Cetuximab and anemia prevention in head and neck cancer patients undergoing radiotherapy.

BACKGROUND: Epidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels intensifies RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, has been associated with lower rates of anemia for locally advanced head and neck squamous cell carcinoma (HNSCC). We hypothesized that concomitant cetuximab could prevent RT-induced anemia. METHODS: We queried our institutional head and neck cancers database for non-metastatic HNSCC cases that received RT with concomitant cetuximab or RT-only between 2006 and 2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. We only included patients who had at least one complete blood count in the 4 months preceding and after RT. We compared the prevalence of anemia (defined as hemoglobin (Hb) below 12 g/dL in females and 13 g/dL in males) and mean Hb levels at baseline and after RT. Improvement of anemia/Hb (resolution of baseline anemia and/or an increase of baseline Hb ≥1 g/dL after RT), and overall survival (OS) in relation to anemia/Hb dynamics were also compared. RESULTS: A total of 171 patients were identified equally distributed between cetuximab-plus-RT and RT-only groups. The cetuximab-plus-RT group had more locally-advanced stage, oropharyngeal and high grade tumors (p < 0.001 for all). Baseline anemia/Hb were similar, however anemia after RT conclusion was higher in the cetuximab-plus-RT vs RT-only (63.5% vs. 44.2%; p = 0.017), with a mean Hb of 11.98 g/dL vs. 12.9 g/dL; p = 0.003, for both respectively. This contributed to significantly worse anemia/Hb improvement for cetuximab-plus-RT (18.8% vs. 37.2%; p = 0.007). This effect was maintained after adjusting for other factors in multivariate analysis. The prevalence of iron, vitamin-B12 and folate deficiencies; and chronic kidney disease, was non-different. Baseline anemia was associated with worse OS (p = 0.0052) for the whole study cohort. Nevertheless, improvement of anemia/Hb was only marginally associated with better OS (p = 0.068). CONCLUSIONS: In contrast to previous studies, cetuximab was not associated with lower rates of anemia after RT for nonmetastatic HNSCC patients compared to RT-alone. Dedicated prospective studies are needed to elucidate the effect of cetuximab on RT-induced anemia.

Randomized Phase 3, Double-Blind, Placebo-Controlled Study of Prophylactic Gabapentin for the Reduction of Oral Mucositis Pain During the Treatment of Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: The purpose of this paper is to determine whether prophylactic gabapentin usage in patients undergoing definitive concurrent chemotherapy and radiation therapy (chemoRT) for oropharyngeal cancer (OPC) improves treatment-related oral mucositis pain, opioid use, and feeding tube (FT) placement. METHODS AND MATERIALS: This double-blind, randomized phase 3 study for patients with locally advanced OPC undergoing chemoRT randomly allocated patients to prophylactic gabapentin (600 mg thrice daily) or placebo. The primary endpoint was change in Patient-Reported Oral Mucositis Symptom (PROMS) scores over the entire treatment period (baseline to 6 weeks post-radiation therapy [RT] follow-up) with higher scores indicating worse outcomes. Opioid requirements, FT placement, and other patient-reported quality of life (QOL) metrics (Functional Assessment of Cancer Therapy-Head and Neck [FACT-HN] and Patient-Reported Outcomes version of the National Cancer Institute Common Terminology Criteria for Adverse Events [PRO-CTCAE]) were assessed. Lower scores suggested poorer QOL with the FACT-HN questionnaire, and higher scores suggested worse outcomes with the PRO-CTCAE questionnaire. Questionnaires were administered at baseline, weekly during RT, and at 6 weeks post-RT follow-up. Repeated measures analysis of variance was used to detect differences in PROMS scores and change in opioid use from baseline. Wilcoxon rank sum tests were used to compare averages for the other secondary endpoints. A P value less than .05 was considered statistically significant. RESULTS: Treatment arms were well balanced overall, including T and N staging and dosimetric variables. There were 58 patients analyzed. No significant difference was found in PROMS scores (mean 29.1, standard deviation [SD] 22.5 vs 20.1, SD 16.8 for gabapentin vs placebo, respectively, P = .11). The FACT-HN functional well-being index had a significant decrease in scores from baseline to follow-up in the gabapentin arm (median -6, interquartile range [IQR] -10.0 to -0.5 vs -1, IQR -5.5 to 3.0, P = .03). PRO-CTCAE scores increased significantly at follow-up for gabapentin (median 6.5, IQR 3.5-11.8 vs 1, IQR -2.0 to 6.0, P = .01). There was no significant difference in average or change in opioid use. FT placement was significantly higher in the gabapentin arm (62.1% vs 20.7%, P < .01). CONCLUSIONS: This study suggests that prophylactic gabapentin is not effective in improving treatment-related oral mucositis symptoms in a select population of patients with OPC undergoing definitive chemoRT.

Thrombocytapheresis for acquired von Willebrand syndrome in a patient with essential thrombocythemia and recent multivisceral transplantation.

BACKGROUND: Essential thrombocythemia (ET) is associated with increased risk of bleeding secondary to acquired von Willebrand syndrome (AVWS). Bleeding in ET requires urgent platelet reduction by cytoreductive therapy such as hydroxyurea or thrombocytapheresis. We report on the efficacy and safety of thrombocytapheresis in managing AVWS in a patient with ET and multivisceral transplantation. CASE REPORT: The patient was a 51-year-old female who underwent multivisceral transplantation. Her postoperative course was complicated by bleeding from oral cavity, IV lines, gastrointestinal and upper respiratory tracts as well as vaginal bleeding, which coincided with ET flare with a platelet count of 1512 × 109 /L. Coagulation studies including von Willebrand factor (vWF) antigen and activity, vWF propeptide antigen, and vWF multimer analysis were consistent with AVWS. Hydroxyurea was initiated. However, due to major bleeding, rapidly increasing platelet count, and uncertainty of response to hydroxyurea being given through the enteral tube, thrombocytapheresis was initiated for rapid platelet reduction. The patient tolerated the procedure well. Platelet count was reduced from 1636 × 109 /L to 275 × 109 /L with rapid cessation of bleeding. The patient's condition stabilized over the next few days; however, bleeding recurred with increasing platelet count, which required a second thrombocytapheresis 8 days after the first one. The patient was maintained on hydroxyurea 500 mg twice/day. At 11-month follow-up, she had a normal platelet count and no recurrence of bleeding. DISCUSSION: Thrombocytapheresis is safe and efficient in managing postoperative bleeding due to ET/AVWS in solid organ transplant patients. The procedure can be an adjunct to bridging therapy before response to hydroxyurea is achieved.

NRG-HN003: Phase I and Expansion Cohort Study of Adjuvant Pembrolizumab, Cisplatin and Radiation Therapy in Pathologically High-Risk Head and Neck Cancer.

The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin-radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III-IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted.

The effect of treatment package time in head and neck cancer patients treated with adjuvant radiotherapy and concurrent systemic therapy.

OBJECTIVES: In patients with head and neck carcinoma, "treatment package time" (TPT) was proven to impact outcomes in cases receiving adjuvant radiotherapy alone. Its impact in patients receiving radiotherapy with concurrent systemic therapy has not been studied previously. The TPT influence on survival endpoints for patients treated with surgery followed by radiation and concurrent systemic therapy was analyzed. METHODS: Institutional database to identify head and neck carcinoma cases treated with definitive surgery followed by concomitant chemo(bio) radiotherapy (CRT) was used. TPT was the number of days elapsed between surgery and the last day of radiation. %FINDCUT SAS macro tool was used to search for the cutoff TPT that was associated with significant survival benefit. Kaplan-Meier curves, log-rank tests as well as univariate and multivariate analyses were used to assess overall survival (OS) and recurrence free survival (RFS). RESULTS: One hundred and three cases with a median follow up of 37 months were included in the study. Oropharyngeal tumors were 43%, oral cavity 40% and laryngeal 17% of cases. Concurrent systemic therapy included platinum and cetuximab in 72% and 28%, respectively. Optimal TPT was found to be < 100 days with significantly better OS (P = 0.002) and RFS (P = 0.043) compared to TPT ≥100 days. On multivariate analysis; TPT<100 days, extracapsular nodal extension, high-risk score, lymphovascular space and perineural invasion were independent predictors for worse OS (P < 0.05). T4, extracapsular nodal extension and high-risk score were all significantly detrimental to RFS (P < 0.05). CONCLUSIONS: Addition of concomitant systemic therapy to adjuvant radiotherapy did not compensate for longer TPT in head and neck squamous cell carcinoma. Multidisciplinary coordinated care must be provided to ensure the early start of CRT with minimal treatment breaks.

Idiopathic erythrocytosis in dialysis patients: a case report and literature review.

Anemia is a common complication in end-stage renal disease (ESRD) patients. On the other hand, idiopathic erythrocytosis is extremely rare, with only a few cases reported in the literature. We present a case of erythrocytosis that developed after initiating hemodialysis. A 68-year-old male with a history of ESRD secondary to diabetes presented with erythrocytosis that started a few months after initiating dialysis in the absence of having received erythropoietin-stimulating agents or iron supplements. His erythropoietin level was elevated, with a negative JAK2 mutation. Blood gases showed normal oxygen and CO(2), with slightly elevated carboxyhemoglobin. Tiny foci in both kidneys were noted, representing vascular calcifications or renolithiasis. There was no radiological evidence of neoplasms or cysts. After excluding secondary causes, a diagnosis of idiopathic erythrocytosis was made. The patient underwent intermittent phlebotomies during dialysis, and his hemoglobin went from 18.5 to 14 mg/dl. Erythrocytosis in ESRD patients is very rare. So far, there is no complete understanding of the underlying pathophysiology; however, there seem to be multiple possible reasons for an increased erythropoietin level. Phlebotomy is a successful and easy way to control erythrocytosis in such patients. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, currently being used in posttransplant erythrocytosis, might also be considered.