symptom alleviation at end of life. This study described the patterns of opioid use among cancer patients referred to a hospital-based specialist palliative care service for symptom management. This study also examined whether opioid use among terminally ill cancer patients during the last 2 days of life had any influence on survival. MATERIALS AND METHODS: A retrospective review of case notes of patients who were diagnosed with terminal cancer and had passed away in a 95-bedded oncology ward between September 2006 and September 2007 was conducted. Data were collected on patients' characteristics and patterns of opioid use including opioid doses and dose changes at 48 hours and 24 hours before death. RESULTS: There were 238 patients who received specialist palliative care, of whom 132 (55.5%) were females. At 48 hours and 24 hours before death, 184 (77.3%) patients and 187 (78.6%) patients had received opioids, respectively. The median daily doses at 48 hours and 24 hours were 48 mg and 57 mg oral morphine equivalent doses (OME), respectively. Indications for opioid use were pain (41.1%), dyspnoea, (29.1%) and both dyspnoea and pain (30.8%). In the fi nal 24 hours, 22.3% patients had a reduction in their mean opioid dose while 22.7% required an increase in their mean opioid dose. Increased age was associated with decreasing opioid doses (P = 0.003). Patients with spinal metastases required higher doses of opioids (P = 0.03) while those with lung metastases required lower doses (P = 0.011). Survival analysis using Kaplan-Meier survival curve revealed no significant survival difference between those who were on opioids and those who were not. Log rank test (Mantel-Cox) (P = 0.69). CONCLUSION: Our results showed that opioids are safe medications for symptom alleviation in terminally ill cancer patients during the last days of life and have no deleterious influence on survival.

Artificial Hydration at the end of Life in an Oncology Ward in Singapore.

AIM: The objective of this study has been to examine the frequency of use of artificial hydration in terminally ill cancer patients during the last 48 h of life and the occurrence of symptoms specific to hydration status. Other objectives were to find out if artificial hydration has any impact on survival or had any influence on the patterns of use of opioids and sedatives while under palliative care. MATERIALS AND METHODS: Retrospective review of case notes of palliative care patients who died in a 95 bedded oncology ward was done. Information on demographic profile, duration of palliative care, medication use and on symptoms related to hydration status was collected. Patients on artificial hydration were compared to those who were not on artificial hydration for the above parameters. Survival curves were plotted for both groups using Kaplan-Meier method. RESULTS: There were 238 patients of which 55.5% were females. The median age was 62 years and the median duration of palliative care was five days. Artificial hydration was given to 59.2% of patients. There was no significant difference in the incidence of symptoms related to hydration status or in the patterns of medication use between patients who received artificial hydration and those who did not. Kaplan-Meier survival curves did not show any significant survival difference (P value=0.9) between the two groups. CONCLUSION: Artificial hydration during the last 48 h of life did not have any significant impact on symptoms related to hydration status, medication use or on survival in terminally ill cancer patients under palliative care.