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Phase II Multicenter Study of the Antiepidermal Growth Factor Receptor Monoclonal Antibody Cetuximab in Combination With Platinum-Based Chemotherapy in Patients With Platinum-Refractory Metastatic and/or Recurrent Squamous Cell Carcinoma of the Head and Neck
Abstract
Purpose To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).
Patients and Methods Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m² followed by subsequent weekly doses of 250 mg/m²) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study.
Results The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%. The median time to progression and overall survival were 85 and 183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294 days, respectively). Treatment was well tolerated. The most common cetuximab-related adverse events were skin reactions, particularly an acne-like rash.
Conclusion The combination of cetuximab and platinum chemotherapy is an active and well-tolerated approach to the treatment of this poor-prognosis patient population with platinum-refractory recurrent or metastatic SCCHN for whom there are no recommended standard therapeutic options.
... В связи с низкой эффективностью цитотоксической химиотерапии в клиническую практику был внедрен цетуксимаб, представляющий собой химерные моноклональные антитела к рецепторам эпидермального фактора роста [16]. Монотерапия цетуксимабом была изучена в 3 клинических исследованиях II фазы при платинорезистентном ПРГШ [17][18][19]. В 2 исследованиях цетуксимаб сочетали с препаратом платины, в 1 он использовался в монорежиме. Исходы лечения во всех 3 исследованиях оказались одинаковыми. ...
Recurrent and metastatic head and neck squamous cell carcinoma is a hard-to-treat pathology. median overall survival for standard chemotherapy regimens does not exceed 11 months. One of the factors decreasing treatment effectivenessis frequency of severe adverse events which are observed in every 2nd patient during standard therapy regimens. moreover, even if notable tumor regression is achieved, this effect is transient. Development of immunotherapy drugs, namely pembrolizumab, helps solve these problems. Clinical trials and real-world use of the drug show that in the 1st and 2nd therapy lines for recurrent and metastatic head and neck squamous cell carcinoma, pembrolizumab allows to achieve persistent treatment response, increase overall survival, and decrease the frequency of adverse events.
... If the cancer is progressed (stage III or IV), chemotherapy is added to the radiation treatment programme [56,57]. Anticancer medications, such as cisplatin, cetuximab, fluorouracil, paclitaxel, docetaxel (DTX), and methotrexate, are being used in OC chemotherapy treatments [57][58][59][60][61][62][63][64][65][66][67]. This is merely a list of some chemotherapy drugs. ...
Throughout the world, oral cancer is a common and aggressive malignancy with a high risk of morbidity, mortality, and recurrence. The importance of early detection in cancer prevention and disease treatment cannot be overstated. Conventional therapeutic strategies have minor difficulties but considerable side effects and unfavourable consequences in clinical applications. Hence, there is a requirement for effective ways for early detection and treatment of oral cancer. At present, numerous forms of nanoparticles have piqued researchers’ interest as a potentially useful tool for diagnostic probes and medicinal devices. Because of their inherent physicochemical properties and customizable surface modification, they are able to circumvent some of restrictions and accomplish the intended diagnostic and therapeutic impact. Nanotechnology is a unique field that has revolutionised the industry and is paving the way for new treatments for oral cancer. It can help with a better diagnosis with less harmful substances and is setting current guidelines for treatment. The use of nanotechnology in cancer diagnosis, therapy, and care improves clinical practise dramatically. The different types of nanoparticles that have been developed for the diagnosis and therapy of oral cancers will be covered in this study. The difficulties and potential uses of nanoparticles in the treatment and diagnosis of oral cancer are then highlighted. In order to emphasise existing difficulties and potential remedies for oral cancer, a prospective view of the future is also provided.
... 414 Combining cetuximab with cisplatin contributed to a significant improvement in ORR (26% vs. 10%) but failed to prolong survival for R/M-HNSCC patients when compared with cisplatin monotherapy. [415][416][417] In the landmark EXTREME study, cetuximab combined with platinum (cisplatin or carboplatin) and fluorouracil (PCF) resulted in improved median PFS (5.6 months vs. 3.3 months), OS (10.1 months vs. 7.4 months), and response rates (36% vs. 20%) compared with chemotherapy alone. 26 This led to the approval of cetuximab in combination with platinum-based therapy with fluorouracil as the first-line treatment for R/M-HNSCC patients. ...
Head and neck cancer (HNC) is malignant, genetically complex and difficult to treat and is the sixth most frequent cancer, with tobacco, alcohol and human papillomavirus being major risk factors. Based on epigenetic data, HNC is remarkably heterogeneous, and treatment remains challenging. There is a lack of significant improvement in survival and quality of life in patients with HNC. Over half of HNC patients experience locoregional recurrence or distal metastasis despite the current multiple traditional therapeutic strategies and immunotherapy. In addition, resistance to chemotherapy, radiotherapy and some targeted therapies is common. Therefore, it is urgent to explore more effective and tolerable targeted therapies to improve the clinical outcomes of HNC patients. Recent targeted therapy studies have focused on identifying promising biomarkers and developing more effective targeted therapies. A well understanding of the pathogenesis of HNC contributes to learning more about its inner association, which provides novel insight into the development of small molecule inhibitors. In this review, we summarized the vital signaling pathways and discussed the current potential therapeutic targets against critical molecules in HNC, as well as presenting preclinical animal models and ongoing or completed clinical studies about targeted therapy, which may contribute to a more favorable prognosis of HNC. Targeted therapy in combination with other therapies and its limitations were also discussed.
... Standard therapies based on stage, chemoradiation therapy, and induction chemotherapy are the conventional treatments for OC [95]. For the treatment of OC in modern therapy, anticancer medications such as cisplatin, fluorouracil, cetuximab, paclitaxel, methotrexate, and docetaxel (DTX) have been used either solely or in combination [96][97][98][99]. Traditional cancer therapy approaches for solid and malignant tumors, such as surgery, are frequently used as the initial course of therapy. ...
Simple Summary
Oral cancer is a major cause of death worldwide. The major challenges associated with the conventionally used treatment modalities include the recurrence of the cancer and the adverse effects of the chemotherapeutic drugs. Natural products play a very important role in drug discovery and have potential effects against various cancers in general and oral cancer in particular. The major problem with natural products is their poor bioavailability, which limits their therapeutic application. Therefore, an attempt is made to comprehensively utilize various formulation strategies that can help in improving the bioavailability of various anticancer natural compounds. In this work, we have presented recent advancements in novel strategies for natural product delivery that lead to the significant enhancement of bioavailability, in vivo activity, and fewer adverse events for the prevention and treatment of oral cancer.
Abstract
Oral cancer is emerging as a major cause of mortality globally. Oral cancer occupies a significant proportion of the head and neck, including the cheeks, tongue, and oral cavity. Conventional methods in the treatment of cancer involve surgery, radiotherapy, and immunotherapy, and these have not proven to completely eradicate cancerous cells, may lead to the reoccurrence of oral cancer, and possess numerous adverse side effects. Advancements in novel drug delivery approaches have gained popularity in cancer management with an increase in the number of cases associated with oral cancer. Natural products are potent sources for drug discovery, especially for anticancer drugs. Natural product delivery has major challenges due to its low solubility, poor absorption, inappropriate size, instability, poor permeation, and first-pass metabolism. Therefore, it is of prime importance to investigate novel treatment approaches for the delivery of bioactive natural products. Nanotechnology is an advanced method of delivering cancer therapy with minimal damage to normal cells while targeting cancer cells. Therefore, the present review elaborates on the advancements in novel strategies for natural product delivery that lead to the significant enhancement of bioavailability, in vivo activity, and fewer adverse events for the prevention and treatment of oral cancer. Various approaches to accomplish the desired results involve size reduction, surface property modification, and polymer attachment, which collectively result in the higher stability of the formulation.
... ICIs can be combined with other therapeutics with complementary effects to improve the therapeutic effect (Chowdhury et al. 2018;Mahoney et al. 2015). Cetuximab, combined or not with cisplatin, showed significant tumor regression rates in platinum-refractory head and neck cancer patients (Baselga et al. 2005;Herbst et al. 2005). In addition, conjugated with therapeutic drugs, checkpoint inhibitors can also produce a cytotoxic effect on cancer cells (Vermorken et al. 2008). ...
Oral squamous cell carcinoma (OSCC) is a malignant disease in the world which has a profound effect on human health and life quality. According to tumor stage and pathological diagnosis, OSCC is mainly treated by combinations of surgery, radiotherapy and chemotherapy. However, traditional treatment methods suffer from some limitations, such as systemic toxicity, limited therapeutic effect and drug resistance. With the rapid development of nanotechnology, nanodrug delivery systems (DDSs) and intelligent DDSs have been widely used in targeted therapy for OSCC. Meanwhile, the newly developed therapeutic techniques such as immunotherapy, gene therapy and bionic technology provide the possibility to realize the active targeted therapy. Here, the latest advances of target therapy for OSCC are reviewed, and their therapeutic remarks, current limits and future prospects are also systematically interpreted. It is believed that active and passive targeted therapies have great potentials for clinical transformation and application of OSCC, which will greatly improve human quality of life.
... The disappointing results of anti-EGFR treatments in oesophageal cancer somehow reflect what has been observed in gastric cancer, in which no clinical trial has been able to demonstrate a survival advantage so far [108,109]. On the contrary, the anti-EGFR antibody cetuximab is a standard treatment in metastatic head and neck squamous cell carcinomas [110][111][112], another disease type commonly associated with oesophageal cancer. Hence, understanding why oesophageal cancers resist anti-EGFR therapies in spite of frequent EGFR amplifications will be important to design novel therapies targeting this pathway. ...
Simple Summary
Prognosis for patients with oesophageal cancer is poor, because of its aggressive nature and the lack of targeted therapies. Advances in cancer biology and sequencing technology have enabled the selection of targeted therapies for individual patients with various types of tumors, such as breast or lung cancers as well as melanoma. However, precision oncology for patients with oesophageal cancer is still virtually non-existent. This review outlines the recent advances in oesophageal molecular profiling and the outcome of clinical trials based on targeted therapies in this disease. The signaling pathways that should be further investigated and the impact of tumor heterogeneity on resistance to therapy are also discussed.
Abstract
Oesophageal cancer is one of the leading causes of cancer-related death worldwide. Oesophageal cancer occurs as squamous cell carcinoma (ESCC) or adenocarcinoma (EAC). Prognosis for patients with either ESCC or EAC is poor, with less than 20% of patients surviving more than 5 years after diagnosis. A major progress has been made in the development of biomarker-driven targeted therapies against breast and lung cancers, as well as melanoma. However, precision oncology for patients with oesophageal cancer is still virtually non-existent. In this review, we outline the recent advances in oesophageal cancer profiling and clinical trials based on targeted therapies in this disease.
... However, many patients disease recurs; the recurrence rate in early stage HNC is ≈10-20% [5], whereas the recurrence rate in locally advanced HNC (CS III-IV, cT3-T4, and/or N1-N3) is ≈50% with a predominance of locoregional failure [6][7][8]. Patients with recurrent or metastatic (R/M) SCCHN have a poor prognosis with median overall survival (OS) of under 1 year [9]. Therefore, the treatment is based on extensive resections followed by concurrent chemoradiotherapy (CRT) with platinum derivatives or concurrent RTH with cetuximab (BRT) or on definitive concurrent chemoradiotherapy in inoperable cases [10,11]. ...
Simple Summary
The nutritional status of patients with head and neck cancer (HNC) during concurrent chemoradiotherapy (CRT) with platinum derivatives or concurrent radiotherapy with cetuximab (bioradiotherapy, BRT) inevitably deteriorates during treatment. Malnutrition is responsible for increased treatment-related toxicity, an increased incidence of infectious complications, the risk of postponing or discontinuing therapy, reduced drug doses (platinum derivatives or cetuximab), deteriorating quality of life (QoL), worse outcome, and increased treatment costs. A nutritional care programme, which included prophylactic dietary counselling and early enteral nutrition, reduced the incidence of complications and prevented drug dose reduction and the deterioration of patients’ anthropometric and laboratory parameters. The study confirmed that nutritional care before and during CRT and BRT in patients with HNC is a determinant of therapeutic benefit.
Abstract
The treatment of locally advanced head and neck cancer (HNC) is based on extensive resections followed by concurrent chemoradiotherapy (CRT) with platinum derivatives or concurrent radiotherapy with cetuximab (bioradiotherapy; BRT). Malnutrition, which occurs in up to 60% of patients before treatment commencement, severely increases the risk of CRT/BRT drug dose reductions and the incidence of treatment-related adverse events. A prospective observational study was performed regarding the influence of nutritional care on nutritional status, compliance with the treatment’s planned regimen, and the incidence of treatment-related complications in patients with advanced HNC during CRT and BRT. The study population encompassed 153 patients compared with a retrospective control group of 72 patients treated before nutritional care was included in the standard of oncological care. Patients enrolled in the nutritional care programme received significantly higher doses of platinum derivatives or cetuximab than patients in the control group. A significant difference between the compared populations was observed in patients below 70 years of age (92.8% of the study population), after prior surgery, and with initial weight loss lower than 10%. Nutritional care reduced final weight loss and prevented a decline within the laboratory markers of nutritional status. Weight loss was comparable in both modes of treatment—CRT and BRT. The incidence of treatment-related complications was significantly higher in patients without nutritional support in the subgroups of patients under 70 years of age and after primary surgery. Nutritional care before and during CRT and BRT in patients with HNC is a determinant of therapeutic benefit, defined as preventing down-dosing, weight loss, and the incidence of complications. Platinum derivatives and cetuximab had comparable influence on weight loss.
... Moreover, as EGFR was previously targeted with our first-generation M6Pn-LYTACs, we sought to compare GalNAc-LYTACs to earlier congeners. Cetuximab (Ctx) is an FDA-approved blocking antibody against EGFR for colorectal cancer and head and neck cancer 31,32 . We conjugated Ctx to the tri-GalNAc ligand (Fig. 2a), and MALDI-MS analysis of the product (Ctx-GalNAc) revealed an average of 10.5 tri-GalNAc moieties per antibody ( Supplementary Fig. 3). ...
Selective protein degradation platforms have afforded new development opportunities for therapeutics and tools for biological inquiry. The first lysosome-targeting chimeras (LYTACs) targeted extracellular and membrane proteins for degradation by bridging a target protein to the cation-independent mannose-6-phosphate receptor (CI-M6PR). Here, we developed LYTACs that engage the asialoglycoprotein receptor (ASGPR), a liver-specific lysosome-targeting receptor, to degrade extracellular proteins in a cell-type-specific manner. We conjugated binders to a triantenerrary N-acetylgalactosamine (tri-GalNAc) motif that engages ASGPR to drive the downregulation of proteins. Degradation of epidermal growth factor receptor (EGFR) by GalNAc-LYTAC attenuated EGFR signaling compared to inhibition with an antibody. Furthermore, we demonstrated that a LYTAC consisting of a 3.4-kDa peptide binder linked to a tri-GalNAc ligand degrades integrins and reduces cancer cell proliferation. Degradation with a single tri-GalNAc ligand prompted site-specific conjugation on antibody scaffolds, which improved the pharmacokinetic profile of GalNAc-LYTACs in vivo. GalNAc-LYTACs thus represent an avenue for cell-type-restricted protein degradation. Lysosome-targeting chimeras (LYTACs) based on glycan ligands of the asialoglycoprotein receptor facilitate the cell-specific targeting and turnover of proteins by lysosomal enzymes, expanding the scope of LYTAC-mediated targeted protein degradation.
... In current therapies, anticancer drugs (e.g., 5-fluorouracil, paclitaxel, cisplatin, and docetaxel) are used alone or in combination, which have been employed in chronochemotherapy for oral cancer treatment (Catimel et al., 1994;Baselga et al., 2005;Bonner et al., 2006;Agüeros et al., 2009;Haddad et al., 2009). However, they are highly toxic to normal cells as intravenously administered with non-specific tissue distribution within the bodies, easily causing greater damages to healthy tissues with severely adverse reactions (Kruijtzer et al., 2002). ...
Oral cancer is an aggressive tumor that invades the local tissue and can cause metastasis and high mortality. Conventional treatment strategies, e.g., surgery, chemotherapy, and radiation therapy alone or in combinations, possess innegligible issues, and significant side and adverse effects for the clinical applications. Currently, targeting drug delivery is emerging as an effective approach for oral delivery of different therapeutics. Herein we provide a state-of-the-art review on the current progress of targeting drug delivery for oral cancer therapy. Variously oral delivery systems including polymeric/inorganic nanoparticles, liposomes, cyclodextrins, nanolipids, and hydrogels-based forms are emphasized and discussed, and biomimetic systems with respect to oral delivery like therapeutic vitamin, exosomes, proteins, and virus-like particles are also described with emphasis on the cancer treatment. A future perspective is also provided to highlight the existing challenges and possible resolution toward clinical translation of current oral cancer therapies.
... As the EGF pathway is expressed in the basal layer of skin epithelium, hypersensitivity to Cetuximab has been reported with a specific skin toxicity [146]. Instead, head and neck cancer patients did not show increased xerostomia, pain, or mucositis upon Cetuximab administration, and, therefore, treatment can be used in conjunction with other classical therapies, such as radiotherapy [147,148]. ...
Simple Summary
This review elaborates the current knowledge on salivary gland tumors, with a specific focus on classical histological classification, cellular mechanisms and molecular pattern at the origin of the most common glandular malignancies. We dive into novel approaches for modeling, diagnosis and therapy, giving an overview of the biomedical advances for the study of salivary cancers. Thereby this review helps to understand the complexity of these malignancies and paves the way for novel and efficient treatments.
Abstract
Salivary gland tumors are neoplasms affecting the major and minor salivary glands of the oral cavity. Their complex pathological appearance and overlapping morphological features between subtypes, pose major challenges in the identification, classification, and staging of the tumor. Recently developed techniques of three-dimensional culture and organotypic modelling provide useful platforms for the clinical and biological characterization of these malignancies. Additionally, new advances in genetic and molecular screenings allow precise diagnosis and monitoring of tumor progression. Finally, novel therapeutic tools with increased efficiency and accuracy are emerging. In this review, we summarize the most common salivary gland neoplasms and provide an overview of the state-of-the-art tools to model, diagnose, and treat salivary gland tumors.
... 6 8 9 Patients who experience progression on cetuximab with chemotherapy have few treatment options, with low response rates (<15%) 10 11 and response durability or disease stabilization rarely exceeding 3 months. [12][13][14][15] Patients with advanced SCCHN that progressed within 6 months after the last dose of platinum-based therapy in either the locally advanced or recurrent/metastatic setting have aggressive tumor biology and a poor prognosis and represent an unmet clinical need. 8 9 16 Anti-programmed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors, including nivolumab and pembrolizumab, have shown clinical activity in the second-line setting for the treatment of SCCHN-objective response rates (ORRs) of 13%-16% 4 7 17 -and are approved for the Open access treatment of patients with SCCHN who experienced disease progression on or after platinum-containing chemotherapy. ...
Background
We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β)RII receptor (a TGF-β ‘trap’) fused to a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated squamous cell carcinoma of the head and neck (SCCHN).
Methods
In this phase I dose-expansion cohort, patients with advanced SCCHN not amenable to curative therapy that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or <6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg intravenously every 2 weeks. The primary endpoint was confirmed best overall response (BOR; Response Evaluation Criteria for Solid Tumors (RECIST) 1.1) per independent review committee (IRC); other endpoints included BOR per investigator and safety.
Results
As of August 24, 2018, 32 patients had received bintrafusp alfa (median follow-up 86.4 weeks; range 2–97). Per IRC, the confirmed objective response rate (ORR) was 13% (95% CI 4% to 29%; 4 partial responses (PR)); 4 patients had stable disease (SD) (disease control rate 25%; 95% CI 12% to 43%). Per investigator, there were 5 PRs (ORR, 16%), including 2 patients who developed delayed PRs after initial disease increase (total clinical response rate 22%). Responses (ORRs) were observed in patients with PD-L1-positive (12%), PD-L1-negative (17%; 73-10 antibody for immunohistochemistry), human papillomavirus (HPV)-positive (33%) and HPV-negative tumors (5%). Grade 3 treatment-related adverse events (TRAEs) were reported in 11 patients (34%), with no grade 4 TRAEs or treatment-related deaths.
Conclusions
Bintrafusp alfa showed clinical activity across subgroups of PD-L1 expression and in HPV-positive tumors and had a manageable safety profile in patients with heavily pretreated advanced SCCHN. Activity in HPV-positive tumors is favorable compared with historical data from PD-L1 inhibitors and is being further investigated in an ongoing study of HPV-associated tumors.
Trial registration number
NCT02517398 .
... This is supported by 5 phases II studies performed in R/M patients who had progressed during or after platinum first line chemotherapy. Four of them were performed with a combination of cetuximab and a platinum salt which was reintroduced after the last 1st line chemotherapy administration [9][10][11]. Response rates reported in these clinical trials were ranged from 6% to 10%, and median survival were between 4.3 to 6.1 months. ...
Background:
The EXTREME protocol is the standard of care for recurrent or metastatic head and neck squamous-cell carcinoma (R/M HNSCC) in first line. Beyond the first-line except immunotherapy, poor efficacy was reported by second-line chemotherapy. Re-challenge strategies based on a repetition of the first line with platinum and cetuximab regimens might have been an option to consider.
Methods:
We performed a retrospective study in order to assess the efficacy of the cetuximab plus platinum doublet-based chemotherapy regimen in patients with R/M HNSCC progressing after at least 3 months of cetuximab maintenance (EXTREME protocol). We complete a retrospective review of all medical records from R/M HNSCC patients treated after 16 weeks with the EXTREME regimen and treated with a re-challenge strategy between January 2010 and December 2014 in our institution (Centre Paul Strauss, Strasbourg, France).
Results:
33 patients were identified. The re-challenged strategy provided an ORR in 33.3% of cases and a DCR of 69.6% of cases. The median OS and PFS observed from the second line were 11.2 months and 6.5 months for the subset re-challenged by EXTREME or PCC regimens respectively. The response rate between patients with a platin free interval within 3 and 6 months and greater than 6 months were equal. Drugs dose intensity were better with the PCC protocol than the EXTREME regimen used as a rechallenge.
Conclusions:
This study suggest re-challenging strategy by these regimens could be considered beyond the first line as an option when the platin free interval is greater than 3 months.
Breast cancer is the most common malignancy in women worldwide and despite significant advancements in detection, treatment, and management of cancer, it is still the leading cause of malignancy related deaths in women. Understanding the fundamental biology of breast cancer and creating fresh diagnostic and therapeutic strategies have gained renewed focus in recent studies. In the onset and spread of breast cancer, a group of enzymes known as kinases are extremely important. Small-molecule kinase inhibitors have become a promising class of medications for the treatment of breast cancer owing to their capacity to specifically target kinases involved in the growth and progression of cancer. The creation of targeted treatments that block these kinases and the signalling pathways that they activate has completely changed how breast cancer is treated. Many of these targeted treatments have been approved for the treatment of breast cancer as clinical trials have demonstrated their great efficacy. CDK4/6 inhibitors, like palbociclib, abemaciclib, and ribociclib, EGFR inhibitors such as gefitinib and erlotinib and HER2-targeting small-molecule kinases like neratinib and tucatinib are some examples that have shown potential in treating breast cancer. Yet, there are still difficulties in the development of targeted medicines for breast cancer, such as figuring out which patient subgroups may benefit from these therapies and dealing with drug resistance problems. Notwithstanding these difficulties, kinase-targeted treatments for breast cancer still have a lot of potential. The development of tailored medicines will continue to be fuelled by the identification of novel targets and biomarkers for breast cancer as a result of advancements in genomic and proteomic technology.
Oral and maxillofacial diseases have an important impact on local function, facial appearance, and general health. As a multifunctional platform, hydrogels are widely used in the biomedical field due to their excellent physicochemical properties. In recent years, a large number of studies have been conducted to adapt hydrogels to the complex oral and maxillofacial environment by modulating their pore size, swelling, degradability, stimulus-response properties, etc. Meanwhile, many studies have attempted to use hydrogels as drug delivery carriers to load drugs, cytokines, and stem cells for antibacterial, anticancer, and tissue regeneration applications in oral and maxillofacial regions. This paper reviews the application and research progress of hydrogel-based drug delivery systems in the treatment of oral and maxillofacial diseases such as caries, endodontic diseases, periodontal diseases, maxillofacial bone diseases, mucosal diseases, oral cancer, etc. The characteristics and applications of hydrogels and drug-delivery systems employed for the treatment of different diseases are discussed in order to provide a reference for further research on hydrogel drug-delivery systems in the future.
Background:
The prevalence of head and neck cancer (HNC) is increasing rapidly, and the prognosis is poor in the advance stage. For the patient suffering from advance stage HNC, the improvement in quality of life and decrease mortality remain as the mainstay of treatment. The aim was to assess the change in quality-adjusted life-years (QALYs) in recurrent or metastatic HNC patients receiving cetuximab plus cisplatin and cetuximab plus cisplatin-paclitaxel.
Methods:
It was a single-centric prospective-observational study. Patients were divided into two cohorts based on the chemotherapy regimens they were prescribed. Patients in cohort 1 were prescribed with cetuximab and cisplatin and in cohort 2 were prescribed with cetuximab, cisplatin, and paclitaxel. The QALYs were the primary outcome of the study, and it was calculated using EQ-5D-5L instrument. Patients were followed until the completion of the therapy, i.e., six chemotherapy cycles. The statistical analysis was carried out using SPSS for descriptive and inferential analysis.
Results:
Amongst 175 patients screened, 100 patients were enrolled which further distributed in cohorts 1 and 2 equally. The mean QALYs were 0.016 and 0.017 at the time of diagnosis, i.e., before initiation of chemotherapy for patients in cohorts 1 and 2, respectively. At every chemotherapy cycle, the QALYs were calculated. After the completion of six chemotherapy cycles, the mean QALYs were 0.029 and 0.032 for patients in cohorts 1 and 2, respectively.
Conclusion:
The three-drug therapy consisting of cetuximab, cisplatin, and paclitaxel has shown significant improvement in patients' QALYs compared to two-drug regimens of cetuximab and cisplatin. Thus, if the therapy consisted of three-drug regimen is used instead of two-drug regimen, it will have a positive impact on humanistic outcome in recurrent or metastatic HNC patients.
Patients with R/M HNSCC treated with palliative first line therapy at Hannover Medical School between October 2005 and December 2016 have been included to show changes in survival following broad utilization of cetuximab. Treatment periods were defined from 10/2005 to 12/2008 (Period A) and 01/2009 to 12/2016. Overall survival did not improve over time. However, in subgroup analysis cetuximab utilized at any time vs. never showed a significant improve of overall survival (11.3 vs. 6.3 months, HR: 0.55, 95%-CI: 0.4-0.8, p = 0.04). Therefore this study supports the application of cetuximab in this real world population.
Preclinical data support investigation of selective CDK4/6 inhibition as a therapeutic strategy for human papillomavirus (HPV)–unrelated head and neck squamous cell carcinoma (HNSCC). Phase 1 clinical trials established the feasibility of combining palbociclib with cetuximab in patients with recurrent or metastatic HNSCC. Nonrandomized phase II trials showed that palbociclib plus cetuximab resulted in efficacy outcomes better than cetuximab in biomarker-unselected, platinum-resistant or cetuximab-resistant, HPV-unrelated HNSCC. A double-blind, randomized phase II trial (PALATINUS) evaluated the efficacy of palbociclib or placebo and cetuximab in patients with biomarker-unselected, platinum-resistant, cetuximab-naive, HPV-unrelated HNSCC. Palbociclib and cetuximab did not significantly prolong overall survival compared with placebo and cetuximab. However, correlative biomarker analyses identified that trends for better overall survival with palbociclib and cetuximab were observed in certain prespecified subsets; the largest reduction in risk of death with palbociclib versus placebo and cetuximab occurred in the subset with CDKN2A mutations. Several phase II–III trials are underway investigating palbociclib in biomarker-selected patients with HPV-unrelated locally advanced or recurrent or metastatic HNSCC.
Systemic therapy remains a cornerstone in the multidisciplinary approach and management of locally advanced squamous cell carcinoma of the head and neck (SCCHN) and the primary treatment modality for recurrent/metastatic SCCHN.Within the past decade, we have seen major advances in the management of recurrent/metastatic SCCHN, most notably the advent of the second- and first-line immunotherapy. Despite this, outcomes remain poor. Ongoing research is being done evaluating the use of checkpoint inhibition combinations, as well as alternative anti-EGFR inhibitors. Exciting areas of future research include the development of targeted therapies based on molecular profiling of SCCHN as well as adaptive cellular immunotherapy.Management of locally advanced SCCHN involves both maximizing the curative potential of therapy while minimizing unnecessary treatment related morbidity. There is increasing long-term data supporting the use of organ preservation in appropriately selected laryngeal carcinoma patients. Similarly, a number of studies have attempted de-escalation of therapy within the good risk HPV+ oropharyngeal carcinoma population. Unfortunately, these studies have demonstrated inferior survival outcomes compared with standard cisplatin/radiation therapy, and cisplatin-based chemoradiation therapy remains the standard of care. Future research is focused on the incorporation of immunotherapy in locally advanced SCCHN, both as adjuvant therapy and in combination with radiation therapy.KeywordsHead and neck cancerChemoradiation therapyCheckpoint inhibitorsAnti-EGFR therapyDe-escalation of therapyImmunotherapy-refractoryCisplatin-ineligibleAdoptive cellular therapy
Head and neck squamous cell carcinoma (HNSCC) is among the common tumors associated with high mortality. The aim of our meta-analysis was to determine how additional anti-EGFR (epidermal growth factor receptor) therapy to standard chemotherapy affects the progression-free (PFS) and overall survival (OS) of the patients, besides the most common side effects. We used CENTRAL, MEDLINE and Embase databases until October 26, 2020, and included 13 eligible randomized controlled trials in our systematic research. The pooled hazard ratios (HR) for the main outcomes from the original data were estimated and for the other dichotomous outcomes, odds ratios (ORs) with their 95% confidence intervals (CI) were calculated. Addition of EGFR inhibitors to conventional chemotherapy significantly decreased the death and disease progression (for PFS HR:0.68, 95% CI:0.55-0.81, I2 =65.5%, p=0.005) and mortality (for OS HR:0.83, 95% CI:0.72-0.94, I2 =42.3%, p=0.076). In the EGFR inhibitor group, we revealed an increased chance of the over Grade 3 skin rashes (OR:4.86; 95% CI:1.52-15.49, I2 =2.3%, p=0.407), as well as all Grade skin rashes (OR:18.32, 95% CI:8.07-41.60, I2 =56.6 %, p=0.032). Despite their unwanted dermatological side effects, the addition of EGFR inhibitors are recommended to be included in advanced HNSCC therapy.
Purpose of Review
The purpose of this study is to review the treatment options for recurrent and metastatic human papillomavirus-associated oropharyngeal squamous cell carcinoma (R/M HPV + OPSCC).
Recent Findings
Researchers are currently investigating novel biomarkers to predict response to immunotherapy as well as innovative treatments to improve patient outcomes, such as tumor vaccines and T-cell therapies.
Summary
While some patients with R/M HPV + OPSCC may benefit from surgery and/or radiation, many individuals require systemic therapies, including cytotoxic chemotherapy, molecular targeted agents, and immune checkpoint inhibitors.
Purpose:
A phase II multi-institutional clinical trial was conducted to determine overall survival (OS) in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with a combination of cetuximab and nivolumab.
Experimental design:
Patients with R/M HNSCC were treated with cetuximab 500 mg/m2 IV Day (D) -14 as a lead-in followed by cetuximab 500 mg/m2 IV and nivolumab 240 mg IV on D1 and D15 of each 28-D cycle. Expression of p16 and programmed cell death-ligand 1 (PD-L1) in archived tumors were determined. Tumor-tissue-modified human papillomavirus (TTMV) DNA was quantified in plasma.
Results:
Ninety-five patients were enrolled, and 88 patients were evaluable for OS with a median follow-up of 15.9 months. Median OS in the 45 patients who had prior therapy for R/M HNSCC (Cohort A) was 11.4 months, with a 1-year OS 50% (90% CI, 0.43-0.57). Median OS in the 43 patients who had no prior therapy (Cohort B) was 20.2 months, with a 1-year OS 66% (90% CI, 0.59-0.71). In the combined cohorts, the p16-negative immunostaining was associated with higher response rate (RR, p=0.02) but did not impact survival while higher PD-L1 combined positive score was associated with higher RR (p=0.03) and longer OS (log-rank p=0.04). In the p16-positive patients, median (log-rank p=0.05).
Conclusion:
The combination of cetuximab and nivolumab is effective in patients with both previously treated and untreated R/M HNSCC and warrants further evaluation.
Identification of vulnerability or frailty is an important parameter for cancer treatment decisions, particularly in older patients. Chronological age is a poor indicator of an older adult’s health status. The integration of frailty screening and comprehensive geriatric assessment (CGA) provides additional information on medical, cognitive, psychological, social, physical, and functional domains. Although CGA is considered the standard of care, it may be preceded by a short screening tool to identify those patients in need of further assessment. A screening tool may provide prognostic and predictive value but, whenever abnormal, it should be followed by a CGA. The CGA identifies the often-unknown vulnerabilities on the different domains evaluated, which then guides tailored interventions aimed at reversing these vulnerabilities and/or providing additional support to prevent/delay a decline in health. It may also provide information on prognosis, the risk for treatment-related toxicity and other outcomes, which supports the decision-making process in oncology. Furthermore, the integration of a CGA-based approach in the treatment of older patients with cancer has shown to improve quality of life. This chapter will review and discuss the value of frailty/geriatric screening for older cancer patients and the different tools available, as well as review the principles and challenges of implementing a CGA.KeywordsComprehensive geriatric assessmentCGAScreeningFrailtyOlder patientsCancer
Head and Neck Cancer (HNC) is predominantly a disease of older adults despite a rise in its incidence in younger patients related to human papillomavirus (HPV) infection. HNC is also amongst the cancers with the highest proportion of patients presenting with frailty and significant multimorbidity. This is challenging particularly when considering any radical treatment plan due to a lack of physiological reserve. Moreover, there is a generalised underrepresentation of older patients with HNC clinical trials. The implementation of Comprehensive Geriatric Assessment and other frailty screening tools help in directing appropriate management plans for individual patients, which with the use of shared decision-making protocols, will allow for a better informed choice for patients and their carers, illustrating more clearly the likely outcomes. This should give a more acceptable individualised management plan for patients in this often unrecognised heterogeneous cohort. This chapter reviews the evidence regarding the management of HNC cancer in older patients with frailty.KeywordsHead and neck cancerOlderFrailty
Palliative care is an approach to care addressing quality of life, pain and distress symptoms, and psychological and spiritual well-being in patients with serious illness. Access to palliative care is critical, and the early integration of palliative care has a substantial benefit for patients with cancer. In older patients with cancer who are frail, palliative care may be the primary initial treatment approach, helping to mitigate or even avoid the significant adverse effects from cancer therapy to which frail older adults are more susceptible. Frail older adults have unique palliative needs due to higher rates of comorbid conditions, functional impairments, and high rates of complications and symptoms at the end-of-life. This chapter will discuss the availability of palliative care, the ease of access in older adults, the benefits of early integration of palliative care in oncology treatments, pharmacological considerations in older adults, and a special focus on the specifics of care in older cancer patients with frailty.KeywordsFrailtyOlderOncologyCancerPalliative careQuality of life
Introduction
Recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is associated with dismal prognosis and has limited therapeutic options. PD-1/PD-L1 axis blockade was initially shown to improve outcomes in platinum-refractory HNSCC. More recently, pembrolizumab monotherapy or pembrolizumab combined with chemotherapy resulted in better overall survival than platinum, 5-fluorouracil, and cetuximab (EXTREME regimen) as first-line therapy for R/M HNSCC, establishing a new standard-of-care therapy for this disease.
Areas covered
We review pembrolizumab in the first-line treatment of R/M HNSCC and summarize the impact of PD-L1 expression, tumor and symptom burden, and patient’s performance status on treatment decisions. Future perspectives are summarized.
Expert opinion
The standard-of-care first-line therapy for R/M HNSCC is pembrolizumab monotherapy for patients with a PD-L1 combined positive score (CPS)≥1 or pembrolizumab combined with platinum and 5-fluorouracil for patients with any PD-L1 status. Addition of chemotherapy to pembrolizumab increases the response rate but also toxicity and is preferred for patients with good performance status and significant tumor and symptom burden. For patients with a PD-L1 CPS <1, the EXTREME regimen should be considered. New strategies combining pembrolizumab with targeted therapies and immune checkpoints inhibitors are being explored to synergize or overcome resistance to anti-PD-1.
Introduction: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and is a leading cause for cancer-related mortality. This review attempts to give a comprehensive summary of the recent developments in pharmacotherapeutic options for locally advanced/metastatic HNSCC.
Areas covered: In this review, the authors conducted a systematic literature search for published articles on HNSCC in the PubMed database using the keywords ‘head and neck squamous cell carcinoma or HNSCC,’ ‘targeted therapy,’ ‘immunotherapy.’ The search was restricted to meta-analyses, clinical trials, practice guidelines, and abstract presentations at international meetings. The final search encompassed articles published from 2010 to 2021. Articles published in languages other than English were excluded.
Expert opinion: Immune checkpoint inhibition has been the most significant advance in the treatment of R/M HNSCC. Oral metronomic therapy has emerged as an important therapeutic option for low to middle-income countries. H-RAS inhibition is one of the most promising areas of research.
In Japan, as of September 2020, two immune checkpoint inhibitors, nivolumab and pembrolizumab, have been approved for squamous cell carcinoma of the head and neck, and clinical evidence is being generated. Here, we review the two clinical trials （CheckMate 141 trial and KEYNOTE-048 trial） that were registration studies for marketing authorization, focusing on the differences between the two studies in the eligible patients, study design, concomitant drugs, and control drugs. In particular, both trials have different eligibility criteria for prior platinum treatment, which will also be explained.
Objectives
The aim of this study was to assess the clinical usefulness of cetuximab and cisplatin alone or in combination with paclitaxel as the first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).
Methodology
Three hundred patients with confirmed HNSCC from 20 different hospitals were included in this study. Patients in group I underwent a 2-hour infusion of 400 mg/m ² cetuximab (day 1), followed by a 1-hour infusion of 250 mg/m ² cetuximab weekly and 1-hour infusion of 100 mg/m ² cisplatin (days 1 and 21) per treatment cycle. Patients in group II were treated with a combination of cetuximab, cisplatin, and paclitaxel. Patients received 6 cycles of 175 mg/m ² paclitaxel given on days 1 and 21. The primary outcome of the study was progression-free survival (PFS); overall survival (OS) and objective response rate (ORR) were the secondary endpoints.
Results
The median PFS was 5 months and 8 months for patients in groups I and II, respectively (HR, 0.93; 95% CI, 0.85–1.78; P > 0.05). Similarly, we found no significant differences in OS between the 2 groups (median OS, 13 vs. 11 months, respectively; HR, 0.67; 95% CI, 0.42–1.43; P = 0.198). Moreover, we observed no significant difference in ORR between the 2 groups (ORR, 63.3% vs 69.9%, respectively; HR, 0.87; 95% CI, 0.36–1.67; P = 0.231).
Conclusions
The combination of paclitaxel with cetuximab and cisplatin did not improve patient outcomes compared to cetuximab plus cisplatin alone. Therefore, the 2-drug regimen could be used as first-line treatment in patients with recurrent or metastatic HNSCC.
Cancer nanotechnology is a relatively novel interdisciplinary area of comprehensive research that combines the basic sciences with engineering and medicine. Nanotechnology involves creating and utilizing the constructs of variable chemistry and architecture with dimensions at the nanoscale level comparable to those of biomolecules or biological vesicles in the human body. Operating with submolecular interactions, it offers the potential for unique and novel approaches with a broad spectrum of applications in cancer treatment including areas such as diagnostics, therapeutics, and prognostics. The early detection and diagnosis of cancer can reduce the death rate of cancer patients. The sharp rise in cases of oral cancer is a big concern for India subcontinent due to lack of awareness and late stage detection. The most common treatment for this cancer is surgery and chemotherapy. However, nanotechnology-based devices are being explored for rapid diagnosis of oral cancer. Micro and nanodevices also open pathways to developing new and efficient therapeutic approaches to cancer treatment that can overcome numerous barriers posed by the human body compared to conventional approaches. In recent years, nanomaterials have exhibited strong promise and progress in radically changing the approach to oral cancer detection and treatment.
We present a proteogenomic study of 108 human papilloma virus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). Proteomic analysis systematically catalogs HNSCC-associated proteins and phosphosites, prioritizes copy number drivers, and highlights an oncogenic role for RNA processing genes. Proteomic investigation of mutual exclusivity between FAT1 truncating mutations and 11q13.3 amplifications reveals dysregulated actin dynamics as a common functional consequence. Phosphoproteomics characterizes two modes of EGFR activation, suggesting a new strategy to stratify HNSCCs based on EGFR ligand abundance for effective treatment with inhibitory EGFR monoclonal antibodies. Widespread deletion of immune modulatory genes accounts for low immune infiltration in immune-cold tumors, whereas concordant upregulation of multiple immune checkpoint proteins may underlie resistance to anti-programmed cell death protein 1 monotherapy in immune-hot tumors. Multi-omic analysis identifies three molecular subtypes with high potential for treatment with CDK inhibitors, anti-EGFR antibody therapy, and immunotherapy, respectively. Altogether, proteogenomics provides a systematic framework to inform HNSCC biology and treatment.
Cancer clinical trials typically generate detailed patient toxicity data. The most common measure used to summarize patient toxicity is the maximum grade among all toxicities and it does not fully represent the toxicity burden experienced by patients. In this article, we study the mathematical and statistical properties of the toxicity index (TI), in an effort to address this deficiency. We introduce a total ordering, (T‐rank), that allows us to fully rank the patients according to how frequently they exhibit toxicities, and show that TI is the only measure that preserves the T‐rank among its competitors. Moreover, we propose a Poisson‐Limit model for sparse toxicity data. Under this model, we develop a general two‐sample test, which can be applied to any summary measure for detecting differences among two population of toxicity data. We derive the asymptotic power function of this class as well as the asymptotic relative efficiency (ARE) of the members of the class. We evaluate the ARE formula empirically and show that if the data are drawn from a random Poisson‐Limit model, the TI is more efficient, with high probability, than the maximum and the average summary measures. Finally, we evaluate our method on clinical trial toxicity data and show that TI has a higher power in detecting the differences in toxicity profile among treatments. The results of this article can be applied beyond toxicity modeling, to any problem where one observes a sparse array of scores on subjects and a ranking based on extreme scores is desirable.
In the United States it is estimated that there will be 51,540 new cases of head and neck cancer in 2018, accounting for 3% of all cancer cases and 1.5% of all cancer deaths. The three major risk factors for head and neck cancer are tobacco, human papillomavirus (HPV) infection, and alcohol. The treatment of head and neck cancer is dictated by the primary site. Most oropharyngeal cancers in the United States are now due to human papillomavirus (HPV) and as such have an improved prognosis. Early-stage oropharynx cancers can effectively be treated with surgery or RT. The standard of care for locally advanced disease is CRT; however, incorporation of transoral robotic surgery (TORS) is under active investigation. Surgery is generally considered the preferred initial treatment modality for oral cavity lesions with adjuvant RT with or without chemotherapy for patients with high-risk features on surgical pathology. In patients with laryngeal cancer, the goal of first-line therapy should be to preserve the function of the larynx, without sacrificing tumor control. Early-stage laryngeal cancer can effectively be treated with either surgery or RT. In early stage disease, the anatomic location and extent of disease will dictate if surgery is feasible. The treatment of choice in most locally advanced larynx cancers is concurrent chemotherapy and radiation. Management of head and neck cancers requires a multidisciplinary approach with effective integration of multiple specialties to achieve the desired goals of cure and functional organ preservation.
Background:
The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in patients who cannot tolerate platinum-based regimens has not been clarified. We aimed to develop a new treatment regimen for patients with R/M SCCHN who are ineligible for platinum-based therapy, by evaluating the effects and safety of tegafur/gimeracil/oteracil (S-1) and cetuximab.
Methods:
Platinum-ineligibility was defined as: elderly (aged ≥ 75 years), poor PS, comorbidity, platinum resistance and refusal to undergo platinum-based therapy. Patients received S-1 (80 mg/m2/day for 14 days followed by a seven-day break) and cetuximab (initial dose, 400 mg/m2, followed by 250 mg/m2 weekly) until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR).
Results:
Between September 2014 and September 2018, we enrolled 23 patients. Among the 21 patients who were evaluable, 20 were male [median age, 69 years (range 49-82)]. The ORR was 9 (43%) of 21 patients [95% confidence interval (CI) 22-66]. One and eight patients achieved complete response (CR) and partial response (PR), respectively. The median overall survival (OS) was 13.7 months (95% CI 9.0-18.3) and progression-free survival (PFS) was 5.7 months (95% CI 3.1-8.2). Grade 3/4 adverse events included acneiform rash and skin reactions (33%), hypomagnesemia (19%), hand-foot syndrome (14%), fatigue (14%), mucositis (10%), and anorexia (10%).
Conclusions:
Combination treatment with S-1 and cetuximab was effective and tolerated well by patients with platinum-ineligible R/M SCCHN. Registered clinical trial number: UMIN000015123.
Cyclin D1 gene (CCND1) numerical aberrations are independent prognostic indicators of head and neck squamous cell carcinomas (HNSCCs). High epidermal growth factor receptor gene (EGFR) copy number is associated with poor prognosis in lung cancer, but such findings are controversial in oral SCCs (OSCCs). We analyzed copy number status in CCND1 and EGFR in OSCC patients and its association with clinical outcome.
EGFR and CCND1 statuses were analyzed in 85 OSCC patients by fluorescence in situ hybridization (FISH) of specimens obtained by fine‐needle aspiration biopsy.
CCND1 numerical aberration was found in 35 of 85 tumors (41%), and aberrant EGFR copy number was observed in 36 (42%). Gene amplification (GA) was dominant among CCND1 copy number changes (14/35:40%). Balanced trisomy (BT) was the most frequently observed EGFR aberration (17/36:47%). In a multivariate Cox’s proportional hazards analysis, CCND1 GA was correlated with disease‐free survival (P < 0.001), whereas EGFR BT was significantly correlated with overall survival (P = 0.001). Patients with a combination of CCND1 GA and/or EGFR BT had significantly poorer clinical outcome.
CCND1 and EGFR copy number changes were frequent in OSCC and had differing aberration patterns. CCND1 GA and EGFR BT statuses by dual‐color FISH were the predominant predictors of clinical outcome. Further investigation is needed to determine the implications for EGFR inhibitor therapy in OSCC.
Background:
The National Cancer Institute Moonshot℠ research initiative calls for improvements in the analysis and reporting of treatment toxicity to advise key stakeholders on treatment tolerability and inform regulatory and clinical decision-making. This study illustrates alternative approaches to toxicity evaluation using the National Surgical Adjuvant Breast and Bowel Project (NSABP-R04) clinical trial as an example.
Methods:
NSABP-R04 was a neoadjuvant chemo-radiation trial in stage II-III rectal cancer patients. A 2x2 factorial design was used to evaluate whether the addition of oxaliplatin (Oxa) to 5-fluorouracil (5FU) or capecitabine (Cape) with radiation therapy improved local-regional tumor control. The toxicity index (TI), which accounts for the frequency and severity of toxicities, was compared across treatments using multivariable probabilistic index models (PIMs), where Pr A < B indicates the probability that higher values of TI were observed for A when compared to B. Baseline age, gender, performance status (PS), body mass index (BMI), surgery type and stage were evaluated as independent risk factors.
Results:
A total of 4,560 toxicities from 1,558 patients were analyzed. Results from adjusted PIMs indicate that oxaliplatin-containing regimens had statistically significant (p < 0.001) probability for higher TI compared to regimens without oxaliplatin: Pr 5FU < 5FU + Oxa = 0.619 (95% CI 0.560-0.674); Pr 5FU< Cape + Oxa = 0.627 (95% CI 0.568-0.682); Pr Cape < 5FU + Oxa =0.587 (95% 0.527-0.644); and Pr Cape < Cape+ Oxa = 0.596 (95% 0.536-0.653).When compared to other existing toxicity analysis methods, TI provided greater power to detect differences between treatments.
Conclusions:
This paper uses standard data collected in a cancer clinical trial to introduce descriptive and analytic methods that account for the additional burden of multiple toxicities. These methods may provide a more accurate description of a patient's treatment experience that could lead to individualized dosing for better toxicity control. Future research will evaluate the generalizability of these findings in trials with similar drugs.
In recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN), the armamentarium of systemic anti-cancer modalities continues to grow in parallel with innovations in and better integration of local approaches. The backbone of cytotoxic chemotherapy remains cisplatin with 5-fluorouracil or a taxane. In contrast to cisplatin, the tumoricidal activity of carboplatin monotherapy is debatable. Adding the epidermal growth factor receptor (EGFR) inhibitor cetuximab to a platinum/5-fluorouracil doublet (the so-called EXTREME regimen) produced a statistically but also clinically significant improvement of survival and became thus the standard first-line palliative treatment in adequately fit patients. Interestingly, three large randomized trials (EXTREME, SPECTRUM, and ZALUTE) evaluating different anti-EGFR monoclonal antibodies (cetuximab, panitumumab, and zalutumumab, respectively) demonstrated preferential anti-tumour efficacy in patients with primary cancer in the oral cavity. Modern immunotherapy with immunomodulating antibodies, dubbed immune checkpoint inhibitors, such as anti-programmed cell death protein-1 (anti-PD-1) inhibitors nivolumab and pembrolizumab, showed unprecedented activity in one first-line (KEYNOTE-048) and several second-line trials (CheckMate-141, KEYNOTE-012, KEYNOTE-055, and KEYNOTE-040). In a minority of also heavily-pretreated patients, these agents generate long-lasting responses without the typical chemotherapy-related toxicity, however, at a price of a low overall response rate, rare but potentially life-threatening immune-related adverse events, the risk of hyperprogression, and high costs. In oligometastatic disease, emerging data indicate long-term benefit with locally ablative techniques including metastasectomy and stereotactic radiotherapy of pulmonary but also hepatic and other distant lesions. In the frame of highly-individualized cancer care, a particularly intriguing approach is a combination of systemic and local therapies.
The pharmacokinetics and potential drug–drug interactions between cetuximab and cisplatin or carboplatin from two studies (JXBA and JXBB) were evaluated. These studies were multicenter, open‐label phase II trials designed to evaluate the drug–drug interactions between cetuximab (400 mg m−2 initial dose) and cisplatin (JXBA; 100 mg m−2) or carboplatin (JXBB; area under the curve [AUC] = 5 mg × min mL−1) with or without 5‐fluorouracil (5FU) in patients with advanced solid tumors. Concentrations of cetuximab, cisplatin and carboplatin were determined using analytical methods. The safety and tolerability of cetuximab in combination with cisplatin or carboplatin was also determined in all treated patients. The JXBA study showed that cetuximab serum concentrations were similar when cetuximab was administered alone or in combination with cisplatin. The Cmax, tmax and overall AUC for the cetuximab group (194 µg mL−1, 2.0 hour, 14 900 µg × h mL−1) and the cetuximab and cisplatin combination group (192 µg mL−1, 1.99 hour, 16 300 µg × h mL−1) were similar. The JXBB study showed that mean cetuximab serum concentrations were similar when cetuximab was administered alone or in combination with carboplatin. The Cmax, tmax and overall AUC for the cetuximab group (199 µg mL−1, 1.15 hour, 17 200 µg × h mL−1) and the cetuximab and carboplatin combination group (199 µg mL−1, 3.17 h, 16 800 µg × h mL−1) were similar. Both studies showed that the safety profile was consistent with known side effects of cetuximab, platinum–based therapies and 5‐FU. There was no clinically relevant change in cetuximab pharmacokinetics when it was administered in combination with cisplatin or carboplatin.
A main influencer of the chaperome is the environmental stress eliciting continuously degraded proteins. To avoid proteotoxic stress, which hinders the protein homeostasis and cell survival, most proteins are accompanied from the early existence on by heat shock proteins (HSP) and sequestrated into different routes of renaturation, de novo folding or denaturation. Therefore, the regulation of Hsp90 presence and activity is relevant for most cells and their function. In this position, Hsp90 can decide the fate between health and disease by selective refolding of denatured proteins and is a player in the evolution. From the last century on, Hsp90 was validated as a target due to its susceptibility for natural products and to make them perfect with the aim to hinder refolding and enhance the proteotoxic stress. In this review, the links between natural producer, chemical synthesis with Hsp90 as a target as well as alternative chaperoning routes by chemical compounds are illuminated.
Background:
It is unclear whether cetuximab (CTX) plus cisplatin-based concurrent chemoradiotherapy (CCRT) delivers equivalent or improved results over standard CCRT in locoregionally advanced nasopharyngeal carcinoma (NPC).
Methods:
The strategy involved searching the PubMed, Embase, Cochrane Library, and Web of Science. Pooled hazard ratios (HRs) for overall survival (OS), distant metastasis-free survival (DMFS), locoregional relapse-free survival (LRFS), and disease-free survival (DFS), and pooled risk ratios for adverse events were meta-analyzed.
Results:
In all, 1744 patients in 5 clinical trials were included in the analysis. Compared with CCRT group, CTX plus CCRT significantly improved DFS (HR = 0.59, 95% confidence interval [CI]: 0.41-0.86, P = .006) and distant metastasis failure-free survival (HR = 0.54, 95% CI: 0.38-0.76, P = .0004), rather than OS (HR = 0.70, 95% CI: 0.44-1.09, P = .12) and local-regional failure-free survival (HR = 0.82, 95% CI: 0.54-1.22, P = .33).
Conclusions:
CTX plus CCRT might achieve higher DFS and DMFS with no significant difference in OS and LRFS. CTX plus CCRT group was associated with more grade 3-4 skin rash, mucositis and dermatitis. Large randomized trials were urgent to fully explore the usefulness of this treatment in the locally advanced NPC patients.
The length and quality of head and neck cancer survivorship continues to meaningfully improve. Radiotherapy has been central to this process through advances in treatment delivery, fractionation schemas, radiosensitizing systemic therapy, and thoughtful interplay with technical surgical improvements. The future looks brighter still, with ongoing progress in targeted biologic therapy, immuno-oncology, and molecular-genetic tumor characterization for personalized treatment. Head and neck cancer, a disease once fraught with nihilism and failure, is evolving into a major success story of modern multidisciplinary cancer care.
Background:
Most head and neck squamous-cell carcinomas (HNSCCs) are driven by p16INK4A inactivation and cyclin D1 overexpression that results in hyperactivation of cyclin-dependent kinase 4 and 6 (CDK4/6), rather than by the human papillomavirus (HPV). Deregulated cyclin D1 expression also causes resistance to EGFR inhibitors. We previously reported that palbociclib (a selective CDK4/6 inhibitor) given with cetuximab (an EGFR inhibitor) was safe. The aim of this study was to establish the proportion of patients achieving an objective response with palbociclib and cetuximab in recurrent or metastatic HNSCC.
Methods:
We did a multicentre, multigroup, phase 2 trial to evaluate the activity of palbociclib and cetuximab in platinum-resistant (group 1) and cetuximab-resistant (group 2) HPV-unrelated HNSCC. The study was done across eight university sites in the USA. Eligibility required measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1·1 [RECIST 1·1]), Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, age of 18 years or older, and disease progression on platinum but cetuximab-naive (group 1) or disease progression on cetuximab (group 2). All patients received palbociclib orally (125 mg/day, on days 1-21) and intravenous cetuximab (400 mg/m2 on cycle one, day 1, then 250 mg/m2 once per week) in 28-day cycles. The primary endpoint was objective response (complete responses and partial responses per RECIST 1·1). Analyses were done per protocol. This trial was registered with ClinicalTrials.gov, NCT02101034, and is ongoing, but both groups are closed to accrual.
Findings:
Between Oct 19, 2015, and Nov 7, 2018, 62 patients were enrolled onto the trial: 30 patients were enrolled in group 1 and 32 in group 2. Median follow-up was 5·4 months (IQR 4·4-12·1) for group 1 and 5·5 months (4·3-8·3) for group 2. In group 1, of 28 evaluable patients, an objective response was achieved by 11 (39%; 95% CI 22-59). In group 2, of 27 evaluable patients, an objective response was achieved by five (19%; 6-38) in group 2. The most common grade 3-4 palbociclib-related adverse event was neutropenia (in 21 [34%] of 62 patients). No treatment-related deaths occurred.
Interpretation:
In patients with platinum-resistant or cetuximab-resistant HPV-unrelated HNSCC, palbociclib and cetuximab results in promising activity outcomes. Further studies of CDK4/6 inhibitors are warranted in HPV-unrelated HNSCC.
Funding:
Pfizer.
Head and neck squamous cell carcinoma (HNSCC) has an estimated annual global death rate of approximately 300,000. Despite advances in surgical techniques, the advent of efficient radiation delivery methods, and the introduction of newer chemotherapeutic agents, the survival rate for HNSCC has alarmingly remained unchanged for the past 50 years. However, there have been some promising developments in this field recently. Tumor protein 53 (TP53)-based gene therapeutics such as Gendicine® and Advexin®, and oncolytic viral therapeutics such as ONYX-015 and H101 have shown encouraging results and are gaining momentum. Cetuximab, the first US Food and Drug Administration-approved targeted therapeutic in HNSCC, although had a promising run initially, failed to garner enough attention subsequently due to its poor results in locally advanced HNSCC. Currently, its major utility is in palliation of recurrent and/or metastatic HNSCC as a part of the EXTREME regimen alongside cisplatin/carboplatin and fluorouracil. Of late, immunotherapeutics are evolving rapidly in HNSCC by demonstrating satisfactory effectiveness and acceptable tolerance both in locally advanced and recurrent tumors, and both as monotherapy and in combination with other agents. Recent accelerated approval of two immune checkpoint receptor blockers, pembrolizumab and nivolumab, has rejuvenated enthusiasm among clinicians and researchers by opening up a new domain for targeted and co-targeted therapeutics. The interim results of many ongoing trials and the latest updates of previous landmark trials such as KEYNOTE and CheckMate show promising trends in this regard. Immunotherapeutic agents belonging to different classes, such as durvalumab, epacadostat, motolimod, and T4 immunotherapy, are all being investigated presently in various therapeutic roles. Human papilloma virus (HPV)-based vaccines are now understood to have both a preventive and therapeutic role in HNSCC. Phase I/II trials are underway evaluating the safety profile, tolerable limits, and therapeutic efficacy of several therapeutic vaccines against HPV-driven HNSCC. Similarly, co-targeting therapeutics and precision medicine concepts are exploring newer and effective options including individuating the therapy based on particular tumor’s molecular makeup and so on, the results of which are expected to change the landscape of HNSCC.
Bösartiger Hauttumor ausgehend von den Keratinozyten des Stratum spinosum (Synonym Spinaliom, squamous cell carcinoma, SCC), der meist auf dem Boden einer Präkanzerose entsteht, lokal invasiv wächst und bei etwa 5% der Patienten metastasiert.
Recurrent or metastatic head and neck squamous-cell carcinomas (R/M HNSCC)are a group of cancers with a very poor prognosis. Many clinical trials testing novel target therapies in this setting are currently ongoing. We performed a systematic review focusing our attention on all clinical trials, ongoing or already published, concerning the use of novel drugs for treatment of R/M HNSCC. We found that the research of novel molecules effective in treatment of R/M HNSCC has been intense during last decade, and nowadays it is still very active. Unfortunately, the results in this setting have been, overall, disappointing: until now, only cetuximab and, recently, nivolumab and pembrolizumab received authorization for treatment of R/M HNSCC. Nevertheless, the promising results showed by some novel drugs may lead to continue the research in this field, with the aim of producing more evidence and finding new therapeutic indication.
Background
Oral squamous cell carcinoma (OSCC) is a deadly disease with a mere 40% five‐year survival rate for patients with advanced disease. Previously we discovered that capsazepine (CPZ), a transient receptor potential channel, Vanilloid subtype 1 (TRPV1) antagonist, has significant anti‐tumor effects against OSCC via a unique mechanism‐of‐action that is independent of TRPV1. Thus we developed novel CPZ analogs with more potent anti‐proliferative effects (CIDD‐24, ‐99, and ‐111).
Methods
Using OSCC xenograft models, we determined the efficacy of these analogs in vivo. TRPV1 interactions were evaluated using calcium imaging and a rat model of orofacial pain. Anti‐cancer mechanism(s)‐of‐action were assessed by cell cycle analysis and mitochondrial depolarization assays.
Results
CIDD‐99 was the most potent analog demonstrating significant anti‐tumor effects in vivo (p<0.001). CIDD‐24 was equipotent to the parent compound CPZ, but less potent than CIDD‐99. CIDD‐111 was the least efficacious analog. Calcium imaging studies confirmed that CIDD‐99 neither activates nor inhibits TRPV1 confirming that TRPV1 activity is not involved in its anti‐cancer effects. All analogs induced an S‐phase block, dose‐dependent mitochondrial depolarization, and apoptosis. Histological analyses revealed increased apoptosis and reduced cell proliferation in tumors treated with these analogs. Importantly, CIDD‐99 had the most dramatic anti‐tumor effects with 85% of tumors resolving leaving only minute traces of viable tissue. Additionally, CIDD‐99 was non‐noxious and demonstrated no observable adverse reactions
Conclusion
This study describes a novel, highly efficacious, CPZ analog, CIDD‐99, with dramatic anti‐tumor effects against OSCC that may be efficacious as a lone therapy or in combination with standard therapies.
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We previously reported that anti-epidermal growth factor (EGF) receptor monoclonal antibody (mAb) 225 can block receptor activation and inhibit proliferation of tumor cells bearing EGF receptors. To further explore the mechanism of mAb-mediated growth inhibition, we compared the capacities of bivalent 225 mAb and 225 F(ab')2, and monovalent 225 Fab' fragment to block ligand binding to EGF receptors, inhibit activation of receptor tyrosine kinase by exogenous and endogenous ligand, produce receptor dimerization, down-regulate receptors, and inhibit proliferation of cultured A431 squamous carcinoma cells. Unlike 225 mAb and 225 F(ab')2, 225 Fab' fragment was a poor inhibitor of A431 cell proliferation. The weak antiproliferative capacity of 225 Fab' was not due to depletion of active fragment from cultures. When cells were exposed to exogenous EGF, monovalent 225 Fab' remaining in conditioned culture medium could act as well as the bivalent forms of mAb to block binding and tyrosine kinase activation by exogenous EGF. However, unlike the bivalent forms, 225 Fab' fragment was unable to induce receptor dimerization and down-regulation, and it lacked the capacity to block autocrine activation of EGF receptors by endogenous ligand. These deficiencies were corrected by addition of rabbit anti-mouse IgG antibody, which also enabled 225 Fab' fragment to inhibit cell proliferation. We conclude that in A431 cells, inhibition of autocrine-stimulated proliferation by anti-EGF receptor mAbs requires antibody bivalency, which provides the capacity to produce EGF receptor dimerization accompanied by receptor down-regulation. These properties may explain the greater efficacy of bivalent mAb and F(ab')2, compared with monovalent Fab' fragment, in inhibiting proliferation of a variety of malignant and nonmalignant cultured cell lines.
The most accurate predictor of disease recurrence in patients treated for head and neck squamous cell carcinoma is, at present, the extent of regional lymph node metastasis. Since elevated levels of epidermal growth factor receptor (EGFR) and of its ligand, transforming growth factor-alpha (TGF-alpha), have been detected in primary tumors of patients with head and neck squamous cell carcinoma, we determined whether tumor levels of these proteins were of prognostic importance.
Monoclonal antibodies specific for EGFR and TGF-alpha were used for immunohistochemical detection of each protein in tissue sections of primary tumors from 91 patients who were treated by surgical resection. Levels of immunoreactive EGFR and TGF-alpha were quantified by use of a computerized image analysis system and were normalized to appropriate standards. The logrank test and proportional hazards regression analysis were used to calculate the probability that EGFR and TGF-alpha levels were associated with disease-free survival (i.e., no recurrence of cancer) and cause-specific survival (i.e., patients do not die of their disease). All P values were two-sided.
When tumor levels of EGFR or TGF-alpha were analyzed as continuous variables, disease-free survival and cause-specific survival were reduced among patients with higher levels of EGFR (both P = .0001) or TGF-alpha (both P = .0001). In a multivariate analysis, tumor site, tumor level of EGFR, and tumor level of TGF-alpha were statistically significant predictors of disease-free survival; in a similar analysis, regional lymph node stage and tumor levels of EGFR and of TGF-alpha were significant predictors of cause-specific survival.
Quantitation of EGFR and TGF-alpha protein levels in primary head and neck squamous cell carcinomas may be useful in identifying subgroups of patients at high risk of tumor recurrence and in guiding therapy.
A correlative study was performed to address the impact of epidermal growth factor receptor (EGFR) overexpression on survival and pattern of failure in patients with advanced head and neck squamous cell carcinomas (HNSCCs) enrolled in a Phase III trial and randomized to receive conventional radiotherapy. The study population comprised 155 of 268 (58%) randomized patients with sufficient pretreatment biopsy specimens for immunohistochemical assay. The specimens were dewaxed and incubated after standard preparation with mouse monoclonal antibodies recognizing the extracellular domain of the EGFR molecule. The catalyzed product was visualized with 3,3'-diaminobenzidine Chromogen Kit and lightly counterstained with Mayer's hematoxylin. Quantitative EGFR immunohistochemistry (IHC) was done with SAMBA 4000 Cell Image Analysis System, without knowledge of the clinical outcome, to yield mean absorbance (MOD), staining index (SI), and quick score (QS). These EGFR IHC parameters were correlated with the T stage, N stage, combined stage grouping, and recursive partitioning analysis classes. Subsequently, the EGFR parameters were correlated with the outcome end points, i.e., overall survival (OS), disease-free survival (DFS), local-regional (LR) relapse, and distant metastasis rates. We found that HNSCCs exhibited a wide variation in EGFR expression (MOD, 0.2-66.0; SI, 0.3-97.0; QS, 0.01-69.9) with a relatively strong but nonlinear correlation between MOD and SI (r = 0.79). There was no correlation between EGFR expression and T stage, N stage, stage grouping, and recursive partitioning analysis classes (r = -0.07 to 0.17). The OS and DFS rates of patients with high EGFR-expressing HNSCCs (>median MOD) were highly significantly lower (P = 0.0006 and P = 0.0016, respectively) and the LR relapse rate was highly significantly higher (P = 0.0031) compared with those of patients with low EGFR-expressing HNSCCs. However, there was no difference in the distant metastasis rate between the two groups (P = 0.96). Significant correlations, although somewhat less robust than MOD, were also observed between SI and QS and the OS, DFS, and LR relapse rates. Multivariate analysis showed that EGFR expression was an independent determinant of survival and a robust independent predictor of LR relapse. In summary, this correlative study in a large series of patients revealed that EGFR expression, which varied considerably among HNSCCs, was a strong independent prognostic indicator for OS and DFS and a robust predictor for LR relapse but not for distant metastasis. The data suggest that EGFR IHC should be considered for selecting patients for more aggressive combined therapies or enrollment into trials targeting EGFR signaling pathways.
Receptor tyrosine kinase genes were sequenced in non–small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations
of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor
gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung
adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors
or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.
The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan.
We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment.
The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone.
Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.
To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR).
This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity.
Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity.
Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.
PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of a chimeric anti–epidermal growth factor receptor monoclonal antibody, cetuximab, in combination with radiation therapy (RT) in patients with advanced squamous cell carcinoma of the head and neck.
PATIENTS AND METHODS: We treated 16 patients in five successive treatment schedules. A standard dose escalation procedure was used; three patients entered onto the study at each dose level of cetuximab received conventional RT (70 Gy, 2 Gy/d), and the final three patients received hyperfractionated RT (76.8 Gy, 1.2 Gy bid). Cetuximab was delivered as a loading dose of 100 to 500 mg/m², followed by weekly infusions of 100 to 250 mg/m² for 7 to 8 weeks. Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument. Human antichimeric antibody response was evaluated with a double-antigen radiometric assay. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic parameters and adverse events.
RESULTS: The most commonly reported adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities (grade 1 to 2 in most patients). Skin toxicity outside of the RT field was not strictly dose-dependent; however, grade 2 or higher events were observed in patients treated with higher dose regimens. There was one grade 4 allergic reaction. Most acute adverse effects were associated with RT (xerostomia, mucositis, and local skin toxicity). No antibodies against cetuximab were detected. All patients achieved an objective response (13 complete and two partial remissions).
CONCLUSION: Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m² and a maintenance weekly dose of 250 mg/m².
We have explored the therapeutic effects of anti-epidermal growth factor receptor monoclonal antibodies (MAbs) 225 and 528 on well established A431 epidermoid carcinoma xenografts, approximately 400 mm3 (1 cm in diameter) at the start of treatment. In previous reports we demonstrated that MAbs 225 and 528 prevented the growth of A431 cell xenografts in nude mice when treatment was begun on the day of tumor cell inoculation. Since anti-epidermal growth factor receptor MAb therapy of well established tumors was unable to retard growth, we explored combination therapy with MAb plus the chemotherapeutic agent cis-diamminedichloroplatinum (cis-DDP). Additive and concentration-dependent growth-inhibitory effects of MAb with cis-DDP were observed in cultures of A431 cells. Neither intensive treatment with 225 MAb (1 mg/mouse, i.p. on day 8 after tumor inoculation, and twice weekly for 4 weeks) nor a maximally tolerated single dose of cis-DDP [150 micrograms/25 g (6 mg/kg) mouse weight, i.p. on day 8] had significant effects on tumor growth. However, the two treatments in combination resulted in substantial xenograft growth inhibition, compared with both an untreated control group and animals treated with a single modality. When a second dose of cis-DDP (150 micrograms/25 g) was added after 10 days, combination therapy with 225 MAb produced striking antitumor effects. At the end of 1 month tumor xenografts had disappeared in all but one mouse, and no tumor relapses occurred during 6 months of observation. Identical results were obtained with anti-epidermal growth factor receptor MAb 528 in combination with cis-DDP. The results of these studies provide a novel approach to the treatment of well established tumor xenografts, which may have application in the therapy of human malignancies.
Transforming growth factor-α (TGF-α) and epidermal growth factor receptor (EGFR) mRNA are up-regulated in squamous cell carcinoma of the head and neck (SCCHN) tissues.
Immunohistochemical staining with monoclonal antibodies to TGF-α and EGFR was undertaken to identify the cellular origin in tissue obtained from cancer patients and controls and to determine the correlation between mRNA expression levels and two methods of immunohistochemical evaluation.
TGF-α protein staining occurred in the suprabasal layers and spared the basal layer of normal controls. Conversely, in histologically normal mucosa from SCCHN patients, TGF-α was present throughout the epithelium, including the basal layer. EGFR staining was negligible in normal mucosa from control patients without cancer and relatively increased in SCCHN tissues. Increasing staining intensity was correlated with worsening dysplasia and closer proximity to the tumor. Using computerized image analysis to quantify the intensity of immunostaining, the mean optical density (MOD) of TGF-α staining in histologically normal mucosa (P = 0.049) and tumors (P = 0.005) from SCCHN patients was significantly higher than in control normal mucosa from noncancer patients (1.9- and 1.7-fold, respectively). EGFR MOD was also greater in the histologically normal mucosa (P = 0.009) and tumors (P = 0.006) from SCCHN patients than in control normal mucosa (1.8- and 1.9-fold, respectively). For both TGF-α (P = 0.668) and EGFR (P = 0.116), the MOD was similar for both tumor and histologically normal mucosa from SCCHN patients.
TGF-α and EGFR protein expression is increased early in head and neck squamous cell carcinogenesis and can be quantitated by computerized image analysis of immunohistochemical staining. Altered distribution of TGF-α protein in histologically normal mucosa from SCCHN patients compared with control mucosa from patients without cancer suggests a switch from a paracrine to an autocrine pathway. Cancer 1996;78:1284-92.
We examined effects of the anti-epidermal growth factor receptor monoclonal antibody C225 on proliferation, cell cycle phase distribution, apoptosis, and radiosensitivity in squamous cell carcinoma (SCC) cell lines derived from head and neck cancer patients. Exposure to C225 in culture inhibits SCC proliferation in a time-dependent manner, and the degree of growth inhibition, compared to controls, ranges from 20 to 75%. Flow cytometry analysis demonstrates that C225 treatment induces accumulation of cells in G1, which is accompanied by a 2-3-fold decrease in the percentage of cells in S phase. C225 exposure also induces apoptosis in SCC populations, as demonstrated by flow cytometry analysis using dual stainings of merocyanine 540 and Hoechst 33342. Western blot analysis indicates that C225 exposure induces accumulation of hypophosphorylated retinoblastoma protein and increases expression of p27KIP1. An increase in Bax expression and concurrent decrease in Bcl-2 expression are observed when SCC cells are exposed to C225. Examination of C225 effects on radiation response in SCCs demonstrates enhancement in radiosensitivity and amplification of radiation-induced apoptosis. These effects are observed in both single-dose and fractionated radiation experiments. C225 represents a promising growth-inhibitory agent that can influence cellular proliferation, apoptosis, and radiosensitivity in SCCs of the head and neck.
The epidermal growth factor (EGF) receptor is frequently overexpressed in epithelial tumors. C225 is a human-to-murine chimeric monoclonal antibody that binds to the receptor and inhibits growth of cancer cells expressing the receptor. We evaluated the pharmacokinetics and toxicity of C225 in patients with advanced tumors overexpressing EGF receptors.
We treated 52 patients in three successive phase I clinical trials of C225 as a single dose (n = 13), weekly multiple dose (n = 17), and weekly multiple dose with cisplatin (n = 22). C225 dose levels were 5, 20, 50, and 100 mg/m(2). In the study combining C225 with cisplatin, limited to patients with either head and neck or non-small-cell lung cancer, C225 was further escalated to 200 and 400 mg/m(2). Cisplatin was given at a dose of 60 mg/m(2) once every 4 weeks, and treatment was continued for up to 12 weeks if no disease progression occurred.
C225 displayed nonlinear pharmacokinetics, with antibody doses in the range of 200 to 400 mg/m(2) being associated with complete saturation of systemic clearance. C225 clearance did not change with repeated administration or with coadministration of cisplatin. Antibodies against C225 were detected in only one patient, and C225-associated toxicity was minimal. Patients experiencing disease stabilization were seen in all studies. In the study combining C225 and cisplatin, nine (69%) of 13 patients treated with antibody doses >/= 50 mg/m(2) completed 12 weeks of therapy, and two partial responses were observed.
C225 has dose-dependent pharmacokinetics, and doses that achieve saturation of systemic clearance are well tolerated. C225 given in combination with cisplatin has biologic activity at pharmacologically relevant doses.
Overexpression of epidermal growth factor receptor (EGFR) has been correlated with tumor resistance to cytotoxic agents, including radiation (T. Akimoto et al., Clin. Cancer Res., 5: 2884-2890, 1999), and thus is a candidate target for anticancer treatment. This study investigated whether treatment with C225 anti-EGFR antibody would improve tumor response to radiotherapy. Nude mice bearing 8-mm-diameter A431 tumor xenografts in the hind leg were treated with C225 antibody, 18 Gy of single-dose local tumor irradiation, or both. C225 was given i.p. at a dose of 1 mg/mouse 6 h before irradiation or 6 h before and 3 and 6 days after irradiation. Delay in tumor growth was the treatment end point. C225 dramatically improved the efficacy of local tumor irradiation, particularly when multiple injections of C225 were administered. Tumor radioresponse was enhanced by a factor of 1.59 by a single dose and by a factor of 3.62 by a doses of C225. Histological analyses of tumors revealed that C225 caused a striking increase in central tumor necrosis associated with hemorrhage and vascular thrombosis when combined with radiotherapy. In addition, C225 induced heavy tumor infiltration with granulocytes, increased tumor cell terminal differentiation, and inhibited tumor angiogenesis. We conclude that C225 anti-EGFR antibody enhances tumor radioresponse by multiple mechanisms that may involve direct and indirect actions on tumor cell survival.
Patients with advanced squamous cell head and neck cancer have a dismal long-term survival rate not only because of metastatic disease, but also primarily because of failure in local disease control. The role of chemotherapy in recurrent or metastatic head and neck cancer has largely been palliative. Several chemotherapy agents, including docetaxel, paclitaxel, and ifosfamide, have been extensively studied, either alone or in combination regimens, for the treatment of recurrent or metastatic disease. These have resulted in response rates that are similar or higher than those obtained with the gold standard combination, cisplatin/ fluorouracil. Single-agent and combination studies of vinorelbine and gemcitabine have demonstrated modest activity in recurrent or metastatic disease. Phase III trials are planned that will compare taxane-based regimens with cisplatin and 5-fluorouracil in recurrent or metastatic head and neck cancer. Meanwhile, new drug and compound development, including monoclonal antagonists to the epidermal growth factor receptor, farnesyl transferase inhibitors, and oncolytic viruses are being tested in this setting.
Purpose/objective:
The primary purpose of this presentation is to develop the concept that molecular blockade of specific growth factor receptors and signal transduction pathways in combination with radiation will prove a valuable cancer therapeutic strategy. More specifically, the rationale for molecular blockade of the epidermal growth factor receptor (EGFR) system in combination with ionizing radiation for epithelial tumors, such as squamous cell carcinomas (SCCs) of the head and neck (H&N), is described.
Methods and materials:
Preclinical experimentation with in vitro and in vivo model systems regarding the capacity of EGFR blockade, using the monoclonal antibody C225, to modulate SCC tumor growth behavior and response to radiation is presented. The rationale for new clinical trials that are currently exploring this concept are presented.
Results:
Blockade of the EGFR system in SCC cell lines with C225 induces G1 cell cycle arrest with an associated decrease in the S-phase fraction. Inhibition of tumor cell proliferation is readily measured following C225 exposure and the corresponding alterations in expression of key regulators of the G1-S cell cycle phase transition are identified. Exposure of SCCs to C225 in culture enhances radiosensitivity following single-dose radiation exposure. Profound augmentation of the in vivo radiation response of SCC tumor xenografts in athymic mice is similarly demonstrated following systemic administration of C225. Preliminary studies are presented regarding potential underlying mechanisms of action for this enhanced tumor response to the combination of C225 and radiation including: (a) proliferative growth inhibition, (b) enhancement of radiation-induced apoptosis, (c) inhibition of damage repair, and (d) downregulation of tumor angiogenic response. Preliminary observations from the Phase III multicenter clinical trial examining C225 plus radiation therapy for advanced H&N cancer patients are provided.
Conclusion:
Molecular inhibition of the EGFR signal transduction system in combination with radiation represents a promising investigational area in cancer therapeutics. Epithelial tumors that are rich in their expression of EGFR (e.g., SCC of the H&N) hold special promise for receptor blockade approaches. More broadly, the ultimate therapeutic effect of selected molecular agents which block specific growth factor receptors and signaling pathways may be enhanced when delivered in combination with radiation.
C225, a human-mouse chimerized monoclonal antibody directed against the epidermal growth factor receptor (EGFr), has a synergistic effect with cisplatin in xenograft models. To determine the tumor EGFr saturation dose with C225 and the fate of infused C225, we conducted a Phase Ib study with C225 in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck. Using tumor samples, we assessed tumor EGFr saturation by antibody using immunohistochemistry studies, the EGFr tyrosine kinase assay, and detection of the EGFr/C225 complex formation by immunoblot. Potential candidates were screened for EGFr expression in their tumors, and 12 patients who had high levels of EGFr expression and tumors easily accessible for repeated biopsies (pretherapy, 24 h after first C225 infusion, 24 h before third C225 infusion) were entered at three different dose levels of C225 with a fixed dose of cisplatin. The median value of tumor EGFr saturation increased to 95% at the higher dose levels. EGFr tyrosine kinase activity was significantly reduced after C225 infusion, and EGFr/C225 complexes were also detected at higher doses of C225. The loading dose of C225 at 400 mg/m(2) with a maintenance dose at 250 mg/m(2) achieved a high percentage of saturation of EGFr in tumor tissue, and these doses were recommended for Phases II or III clinical trials. Six (67%) of nine evaluable patients achieved major responses, including two (22%) complete responses. Mild to moderate degrees of allergic reaction and folliculitis-like skin reactions were demonstrated. We conclude that infused C225 binds and significantly saturates tumor EGFr, which may render a high degree of antitumor activity, and provides a novel mechanism for targeting cancer therapy for patients who have EGFr expression in their tumors.
Elevated levels of the epidermal growth factor receptor (EGFR), a growth-factor-receptor tyrosine kinase, and/or its cognate ligands have been identified as a common component of multiple cancer types and appear to promote solid tumour growth. This article examines the relationship between EGFR expression and cancer prognosis based on literature compiled on PubMed between 1985 and September 2000. More than 200 studies were identified that analysed relapse-free-interval or survival data directly in relation to EGFR levels in over 20000 patients. Analysis of the data showed that 10 cancer types both express elevated levels of EGFR relative to normal tissues and have been studied in sufficient depth to allow sound judgements to be made concerning the association between EGFR and patient outlook. The EGFR was found to act as a strong prognostic indicator in head and neck, ovarian, cervical, bladder and oesophageal cancers. In these cancers, increased EGFR expression was associated with reduced recurrence-free or overall survival rates in 70% (52/74) of studies. In gastric, breast, endometrial and colorectal cancers, the EGFR provided more modest prognostic information, correlating to poor survival rates in 52% (13/25) of studies, while in non-small cell lung cancer (NSCLC), EGFR expression only rarely (3/10 studies) related to patient outlook. However, it is likely that the true prognostic significance of the EGFR has been underestimated as the published studies only assessed total cellular EGFR levels, rather than the activated form of the receptor, and were not standardised with regard to patient populations or assay methods. Finally, it is important to stress that failure to detect a prognostic significance for EGFR in any one cancer type does not necessarily preclude patients from benefiting from anti-EGFR therapies.
We studied the profile of four c-erbB receptors in head and neck squamous cell carcinomas (HNSCC) and to determine whether their expression was associated with clinicopathological features and key molecules involved in angiogenesis and metastasis. We also assessed the impact of expression on survival. This study included 54 cases of primary HNSCC, of which 27 cases showed lymph node metastasis. The expression of c-erbB receptors, matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) family members was analysed in the same tissue homogenates by semi-quantitative RT-PCR. HNSCC frequently co-expressed multiple c-erbB receptors and showed significant correlations amongst their levels. High expression of epidermal growth factor receptor (EGFR), c-erbB-2 or c-erbB-3 was associated with an infiltrating mode of invasion, nodal metastases and advanced pathological stages. EGFR and c-erbB-2 levels were strongly correlated (P=0.0004-0.029) with the expression of MMP-2, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, VEGF-A and VEGF-C whereas the levels of c-erbB-3 and B-4 showed a weaker correlation (P=0.049-0.01) with some MMPs and VEGF-C. Only nodal metastasis and EGFR levels were significantly associated with poor outcome in uni- and multi-variate analysis. We conclude that co-operative signalling of all four c-erbB receptors may play a significant role in the pathogenesis of HNSCC. Amongst these, EGFR appears to be the dominant component controlling the invasive and angio-/lymphangiogenic phenotype in HNSCC via upregulation of multiple MMPs and VEGFs.
Head and neck cancers include neoplasms of the oral cavity, pharynx, and larynx. The risk of these cancers is strongly associated with smoking and alcohol ingestion. There have been important advances in understanding of the molecular pathogenesis and progression of head and neck cancer and also in approaches to therapy, which include innovations in surgery, radiation therapy, and cytotoxic-drug therapy.
Traditional cytotoxic approaches to tumor management are associated with efficacy and toxicity limitations. Blockade of the epidermal growth factor receptor (EGFR) and its ligands is a novel approach to the treatment of human tumors that offers a noncytotoxic alternative to cancer treatment.
An English-language literature search was conducted to identify studies assessing the in vitro and in vivo effects of EGFR blockade with an emphasis on approaches that use monoclonal antibody therapy.
The EGF pathway regulates normal cellular processes and appears to be correlated with the development of malignancy. Approximately 30% of human tumors express EGFR, which has been reported to be correlated with poor prognosis and diminished disease-free and overall survival in selected tumor types. A number of anti-EGFR monoclonal antibodies have been developed, which currently are undergoing clinical trials in humans. Effective anti-EGFR monoclonal antibodies compete with endogenous ligands, primarily EGF and transforming growth factor-alpha, for receptor ligand-binding sites. Binding to EGFR blocks critical signaling pathways and interferes with the growth of tumors expressing EGFR. Anti-EGFR monoclonal antibodies that currently are under study include IMC-C225, EMD 55900, ICR 62, and ABX-EGF.
These antibodies have demonstrated promising results and appear to have been well tolerated. EGFR-targeted therapy addresses important, unmet needs in the treatment of human tumors, particularly EGFR-positive epithelial tumors including common malignancies of the head and neck, lung, and colon.
Colon carcinomas frequently express the epidermal growth factor receptor (EGFR), and this expression correlates with more aggressive disease and poor prognosis. Previous studies have shown that EGFR blockade by monoclonal antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these tumors in athymic mice. In this report, we have studied the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice. IMC-C225 was tested at a dose of 1 or 0.5 mg administered q3d. CPT-11 was administered at a dose of 100 mg/kg/week or a maximum tolerated dose of 150 mg/kg/week. Treatment with the combination of IMC-C225 (1 and 0.5 mg) and CPT-11 (100 mg/kg) significantly inhibited the growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (P < 0.05). Combination therapy with IMC-C225 (1 mg) and the MTD of CPT-11 (150 mg/kg) resulted in a regression rate of 100 and 60% of established DLD-1 and HT-29 tumors, respectively. In a refractory tumor model, combined treatment with IMC-C225 and CPT-11 significantly inhibited the growth of CPT-11 refractory DLD-1 and HT-29 tumors, whereas either agent alone did not control tumor growth. Histological examination of treated tumors showed extensive tumor necrosis, decreased tumor cell proliferation, increased tumor cell apoptosis, and a marked decrease in tumor vasculature. These results suggest that EGFR blockade by IMC-C225 combined with topoisomerase I inhibitors may be an effective therapy against chemorefractory colorectal carcinoma tumors.
The epidermal growth factor receptor (EGFR) is a mediator of squamous cell carcinoma of the head and neck (SCCHN) development. ZD1839 is an orally active, selective EGFR tyrosine kinase inhibitor. This phase II study sought to explore the activity, toxicity, and pharmacodynamics of ZD1839 in SCCHN.
Patients with recurrent or metastatic SCCHN were enrolled through the University of Chicago Phase II Consortium. Patients were allowed no more than one prior therapy for recurrent or metastatic disease and were treated with single-agent ZD1839 500 mg/d. Patient tumor biopsies were obtained and stained immunohistochemically for EGFR, extracellular signal-regulated kinase 1 (ERK1), and phosphorylated ERK1 (p-ERK). Study end points included response rate, time to progression, median survival, and inhibition of p-ERK.
Fifty-two patients were enrolled (40 male and 12 female) with a median age of 59 years (range, 34 to 84 years). Fourteen patients received ZD1839 through a feeding tube. Half the cohort received ZD1839 as second-line therapy. Forty-seven patients were assessable for response, with an observed response rate of 10.6% and a disease control rate of 53%. Median time to progression and survival were 3.4 and 8.1 months, respectively. The only grade 3 toxicity encountered was diarrhea in three patients. Performance status and development of skin toxicity were found to be strong predictors of response, progression, and survival. Ten biopsy samples were assessable and revealed no significant change in EGFR or p-ERK expression with ZD1839 therapy.
ZD1839 has single-agent activity and is well tolerated in refractory SCCHN. In contrast to other reports, development of skin toxicity was a statistically significant predictor of response and improved outcome.
This study prospectively examines the prognostic role of p53 oncoprotein (p53), Ki67-antigen (Ki67), tumor angiogenesis (MVD), epidermal growth factor receptor (EGFR), and HER2 receptor protein (HER2) expression in Chinese with undifferentiated nasopharyngeal carcinoma (NPC).
Seventy-eight Chinese were recruited from October 1995 to July 1997 at the Prince of Wales Hospital, Hong Kong. Pretreatment immunohistochemical preparations of the primary tumor were made, and clinical data were collected prospectively until October 30, 2000. The markers were correlated with overall survival (OS), disease-free survival (DFS), time to progression (TTP), and UICC stage.
On univariate analysis, EGFR expression correlated with poorer OS (p =.0001), DFS (p =.01), shorter TTP (p =.0001), and advanced T stage (p =.036). Strong EGFR expression, when compared with weak or moderate, was associated with poorer OS (p =.04) and shorter TTP in a subgroup of patients with UICC stage III-IV disease. HER2 expression was associated with advanced UICC stage (p =.006). The presence of p53 expression correlated with poorer DFS (p =.01) and a trend toward shorter TTP (p =.06). No correlation was found with Ki67-antigen or MVD. On multivariate analysis, only EGFR expression was significantly linked to shorter OS and TTP.
EGFR expression in undifferentiated NPC is associated with a poor clinical outcome. A prognostic role of p53 and HER2 expression is suggestive but not consistently defined in this study. The relatively high prevalence of positive staining for EGFR supports the use of molecular targeted therapy in this disease.
Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown.
We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells.
Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib.
A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.
Treatment of squamous cell carcinoma of the head and neck (SCCHN) has evolved greatly in the last two decades, owing to the integration of chemotherapy, advances in radiotherapeutic techniques, and organ-preserving surgery. Several randomized trials have established new standards of care that should be adopted. Current efforts are building on these earlier trials in order to improve survival and quality of life. Coincident with this, investigators are developing molecularly targeted approaches that hold promise for the future. This review will focus on current therapy for locally advanced, recurrent, and metastatic SCCHN and discuss controversies and directions for future research.
Recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) develops in around 72,000 people in Europe every year. Treatment options are limited, mainly consisting of platinum-based palliative chemotherapy, with median overall survival times of only 6-8 months. No standard second-line treatment after progression on platinum-based chemotherapy is available. Few data have reported the efficacy of these treatments and the outcome of the patients. In an effort to generate such data, this retrospective study analysed clinical records from 151 patients with SCCHN refractory to platinum-based chemotherapy treated between 1990 and 2000 at seven different centres around Europe.
Most patients (45%) received only best supportive care (BSC), and had a median survival of 56 days. A total of 28.5% of the patients received second-line chemotherapies: 16.6% radiotherapy and 9.9% chemoradiotherapy.
No objective response was observed with the various second-line chemotherapies. The overall median survival was 103 days (95% confidence interval [CI]: 77-126 days) for the whole cohort. The overall objective response rate (ORR) to second-line treatment in this population was calculated to be 2.6%.
These results highlight the need for additional treatment options for this disease. Similar, if not superior, response rates have already been observed in initial clinical studies of novel, targeted anti-cancer agents.
The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in many epithelial tumors. Receptor activation leads to recruitment and phosphorylation of several downstream intracellular substrates, leading to mitogenic signaling and other tumor-promoting cellular activities. In human tumors, receptor overexpression correlates with a more aggressive clinical course. Taken together, these observations indicate that the EGFR is a promising target for cancer therapy. Monoclonal antibodies directed at the ligand-binding extracellular domain and low-molecular weight inhibitors of the receptor's tyrosine kinase are currently in advanced stages of clinical development. These agents prevent ligand-induced receptor activation and downstream signaling, which results in cell cycle arrest, promotion of apoptosis, and inhibition of angiogenesis. They also enhance the antitumor effects of chemotherapy and radiation therapy. In patients, anti-EGFR agents can be given safely at doses that fully inhibit receptor signaling, and single-agent activity has been observed against a variety of tumor types, including colon carcinoma, non-small-cell lung cancer, head and neck cancer, ovarian carcinoma, and renal cell carcinoma. Although antitumor activity is significant, responses have been seen in only a minority of the patients treated. In some clinical trials, anti-EGFR agents enhanced the effects of conventional chemotherapy and radiation therapy. Ongoing research efforts are directed at the selection of patients with EGFR-dependent tumors, identification of the differences among the various classes of agents, and new clinical development strategies.
To determine the efficacy and safety profiles of erlotinib in patients with advanced recurrent and/or metastatic squamous cell cancer of the head and neck (HNSCC).
Patients with locally recurrent and/or metastatic HNSCC, regardless of their HER1/EGFR status, were treated with erlotinib at an initial dose of 150 mg daily. Dose reductions or escalations were allowed based on tolerability of erlotinib.
One-hundred fifteen patients were enrolled onto this study. Forty-seven percent of patients received erlotinib at 150 mg daily throughout the entire study, 6% had dose escalations, and 46% required dose reductions and/or interruptions. Five patients achieved partial responses on study, for an overall objective response rate of 4.3% (95% CI, 1.4% to 9.9%). Disease stabilization was maintained in 44 patients (38.3%) for a median duration of 16.1 weeks. The median progression-free survival was 9.6 weeks (95% CI, 8.1 to 12.1 weeks), and the median overall survival was 6.0 months (95% CI, 4.8 to 7.0 months). Subgroup analyses revealed a significant difference in overall survival favoring patients who developed at least grade 2 skin rashes versus those who did not (P =.045), whereas no difference was detected based on HER1/EGFR expression. Rash and diarrhea were the most common drug-related toxicities, encountered in 79% and 37% of patients, respectively, though the severity was mild to moderate in most cases.
Erlotinib was well tolerated in this heavily pretreated HNSCC population and produced prolonged disease stabilization; hence, further evaluation of its role in this tumor type is warranted.
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