Meta-Analysis on Induction Chemotherapy in Locally Advanced Nasopharyngeal Carcinoma.

PURPOSE: Concurrent chemo radiotherapy (CCRT) has been the standard of care in locally advanced nasopharyngeal carcinoma (LA-NPC) for many years. The role of induction chemotherapy (ICT) has always been controversial. This systematic review and meta-analysis investigates the value of adding ICT to CCRT in LA-NPC. MATERIALS AND METHODS: Two reviewers independently assessed the eligibility of randomized controlled trials (RCTs) comparing ICT followed by CCRT versus CCRT alone, including treatment-naive adult patients with histologically proven nonmetastatic LA-NPC. RESULTS: Eight RCTs with in total 2,384 randomized patients, of whom 69% had N2-N3 disease, were selected. ICT was the allocated treatment in 1,200 patients, of whom 1,161 actually received this. Treatment compliance varied, with a median rate of 92% (range, 86%-100%) of patients receiving all cycles of ICT. The percentage of patients completing radiotherapy was 96% and 95% [(Combined Risk difference(CRD)= 0.004; 95% Confidence Interval (CI) -0.001-0.01; p = 0.14)] in the ICT group and CCRT group, respectively, whereas chemotherapy during radiotherapy could be completed in only 28% of the ICT group versus 61% in the CCRT group (CRD, -0.243; 95% CI, -0.403 to -0.083; p = .003). Grade 3-4 acute toxicity was mostly hematologic during the ICT phase (496 events vs. 191 nonhematologic) and was predominant in the ICT group (1,596 events vs. 1,073 in the CCRT alone group) during the CCRT. Adding ICT to CCRT provided a significant benefit in overall survival (hazard ratio [HR], 0.680; 95% CI, 0.511-0.905; p = .001) and progression-free survival (HR, 0.657; 95% CI, 0.568-0.760; p < .001). CONCLUSION: Although ICT followed by CCRT is associated with more acute toxicity and a lower compliance of the chemotherapy during the CCRT phase, this association resulted in a clinically meaningful survival benefit. ICT should be considered as a standard option in patients with LA-NPC, but further study on optimal patient selection for this treatment is warranted. IMPLICATIONS FOR PRACTICE: Locally advanced nasopharyngeal carcinoma (LA-NPC) is a relatively common disease in some parts of the world, with a rather poor prognosis due to its high metastatic potential. The role of induction chemotherapy (ICT) has always been controversial. This meta-analysis found that ICT followed by concurrent chemoradiotherapy (CCRT) in LA-NPC is associated with a significant clinical improvement in both overall survival and progression-free survival compared with CCRT alone. ICT should be considered as a standard option in patients with LA-NPC.

Prophylactic gastrostomy in locally advanced head and neck cancer: results of a national survey among radiation oncologists.

BACKGROUND: Nutritional complications in patients with locally advanced head and neck cancer (LA-HNC) treated by concurrent chemoradiotherapy (CCRT) often lead to placement of a prophylactic gastrostomy (PG) tube, while indication lacks harmonization. Our aim was to explore the current PG tube utilization among Belgian radiation oncology centers. METHODS: A survey was distributed to all 24 Belgian Radiation oncology departments, with questions about the number of patient treated per year, whether the PG indication is discussed at the multidisciplinary board, placement technique, time of starting nutrition and removal, its impact on swallowing function and importance of clinical factors. For the latter Relative Importance and Discordance Indexes were calculated to describe the ranking and agreement. RESULTS: All 24 centers submitted the questionnaire. Twenty three treat more than 20 head and neck (HNC) patients per year, while four (1 in 21-50; 3 in 51-100) are not discussing the gastrostomy tube indication at the multidisciplinary board. For the latter, endoscopic placement (68%) is the dominant technique, followed by the radiologic (16%) and laparoscopic (16%) methods. Seventy-five percent start the enteral nutrition when clinically indicated, 17% immediately and 8% from the start of radiotherapy. Majority of specialists (19/24) keep the gastrostomy tube until the patient assume an adequate oral feeding. Fifteen centres are considering PG decrease swallowing function. Regarding factors and their importance in the decision for the PG, foreseen irradiated volume reached highest importance, followed by 'anatomical site', 'patients' choice' and 'postoperative versus definitive' and 'local expertise', with decreasing importance respectively. Disagreement indexes showed moderate variation. CONCLUSIONS: The use of a PG tube for LAHNC patients treated by CCRT shows disparity at national level. Prospective studies are needed to ensure proper indication of this supportive measure.

Use of granulocyte-colony stimulating factors in older patients: a review of recently published data.

PURPOSE OF REVIEW: This review presents the analysis of recently published studies about the benefit from granulocyte-colony stimulating factors (G-CSF) in older cancer patients receiving chemotherapy. RECENT FINDINGS: During the last years, no major study aiming to confirm the clinical benefit of G-CSF prophylaxis in older patients treated with chemotherapy has been published. Nonetheless, all the data made recently available confirm that age, especially if other comorbid conditions are present as well, is a major risk factor for febrile neutropenia occurrence and that G-CSF prophylaxis can reduce significantly that risk. SUMMARY: New modalities of administering G-CSF prophylaxis might be considered in older people in the future. Among these approaches, the 'same day' administration of prophylaxis and chemotherapy and the development of less-expensive approaches for G-CSF prophylaxis, such as the use of biosimilars are studied.

Tumor Microenvironment Modifications Induced by Afatinib in Squamous Cell Carcinoma of the Head and Neck: A Window-of-Opportunity Study (EORTC-90111-24111).

PURPOSE: The EORTC-90111-24111 phase II window study evaluated afatinib versus no preoperative treatment in patients with primary squamous cell carcinoma of the head and neck (HNSCC). We investigated afatinib-induced tumor and microenvironment modifications by comparing pre- and posttreatment tumor biopsies. PATIENTS AND METHODS: Thirty treatment-naïve patients with primary HNSCC were randomized. Twenty-five patients received afatinib for 14 days before surgery (40 mg 1×/day) and 5 patients were attributed to the control arm. Biopsies were taken at work-up and during surgery. Good quality RNA samples were used for omics analyses. The control arm was enlarged by samples coming from our previous similar window study. RESULTS: IHC analyses of afatinib-treated tumor biopsies showed a decrease in pEGFR (P ≤ 0.05) and pERK (P ≤ 0.05); and an increase in CD3+ (P ≤ 0.01) and CD8+ (P ≤ 0.01) T-cell infiltration, and in CD3+ (P ≤ 0.05) T-cell density. RNA sequencing analyses of afatinib-treated tumor samples showed upregulation of inflammatory genes and increased expression scores of signatures predictive of response to programmed cell death protein 1 blockade (P ≤ 0.05). In posttreatment biopsies of afatinib-treated patients, two clusters were observed. Cluster 1 showed a higher expression of markers and gene sets implicated in epithelial-to-mesenchymal transition (EMT) and activation of cancer-associated fibroblasts (CAF) compared with cluster 2 and controls. CONCLUSIONS: Short-term treatment with afatinib in primary HNSCC induces CD3+ and CD8+ tumor infiltration and, in some patients, EMT and CAF activation. These results open perspectives to overcome resistance mechanisms to anti-HER therapy and to potentiate the activity of immune checkpoint inhibitors.

Patient-reported outcomes in terms of swallowing and quality of life after prophylactic versus reactive percutaneous endoscopic gastrostomy tube placement in advanced oropharyngeal cancer patients treated with definitive chemo-radiotherapy: Swall PEG study.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is often used to provide nutritional support in locally advanced head and neck cancer patients undergoing multimodality treatment. However, there is little published data on the impact of prophylactic versus reactive PEG. PEG placement may affect swallowing-related physiology, function, and quality of life. The Swall PEG study is a randomized controlled phase III trial testing the impact of prophylactic versus reactive PEG on patient-reported outcomes in terms of swallowing and quality of life in oropharyngeal cancer patients. METHODS: Patients with locally advanced oropharyngeal cancer receiving chemo-radiotherapy will be randomized to either the prophylactic or reactive PEG tube group. Randomization will be stratified by human papillomavirus (HPV) status and unilateral versus bilateral positive neck lymph nodes. The primary objective of the study is the patient's reported outcome in terms of swallowing (MD Anderson Dysphagia Inventory (MDADI)) at 6 months. Secondary objectives include health-related quality of life, dosimetric parameters associated with patient-reported outcomes, chemo-radiation toxicities, PEG tube placement complications, the impact of nutritional status on survival and toxicity outcomes, loco-regional control, overall survival, the impact of HPV and tobacco smoking on survival outcomes and toxicities, and the cost-effectiveness of each treatment strategy. DISCUSSION: Findings from this study will enhance clinical evidence regarding nutritional management in oropharyngeal cancer patients treated by concurrent chemo-radiation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04019548, study protocol version 2.0_08/08/2019. Registered on 15 July 2019.

Recurrent thyroid cancer: a molecular-based therapeutic breakthrough.

PURPOSE OF REVIEW: Thyroid cancer is a group of heterogeneous rare malignancies, with an increasing incidence. Management of recurrent thyroid cancer not amenable to local therapy such as surgery, radiotherapy or radio-iodine ablation remains very challenging. Indeed, chemotherapy allows a very limited impact on the outcomes of this cancer. RECENT FINDINGS: During the last decade, huge progress has been made for a better comprehension of carcinogenesis and development of new drugs targeting molecular signalling and cancer cell biology, including angiogenesis process. Several agents have been tested in all subgroups of thyroid cancers, leading to promising results in terms of disease stabilization and response, and recently, with an improvement of progression-free survival. SUMMARY: Molecular-targeted therapies, in particular multitargeted kinase inhibitors, entered into phase III randomized clinical trials, confirming their great interest for clinical practice.

The use of chemotherapy regimens carrying a moderate or high risk of febrile neutropenia and the corresponding management of febrile neutropenia: an expert survey in breast cancer and non-Hodgkin's lymphoma.

BACKGROUND: The use of chemotherapy regimens with moderate or high risk of febrile neutropenia (defined as having a FN incidence of 10% or more) and the respective incidence and clinical management of FN in breast cancer and NHL has not been studied in Belgium. The existence of a medical need for G-CSF primary and secondary prophylaxis with these regimens was investigated in a real-life setting. METHODS: Nine oncologists and six hematologists from different Belgian general hospitals and university centers were surveyed to collect expert opinion and real-life data (year 2007) on the use of chemotherapy regimens with moderate or high risk of febrile neutropenia and the clinical management of FN in patients aged <65 years with breast cancer or NHL. Data were retrospectively obtained, over a 6-month observation period. RESULTS: The most frequently used regimens in breast cancer patients (n = 161) were FEC (45%), FEC-T (37%) and docetaxel alone (6%). In NHL patients (n = 39), R-CHOP-21 (33%) and R-ACVBP-14 (15%) were mainly used. Without G-CSF primary prophylaxis (PP), FN occurred in 31% of breast cancer patients, and 13% had PSN. After G-CSF secondary prophylaxis (SP), 4% experienced further FN events. Only 1 breast cancer patient received PP, and did not experience a severe neutropenic event. Overall, 30% of chemotherapy cycles observed in breast cancer patients were protected by PP/SP. In 10 NHL patients receiving PP, 2 (20%) developed FN, whereas 13 (45%) of the 29 patients without PP developed FN and 3 (10%) PSN. Overall, 55% of chemotherapy cycles observed in NHL patients were protected by PP/SP. Impaired chemotherapy delivery (timing and/or dose) was reported in 40% (breast cancer) and 38% (NHL) of patients developing FN. Based on oncologist expert opinion, hospitalization rates for FN (average length of stay) without and with PP were, respectively, 48% (4.2 days) and 19% (1.5 days). Similar rates were obtained from hematologists. CONCLUSIONS: Despite the studied chemotherapy regimens being known to be associated with a moderate or high risk of FN, upfront G-CSF prophylaxis was rarely used. The observed incidence of severe neutropenic events without G-CSF prophylaxis was higher than generally reported in the literature. The impact on medical resources used is sizeable.

Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: An overview about well-established and recently emerging clinical data.

Despite the overwhelming evidence for the role of granulocyte colony stimulating factors (G-CSF) in managing febrile neutropenia (FN) risk, chemotherapy-induced neutropenia (CIN) and/or FN still remain the most common reasons for reducing relative dose intensity (RDI) and/or delaying chemotherapy schedule. The need to maintain RDI to ensure optimal clinical outcomes is one of the key rationales for utilizing G-CSF. There is a high incidence of reduced RDI in both curative and palliative settings, and this observation is especially evidenced in retrospective analyses. Reduced RDI leads to significantly decreased survival outcomes and quality of life in various malignancies at various clinical settings and stages. Beyond its role as a surrogate prognostic marker, high-grade CIN may have an unexpected predictive role in clinical practice, as illustrated by several data relating CIN occurrence with favorable survival outcomes; this may be due to the fact that body surface area (BSA) - based calculation of dose may not fully account for the pharmacokinetics (PK) of cytotoxic drugs and the fact that there may be variability in drug metabolism between patients treated with same chemotherapy regimens.

Unusual presentation of nasopharyngeal carcinoma with rectal metastasis.

Nasopharyngeal carcinoma (NPC) is a rare tumour that mainly metastasizes in lymph nodes, bones, lungs and liver. Colorectal metastases of NPC are extremely rare phenomenon and associated with a poor prognosis. We reported here a case of NPC with rectal metastasis, we discussed the treatment modalities and the prognosis after reviewing the similar cases described in the literature.

Salivary gland carcinomas, paranasal sinus cancers and melanoma of the head and neck: an update about rare but challenging tumors.

PURPOSE OF REVIEW: This is a review about recent clinical developments in rare cancers of the head and neck. RECENT FINDINGS: Progress in molecular biology techniques has allowed the identification of new prognostic factors, and potential molecular-targeted therapies. This is of importance since chemotherapy continues to play a role but is still limited in this group of malignancies. New techniques of irradiation such as intensity-modulated radiotherapy and three-dimensional conformal radiotherapy appear to improve the locoregional control of these tumors. Surgery continues to be the cornerstone of treatment, with a growing interest in the technique of sentinel lymph node biopsy. SUMMARY: As salivary gland carcinomas, paranasal sinus cancers and melanoma of the head and neck are rare malignancies, these tumors must be treated in specialized anticancer centers with access to the latest surgical and irradiation techniques. Moreover, clinical studies with translational research are needed to identify strong prognostic and predictive factors, and effective molecular-targeted therapies.

Does clinical and radiological response predict complete tumor control in N2-N3 squamous cell head and neck cancer after non-operative management of the neck?

CONCLUSION: A complete clinical and radiological response observed following chemotherapy and radiotherapy is not predictive of the absence of residual disease. Moreover, salvage neck surgery does not always seem to be an effective strategy. Consequently, early neck dissection should be advised for patients with complete clinical and radiological response (CCRR) after chemoradiotherapy for tumors with N2-N3 disease. BACKGROUND: We retrospectively reviewed the outcome of 28 patients with N2-N3 disease treated initially with chemotherapy and radiotherapy. PATIENTS AND METHODS: A neck dissection was performed for all patients with residual disease in the neck. RESULTS: A CCRR in the neck was achieved in 25 of 28 patients. The remaining three patients with residual neck mass underwent a salvage neck dissection: the pathological examination confirmed the persistence of tumoral disease. No regional failure was observed in these three patients. In 25 patients considered to have CCRR in the neck, 5 patients (20%) developed regional recurrence. Successful salvage approach was not possible for any of these patients.

Phase II trial evaluating the efficacy of sorafenib (BAY 43-9006) and correlating early fluorodeoxyglucose positron emission tomography-CT response to outcome in patients with recurrent and/or metastatic head and neck cancer.

BACKGROUND: The purpose of this study was to assess the efficacy and safety of sorafenib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) and to explore the predictive value of early metabolic responses. METHODS: Sorafenib was administered orally at 400 mg bid on a continuous basis. The primary endpoint was the response rate. Correlation of early (18)fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT response to time-to-event outcomes was a secondary objective. RESULTS: Twenty-three patients were included in this study. Grade 3 to 4 toxicities included fatigue (22%), hand-foot syndrome (9%), lymphopenia (17%), hyponatremia (39%), and hypophosphatemia (48%). One patient (5%) had a partial response (PR) and 12 patients (55%) had stable disease. Early metabolic response rate was 38%. Median progression-free survival (PFS) was 2.2 months in early metabolic nonresponders (13 of 21 patients) in comparison to 7.4 months in the 8 patients with class I early metabolic response (p = .006). CONCLUSION: Sorafenib showed a modest antitumor activity. Data suggest a possible role of (18)FDG PET metabolic response as an early predictor of a prolonged PFS.

EORTC 24051: unexpected side effects in a phase I study of TPF induction chemotherapy followed by chemoradiation with lapatinib, a dual EGFR/ErbB2 inhibitor, in patients with locally advanced resectable larynx and hypopharynx squamous cell carcinoma.

BACKGROUND: In this phase I/II study, the addition of lapatinib (LAP) was investigated in combination with the sequential use of both approaches TPF induction chemotherapy (ICT) followed by chemoradiation (CRT) in locally advanced larynx or hypopharynx squamous cell carcinoma. PATIENTS AND METHODS: Objectives were to assess maximum tolerated dose, dose-limiting toxicity (DLT) and to recommend a safe dose of LAP when administered with 4 cycles of TPF followed by CRT. RESULTS: Seven male patients were included. Three patients were included in the first cohort, at dose level 1 (LAP 500 mg daily plus TPF). Renal toxicity was observed among these three patients (grade 3 [n=1], grade 2 [n=1] and grade 1 [n=1]), with 1 DLT, leading to treatment interruption in this group. Nephrotoxicity was reversible after stopping LAP and hydration of the patients. In a second cohort of four patients administering docetaxel from the second cycle, 3 more DLTs were observed (grade 2 renal toxicity and grade 3 diarrhea, grade 3 anorexia and grade 3 stomatitis, and grade 4 neutropenia). Based on the occurrence of 4 DLTs at the first dose level of LAP, patient recruitment was closed. CONCLUSION: These data indicate that LAP cannot be combined safely with full dose TPF.

Management of head and neck cancer in elderly patients.

Head and neck cancer (HNC) represents a heterogeneous group of tumours requiring multimodality approaches. It is debatable whether HNC treatment in geriatric patients should be different to that delivered for younger patients. Furthermore, the risk of death seems to be higher in HNC patients with higher co-morbidity status. Despite the fact that there is no significant difference in outcome in younger versus older patients, older HNC patients are more likely to receive nonstandard, less aggressive therapies than younger patients. Age alone should not be the basis for selecting treatment options in older HNC patients. A thorough pretreatment evaluation of co-morbidities should always be performed, and radical surgical options should not be excluded in older HNC patients treated with curative intent, as postoperative complications occur no more frequently in older patients than in younger patients. Locoregional control and disease-free survival in older patients treated with radiation therapy (either with curative intent or in the palliative setting) are comparable to the results seen in younger HNC patients, with the same acute toxicity profile. In patients receiving systemic therapies, special attention must be given to modification of chemotherapy dosages according to renal and hepatic function. Molecular-targeted therapies appear to be very useful in such patients because of their favourable tolerability. In conclusion, once all physiological and biological risk factors have been addressed, a large proportion of geriatric patients can and should be offered the same HNC treatment as is offered to younger patients.

A phase I clinical and pharmacokinetic study of tipifarnib in combination with docetaxel in patients with advanced solid malignancies.

PURPOSE: This phase I study assessed the maximum tolerated doses (MTDs), safety, pharmacokinetics, and efficacy of combined tipifarnib and docetaxel treatment in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: The study protocol was sensitive to myelosuppression, as both drugs have been associated with this adverse event. Due to myelosuppression incidence, and in order to determine the MTD of docetaxel, multiple treatment regimens were employed. Tipifarnib was administered orally at 200 or 300 mg, twice daily (BID) for 21 days, 14 days, or 7 days for multiple 21-day cycles; intravenous (i.v.) docetaxel was administered on day 1 of each cycle at 60, 75, or 85 mg/m2. RESULTS: A total of 36 patients entered into the study. For each drug, MTDs were identified (tipifarnib: 300 mg BID for 14 days with 60 mg/m2 docetaxel; tipifarnib: 200 mg BID for 14 days with 75 mg/m2 docetaxel). The major dose-limiting toxicity was myelosuppression, particularly febrile neutropenia (44%). Mutual pharmacokinetic interactions (the effect of docetaxel on tipifarnib pharmacokinetics and the effect of tipifarnib on docetaxel pharmacokinetics) were not evident, as maximum plasma concentration (Cmax) and the area under the serum concentration-time curve (AUC) values of both tipifarnib and docetaxel were similar (p > or = 0.43) whether the two drugs were concomitantly administered or not. Seven of 31 evaluable patients (23%) had an objective response, 11 (35%) had stable disease (six > or = 24 weeks), and the overall clinical benefit rate (objective response and/or stable disease > or = 24 weeks) was 42%. CONCLUSIONS: Although the high incidence of febrile neutropenia necessitated a multiple scheduling adaptation of tipifarnib compared to the original protocol, the apparent lack of mutual pharmacokinetic interactions, the ability to coadminister tipifarnib and docetaxel near single-agent MTDs, and suggestive evidence of efficacy make this drug combination attractive for further examination.

Molecular markers of head and neck squamous cell carcinoma: promising signs in need of prospective evaluation.

BACKGROUND: The aim of this article is to review recent developments in the biological understanding of head and neck squamous cell carcinomas. METHODS AND RESULTS: We describe the markers according to their function and their prognostic or predictive roles. Some associations can be found between molecular markers and invasiveness, aggressiveness, degree of differentiation, and tumor stage, but only a few clinical studies have shown an impact on prognosis. In addition, despite an increasing number of articles relating to this topic, the small number of patients included in the studies reported reduces the clinical implications of these results. Few studies applied a more comprehensive molecular analysis approach, such as DNA microarrays or differential expression profiling by polymerase chain reaction, to identify a combination of markers that could be more informative than a single molecular marker. CONCLUSION: Some progress has been made with respect to molecular markers and head and neck cancers. Translational and prospective, hypothesis-driven research must proceed with sufficient rigor to facilitate the clinical applicability of such results.

Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications.

PURPOSE: Since febrile neutropenic patients were recognized to constitute a heterogeneous population, several models have been developed for predicting the risk of serious medical complications. The Multinational Association for Supportive Care in Cancer score and its derived clinical prediction rules have been validated, but thus far there were no data about its use for simplifying therapy in predicted low-risk patients. PATIENTS AND METHODS: In a single institution, we followed all episodes of febrile neutropenia between January 1999 and November 2003. Those patients predicted at low risk for complications, who were not receiving antibacterials at fever onset and were eligible for treatment with oral antibiotics, were treated with ciprofloxacin and amoxicillin-clavulanate and were discharged if they were clinically stable or improving after an initial observation period. The primary end point of the study was the rate of resolution of the febrile neutropenic episode without complications, among these early discharged patients. RESULTS: Of 383 first febrile neutropenic episodes predicted at low risk of complication, 178 patients (33 men and 145 women, mainly with solid tumors) were treated orally; they constituted the basis of our analysis. Seventy-nine patients (44%) were discharged early (with a median time to discharge of 26 hours); no complications occurred among them but three patients had to be readmitted, resulting in a success rate of 96% (95% CI, 92% to 100%). CONCLUSION: Our study shows that oral therapy followed by early discharge was feasible in a small but significant proportion of patients selected by a strategy combining predicted low risk and medical and nonmedical criteria.