Recent insights in the PI3K/Akt pathway as a promising therapeutic target in combination with EGFR-targeting agents to treat head and neck squamous cell carcinoma.

Resistance to therapies targeting the epidermal growth factor receptor (EGFR), such as cetuximab, remains a major roadblock in the search for effective therapeutic strategies in head and neck squamous cell carcinoma (HNSCC). Due to its close interaction with the EGFR pathway, redundant or compensatory activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been proposed as a major driver of resistance to EGFR inhibitors. Understanding the role of each of the main proteins involved in this pathway is utterly important to develop rational combination strategies able to circumvent resistance. Therefore, the current work reviewed the role of PI3K/Akt pathway proteins, including Ras, PI3K, tumor suppressor phosphatase and tensing homolog, Akt and mammalian target of rapamycin in resistance to anti-EGFR treatment in HNSCC. In addition, we summarize PI3K/Akt pathway inhibitors that are currently under (pre)clinical investigation with focus on overcoming resistance to EGFR inhibitors. In conclusion, genomic alterations in and/or overexpression of one or more of these proteins are common in both human papillomavirus (HPV)-positive and HPV-negative HNSCC tumors. Therefore, downstream effectors of the PI3K/Akt pathway serve as promising drug targets in the search for novel therapeutic strategies that are able to overcome resistance to anti-EGFR treatment. Co-targeting EGFR and the PI3K/Akt pathway can lead to synergistic drug interactions, possibly restoring sensitivity to EGFR inhibitors and hereby improving clinical efficacy. Better understanding of the predictive value of PI3K/Akt pathway alterations is needed to allow the identification of patient populations that might benefit most from these combination strategies.

Steering decision making by terminology: oligometastatic versus argometastatic.

Allowing selected patients with few distant metastases to undergo potentially curative local ablation, the designation "oligometastatic" has become a widely popular concept in oncology. However, accumulating evidence suggests that many of these patients harbour an unrecognised microscopic disease, leading either to the continuous development of new metastases or to an overt polymetastatic state and questioning thus an indiscriminate use of potentially harmful local ablation. In this paper, reviewing data on oligometastatic disease, we advocate the importance of identifying a true oligometastatic disease, characterised by a slow speed of development, instead of relying solely on a low number of lesions as the term "oligometastatic" implies. This is particularly relevant in clinical practice, where terminology has been shown to influence decision making. To define a true oligometastatic disease in the context of its still elusive biology and interaction with the immune system, we propose using clinical criteria. As discussed further in the paper, these criteria can be classified into three categories involving a low probability of occult metastases, low tumour growth rate and low tumour burden. Such cases with slow tumour-cell shedding and slow proliferation leave a sufficiently broad window-of-opportunity to detect and treat accessible lesions, increasing thus the odds of a cure.

ESO-ESSO-ESTRO Multidisciplinary Course in Oncology for Medical Students: 4 Years of Experience (2016-2019).

The ESO-ESSO-ESTRO Multidisciplinary Course in Oncology is intended to fill the gap of the undergraduate fragmented oncology education, to provide insight into all theoretical and practical aspects of oncology, and to encourage future professional choices towards an oncology discipline. Students are exposed to (a) preclinical cancer topics; (b) natural history of the disease; (c) laboratory diagnostic tests; (d) medical, radiation, surgical, and palliative treatment; and (e) direct or through multidisciplinary patients' approach. Students are obliged to attend (i) all theoretical lectures, (ii) clinical case presentations, (iii) laboratories and ward visits, and (iv) to prepare and present a specific project under supervision. Participation is limited to 24 medical students who are selected through a competitive application process. Between 2016 and 2019, 96 students from 29 countries have attended. Data analysis derived from a given questionnaire demonstrates that most of the participants have declared that (1) they have achieved their expectations and objectives, (2) they have highly rated both clinical and non-clinical teaching oncological topics, and (3) they have been stimulated in developing a professional career in the field of oncology.

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.

Patterns and quality of care for head and neck cancer in Belgium: A population-based study.

OBJECTIVES: We evaluated the quality of care for patients with squamous cell carcinoma (SCC) of the oral cavity, oropharynx, hypopharynx or larynx in Belgium. METHODS: Data of the Belgian Cancer Registry were coupled with health insurance data and hospital discharge data. Quality of care and the association with hospital volume were evaluated based on six quality indicators. RESULTS: Half of the patients were treated with primary radiotherapy, with or without systemic therapy (49.7%) and 38.1% with surgery, with or without (neo)adjuvant therapy. Single-modality treatment was provided to 78.1% of early-disease patients. Of the patients with cN0 disease, 56.4% underwent neck dissection. Postoperative radiotherapy was completed timely in 48.5% of patients. Concomitant chemotherapy was administered to 58.2% of patients <70 years with locally advanced disease. Imaging of the neck after radiotherapy was performed appropriately in 32.7% of patients. Variability between centres was considerable. No clear relationship between hospital volume and results of the individual QIs was observed. CONCLUSIONS: Results show that for the measured QIs, targets are not met and variability between centres is considerable. Through individual feedback, centres are motivated to improve the quality of care for head and neck cancer patients in Belgium.

Cetuximab-induced natural killer cell cytotoxicity in head and neck squamous cell carcinoma cell lines: investigation of the role of cetuximab sensitivity and HPV status.

BACKGROUND: The epidermal growth factor receptor (EGFR) is overexpressed by 80-90% of squamous cell carcinoma of head and neck (HNSCC). In addition to inhibiting EGFR signal transduction, cetuximab, a monoclonal antibody targeting EGFR can also bind to fragment crystallisable domain of immunoglobulins G1 present on natural killer (NK), causing antibody-dependent cellular cytotoxicity (ADCC). However, presence of cetuximab resistance limits effective clinical management of HNSCC. METHODS: In this study, differences in induction of ADCC were investigated in a panel of ten HNSCC cell lines. Tumour cells were co-cultured with NK cells and monitored using the xCELLigence RTCA. RESULTS: While ADCC was not influenced by HPV status, hypoxia and cetuximab resistance did affect ADCC differentially. Intrinsic cetuximab-resistant cell lines showed an increased ADCC induction, whereas exposure to hypoxia reduced ADCC. Baseline EGFR expression was not correlated with ADCC. In contrast, EGFR internalisation following cetuximab treatment was positively correlated with ADCC. CONCLUSION: These findings support the possibility that resistance against cetuximab can be overcome by NK cell-based immune reactions. As such, it provides an incentive to combine cetuximab with immunotherapeutic approaches, thereby possibly enhancing the anti-tumoural immune responses and achieving greater clinical effectiveness of EGFR-targeting agents.

HIPEC in advanced epithelial ovarian cancer: why is there controversy?

PURPOSE OF REVIEW: The randomized OVHIPEC study provided further evidence that adding heated intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery significantly improved recurrence-free and overall survival in stage III epithelial ovarian cancer (EOC) patients, who were ineligible for primary cytoreductive surgery due to extensive intraperitoneal disease. Because opinions have been divided as to whether HIPEC is now a new standard of care for advanced EOC, the pros and cons of this approach are examined. A comparison with the ongoing discussion about the role of intraperitoneal chemotherapy is made. RECENT FINDINGS: For both techniques, experience is crucial and a learning curve essential. Compared with intraperitoneal chemotherapy, intraoperative application of HIPEC provides superior distribution through the peritoneal cavity. HIPEC, as given in OVHIPEC, did not significantly increase adverse events, had no negative effect on quality of life and was cost-effective. SUMMARY: Despite the ongoing debate about HIPEC, an important first step in attempting to demonstrate the efficacy of HIPEC in the first-line setting has been made with OVHIPEC. Critics have been of value to optimize future trials with HIPEC in patients with EOC.

Mitotic count can predict tamoxifen benefit in postmenopausal breast cancer patients while Ki67 score cannot.

BACKGROUND: Controversy exists for the use of Ki67 protein expression as a predictive marker to select patients who do or do not derive benefit from adjuvant endocrine therapy. Whether other proliferation markers, like Cyclin D1, and mitotic count can also be used to identify those estrogen receptor α (ERα) positive breast cancer patients that derive benefit from tamoxifen is not well established. We tested the predictive value of these markers for tamoxifen benefit in ERα positive postmenopausal breast cancer patients. METHODS: We collected primary tumor blocks from 563 ERα positive patients who had been randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA trial) with a median follow-up of 7.8 years. Mitotic count, Ki67 and Cyclin D1 protein expression were centrally assessed by immunohistochemistry on tissue microarrays. In addition, we tested the predictive value of CCND1 gene copy number variation using MLPA technology. Multivariate Cox proportional hazard models including interaction between marker and treatment were used to test the predictive value of these markers. RESULTS: Patients with high Ki67 (≥5%) as well as low (< 5%) expressing tumors equally benefitted from adjuvant tamoxifen (adjusted hazard ratio (HR) 0.5 for both groups)(p for interaction 0.97). We did not observe a significant interaction between either Cyclin D1 or Ki67 and tamoxifen, indicating that the relative benefit from tamoxifen was not dependent on the level of these markers. Patients with tumors with low mitotic count derived substantial benefit from tamoxifen (adjusted HR 0.24, p <  0.0001), while patients with tumors with high mitotic count derived no significant benefit (adjusted HR 0.64, p = 0.14) (p for interaction 0.03). CONCLUSION: Postmenopausal breast cancer patients with high Ki67 counts do significantly benefit from adjuvant tamoxifen, while those with high mitotic count do not. Mitotic count is a better selection marker for reduced tamoxifen benefit than Ki67.

Weekly Low-Dose Versus Three-Weekly High-Dose Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non-Nasopharyngeal Head and Neck Cancer: A Systematic Review and Meta-Analysis of Aggregate Data.

BACKGROUND: Three-weekly high-dose cisplatin (100 mg/m2) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, due to unsatisfactory patient tolerance, various weekly low-dose schedules have been increasingly used in clinical practice. The aim of this meta-analysis was to compare the efficacy, safety, and compliance between these two approaches. MATERIALS AND METHODS: We systematically searched literature for prospective trials of patients with LA-SCCHN who received postoperative or definitive conventionally fractionated concurrent chemoradiation. Radiation doses were usually 60-66 gray (Gy) in the postoperative setting and 66-70 Gy in the definitive setting. Standard, three-weekly high-dose cisplatin (100 mg/m2, 3 doses) was compared with the weekly low-dose protocol (≤50 mg/m2, ≥6 doses). The primary endpoint was overall survival. Secondary outcomes comprised response rate, acute and late adverse events, and treatment compliance. RESULTS: Fifty-two studies with 4,209 patients were included in two separate meta-analyses according to the two clinical settings. There was no difference in treatment efficacy as measured by overall survival or response rate between the chemoradiation settings with low-dose weekly and high-dose three-weekly cisplatin regimens. In the definitive treatment setting, the weekly regimen was more compliant and significantly less toxic with respect to severe (grade 3-4) myelosuppression (leukopenia p = .0083; neutropenia p = .0024), severe nausea and/or vomiting (p < .0001), and severe nephrotoxicity (p = .0099). Although in the postoperative setting the two approaches were more equal in compliance and with clearly less differences in the cisplatin-induced toxicities, the weekly approach induced more grade 3-4 dysphagia (p = .0026) and weight loss (p < .0001). CONCLUSION: In LA-SCCHN, current evidence is insufficient to demonstrate a meaningful survival difference between the two dosing regimens. Prior to its adoption into routine clinical practice, the low-dose weekly approach needs to be prospectively compared with the standard three-weekly high-dose schedule. IMPLICATIONS FOR PRACTICE: Given concurrently with conventional radiotherapy in locally advanced head and neck cancer, high-dose three-weekly cisplatin has often been replaced with weekly low-dose infusions to increase compliance and decrease toxicity. The present meta-analysis suggests that both approaches might be equal in efficacy, both in the definitive and postoperative settings, but differ in toxicity. However, some toxicity data can be influenced by unbalanced representation, and the conclusions are not based on adequately sized prospective randomized studies. Therefore, low-dose weekly cisplatin should not be used outside clinical trials but first prospectively studied in adequately sized phase III trials versus the high-dose three-weekly approach.

p16, HPV, and Cetuximab: What Is the Evidence?

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide. It has recently been appreciated that human papillomavirus (HPV) status (or p16 status, which is a frequently used surrogate for HPV status) is prognostic for oropharyngeal SCCHN. Here, we review and contextualize existing p16 and HPV data, focusing on the cetuximab registration trials in previously untreated, locoregionally advanced, nonmetastatic SCCHN (LA SCCHN) and in recurrent and/or metastatic SCCHN (R/M SCCHN): the IMCL-9815 and EXTREME clinical trials, respectively. Taken together, the available data suggest that, while p16 and HPV are prognostic biomarkers in patients with LA SCCHN and R/M SCCHN, it could not be shown that they are predictive for the outcomes of the described cetuximab-containing trial regimens. Consequently, although HPV status provides prognostic information, it is not shown to predict therapy response, and so is not helpful for assigning first-line therapy in patients with SCCHN. In addition, we discuss assays currently used to assess p16 and HPV status, as well as the differentiation between these two biomarkers. Ultimately, we believe HPV E6/E7 polymerase chain reaction-based mRNA testing may represent the most informative technique for assessing HPV status in patients with SCCHN. While p16 is a valid surrogate for HPV status in oropharyngeal carcinoma (OPC), there is a higher risk of discordance between p16 and HPV status in non-OPC SCCHN. Collectively, these discussions hold key implications for the clinical management of SCCHN. IMPLICATIONS FOR PRACTICE: Human papillomavirus (HPV) status (or its commonly utilized surrogate p16) is a known prognostic biomarker in oropharyngeal squamous-cell carcinoma of the head and neck (SCCHN). We evaluated implications of the available evidence, including cetuximab registration trials in previously untreated locoregionally advanced (LA) SCCHN and recurrent and/or metastatic (R/M) SCCHN. We conclude that, although p16 and HPV are prognostic biomarkers for both LA and R/M SCCHN, they have not been shown to be predictive of response to the described cetuximab-containing regimens for either indication. Thus, current evidence suggests that benefits of cetuximab are observed in both p16-/HPV-positive and -negative SCCHN.

Immunotherapy in head and neck cancer: aiming at EXTREME precision.

BACKGROUND: Locoregionally advanced, recurrent, and metastatic squamous cell carcinomas of the head and neck (SCCHN) remain difficult to treat disease entities, in which systemic treatment often forms an integral part of their management. Immunotherapy is based on functional restoration of the host immune system, helping to counteract various tumour evasion strategies. Broadly, immunotherapeutic approaches encompass tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating agents. Until 2015, the epidermal growth factor receptor inhibitor cetuximab, a tumour-specific antibody, represented the only Food and Drug Administration (FDA)-approved targeted therapy for SCCHN. Subsequently, in 2016, the results from two prospective trials employing the immune-modulating antibodies nivolumab and pembrolizumab heralded a new era of anticancer treatment. DISCUSSION: Nivolumab and pembrolizumab are monoclonal antibodies against programmed cell death protein-1 (PD-1), an 'immune checkpoint' receptor. Found on the surface of T-cells, PD-1 negatively regulates their activation and can thus be exploited during carcinogenesis. The second-line phase III trial CheckMate-141 randomly assigned 361 patients with recurrent and/or metastatic SCCHN in a 2:1 ratio to receive either single-agent nivolumab (3 mg/kg intravenously every 2 weeks) or standard monotherapy (methotrexate, docetaxel, or cetuximab). Nivolumab improved the objective response rate (13% versus 6%) and median overall survival (OS; 7.5 versus 5.1 months, p = 0.01) without increasing toxicity. Exploratory biomarker analyses indicated that patients treated with nivolumab had longer OS than those given standard therapy, regardless of tumour PD-1 ligand (PD-L1) expression or p16 status. In the non-randomised, multicohort phase Ib study KEYNOTE-012, treatment with pembrolizumab achieved comparable results. Importantly, most of the responding patients had a long-lasting response. CONCLUSION: Based on recent results, nivolumab and pembrolizumab have been approved by the FDA as new standard-of-care options for the second-line treatment of recurrent and/or metastatic SCCHN. Generally well tolerated, these novel drugs demonstrated modest response rates, with tumour regressions usually being durable, even in platinum-resistant/refractory cases. The next step will be to extend the observed benefit to first-line treatment, currently dominated by the EXTREME regimen (platinum/5-fluorouracil/cetuximab), and to the locoregionally advanced setting, where concurrent chemoradiation with cisplatin is standard. Regimens combining immunotherapy with other modalities will probably further improve outcomes.

Human Papillomavirus (HPV): A Criterion for Therapeutic Decision in Squamous Cell Carcinoma of the Head and Neck?

When deciding how to treat patients with squamous cell carcinoma of the head and neck (SCCHN), several factors have to be taken into account: disease factors, patient factors, treatment factors, and the wish of the patient. This symposium article is summarizing the information on HPV (p16) in the context of decision making in SCCHN patients with locoregionally advanced disease and those with recurrent/metastatic disease. The literature data suggest that HPV(p16) has prognostic significance, both in locoregionally advanced disease (in particular, in oropharynx cancer) and in recurrent/metastatic disease, while there are only limited data on its predictive significance. Results of HPV (p16) testing should not change management outside clinical trials.

Feasibility of tongue strength measurements during (chemo)radiotherapy in head and neck cancer patients.

PURPOSE: The aim of this study was to investigate the feasibility of tongue strength measures (TSMs) and the influence of bulb location, sex, and self-perceived pain and mucositis in head and neck cancer (HNC) patients during chemoradiotherapy (CRT). METHODS: Twenty-six newly diagnosed HNC patients treated with CRT performed anterior and posterior maximal isometric tongue pressures by means of the Iowa Oral Performance Instrument (IOPI). The Oral Mucositis Weekly Questionnaire (OMWQ) and a Visual Analogue Scale (VAS) for pain during swallowing were completed weekly from baseline to 1 week post CRT. RESULTS: Feasibility of TSMs during CRT declines significantly from 96 to 100% at baseline to 46% after 6 weeks of CRT. But post-hoc analyses reveal only significant differences in feasibility between baseline and measurements after 4 weeks of treatment. No effect of gender or bulb location was established, but feasibility is influenced by pain and mucositis. CONCLUSIONS: Feasibility of TSMs declines during CRT and is influenced by mucositis and pain. For the majority of subjects, TSMs were feasible within the first 4 weeks, which provides a window of scientific and clinical opportunities in this patient population.

The Impact of an International Network (Gynecologic Cancer InterGroup) for Clinical Research on Global Capacity for Gynecologic Cancer Clinical Trials.

OBJECTIVE: The objective of this study was to demonstrate that the construction of the Gynecologic Cancer InterGroup (GCIG) has increased collaboration and accrual to high-quality phase 3 trials at a global level. MATERIALS AND METHODS: The GCIG is a collaboration of 29 international cooperative clinical trial groups committed to conduct of high-quality phase 3 trials among women with gynecologic cancer. A complete bibliography of the reported phase 3 trials has been developed and is available on the GCIG Web site http://www.gciggroup.com. A "GCIG trial" is a trial in which any 2 or more GCIG member groups are formally involved. We reviewed the output of the GCIG from 1997 to 2015 with respect to member participation and quality of publication (impact factor and citation index). The publications are considered in 3 cohorts, 1997 to 2002, 2003 to 2008, and 2009 to 2014, for the purposes of comparison and progress. A social network map has been developed for these publications to identify how the GCIG has increased capacity for clinical trials globally. RESULTS: Using a global map, the number of member groups in the GCIG has increased in each of the 3 periods. The total annual number of publications and citations within the 1997 to 2015 period has increased significantly. The average number of citations per publication is demonstrated in each of the 3 periods. The steady increase in the number of citations is used as a proxy for the impact of the publications. The impact factor of the journal and the number of citations are reported for the 10 most highly cited publications. Finally, using a social networking methodology, networking has visibly and numerically increased in each of the 3 periods. CONCLUSIONS: Evidence supports that the construction of the GCIG has increased collaboration and accrual to high-quality phase 3 trials at a global level among women with gynecologic cancer.

Gemcitabine-Based Chemoradiation in the Treatment of Locally Advanced Head and Neck Cancer: Systematic Review of Literature and Meta-Analysis.

BACKGROUND: Platinum-based concurrent chemoradiation (CCRT) improves locoregional control and overall survival of locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) when compared to radiotherapy alone, but this approach is hampered by significant toxicity. Therefore, alternative ways to enhance the radiation effects are worth investigating. Gemcitabine (2',2'-difluorodeoxycytidine), in addition to its activity against a variety of solid tumors, including SCCHN, is one of the most potent radiosensitizers, and it has an overall favorable safety profile. In this paper, the clinical experience with gemcitabine-based chemoradiation in the treatment of patients with LA-SCCHN is reviewed. METHODS: We conducted a review of the literature on the clinical experience with radiotherapy combined with either single-agent gemcitabine or gemcitabine/cisplatin-based polychemotherapy for the treatment of patients with LA-SCCHN. We also searched abstracts in databases of major international oncology meetings from the last 20 years. A meta-analysis was performed to calculate pooled proportions with 95% confidence intervals (CIs) for complete response rate and grade 3-4 acute mucositis rate. RESULTS: A total of 13 papers were eligible for the literature review. For schedules using a gemcitabine dose intensity (DI) below 50 mg/m(2) per week, the complete response rate was 86% (95% CI, 74%-93%) with grade 3-4 acute mucositis rate of 38% (95% CI, 27%-50%) and acceptable late toxicity. In one of the studies employing such low DIs, survival data were provided showing a 3-year overall survival of 50%. Compared with DI ≥50 mg/m(2) per week, there was no difference in the complete response rate (71%; 95% CI, 55%-83%; p = .087) but a significantly higher (p < .001) grade 3-4 acute mucositis rate of 74% (95% CI, 62%-83%), often leading to treatment interruptions (survival data provided in 8 studies; 3-year overall survival, 27%-63%). Late toxicity comprising mainly dysphagia was generally underreported, whereas information about xerostomia and skin fibrosis was scarce. CONCLUSION: This review highlights the radiosensitizing potential of gemcitabine and suggests that even very low dosages (less than 50 mg/m(2) per week) provide a sufficient therapeutic ratio and therefore should be further investigated. Refinements in radiation schemes, including intensity-modulated radiation therapy, in combination with low-dose gemcitabine and targeted agents, such as cetuximab, are currently being investigated. IMPLICATIONS FOR PRACTICE: Cisplatin-based concurrent chemoradiation (CCRT) has become the standard treatment of locally advanced head and neck cancer (LAHNC). This approach is hampered by significant toxicity. This paper reviews the studies using gemcitabine as an alternative radio-sensitizer for CCRT in patients with LAHNC. In this capacity, despite its mild intrinsic toxicity, gemcitabine comes with high rates of severe mucositis when used in dosages exceeding 50 mg/m(2) per week. CCRT with low-dose gemcitabine provides a sufficient therapeutic ratio, combining clinical activity, similar to the higher-dose regimens, with lower toxicity. Further investigation is warranted.

Asian expert recommendation on management of skin and mucosal effects of radiation, with or without the addition of cetuximab or chemotherapy, in treatment of head and neck squamous cell carcinoma.

With increasing numbers of patients with unresectable locoregionally advanced (LA) head and neck squamous cell carcinoma (HNSCC) receiving cetuximab/radiotherapy (RT), several guidelines on the early detection and management of skin-related toxicities have been developed. Considering the existing management guidelines for these treatment-induced conditions, clinical applicability and standardization of grading methods has remained a cause of concern globally, particularly in Asian countries. In this study, we attempted to collate the literature and clinical experience across Asian countries to compile a practical and implementable set of recommendations for Asian oncologists to manage skin- and mucosa-related toxicities arising from different types of radiation, with or without the addition of cetuximab or chemotherapy. In December 2013, an international panel of experts in the field of head and neck cancer management assembled for an Asia-Pacific head and neck cancer expert panel meeting in China. The compilation of discussion outcomes of this meeting and literature data ultimately led to the development of a set of recommendations for physicians with regards to the approach and management of dermatological conditions arising from RT, chemotherapy/RT and cetuximab/RT, and similarly for the approach and management of mucositis resulting from RT, with or without the addition of chemotherapy or cetuximab. These recommendations helped to adapt guidelines published in the literature or text books into bedside practice, and may also serve as a starting point for developing individual institutional side-effect management protocols with adequate training and education.

Long-term remission of locally recurrent oropharyngeal cancer after docetaxel-based chemotherapy plus cetuximab.

BACKGROUND: In recurrent head and neck squamous cell carcinoma ineligible for resection or irradiation, treatment aims primarily at symptom control and quality of life enhancement with an expected outcome of 6-12 months. METHODS: In 2005, a male patient, born in 1944, with a second local recurrence of human papillomavirus negative tonsil cancer was enrolled in the EXTREME trial, and randomized to platinum/5-fluorouracil/cetuximab arm resulting in partial remission with progression-free survival of 12 months. The second-line systemic therapy comprised 5 cycles of 3-weekly docetaxel/cisplatin/5-fluorouracil regimen plus weekly cetuximab. RESULTS: As confirmed on imaging and repeated biopsies, complete response was achieved with disease-free survival of 8 years and follow-up period of 12 years. Severe acute toxicities during the taxane-based chemotherapy plus cetuximab included grade 4 anorexia and grade 3 febrile neutropenia. CONCLUSIONS: Poor tumor differentiation, no weight loss, oropharyngeal location, white race, and particularly the induced complete response were most likely the key favorable prognostic factors in the reported patient. The possibility of a synergistic interaction between taxanes and cetuximab should be further explored.