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Treatment options for locally advanced squamous cell carcinoma of the head and neck (SCCHN) include either surgical resection followed by radiation or chemoradiation, or definitive chemoradiation for which single-agent cisplatin is the best studied and established. The increasing understanding of the molecular biology of SCCHN has led to an interest in the development of targeted therapies. The epidermal growth factor receptor (EGFR) is over-expressed in nearly 80-90% of cases of SCCHN and correlates with poor prognosis and resistance to radiation. Preclinical evidence showed that blocking EGFR restores radiation sensitivity and enhances cytotoxicity. This finding led to clinical trials evaluating this class of agents and the approval of cetuximab in combination with radiation for the treatment of locally advanced SCCHN. This review is focused on the anti-EGFR monoclonal antibodies and their role either with radiotherapy or chemoradiation in unresectable LA SCCHN., (Published by Elsevier Ireland Ltd.)

With the incorporation of targeted therapies in routine cancer therapy, it is imperative that the array of toxicities associated with these agents be well-recognized and managed, especially since these toxicities are distinct from those seen with conventional cytotoxic agents. This review will focus on these renal toxicities from commonly used targeted agents. This review discusses the mechanisms of these side effects and management strategies. Anti-vascular endothelial growth factor (VEGF) agents including the monoclonal antibody bevacizumab, aflibercept (VEGF trap), and anti-VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) all cause hypertension, whereas some of them result in proteinuria. Monoclonal antibodies against the human epidermal growth factor receptor (HER) family of receptors, such as cetuximab and panitumumab, cause electrolyte imbalances including hypomagnesemia and hypokalemia due to the direct nephrotoxic effect of the drug on renal tubules. Cetuximab may also result in renal tubular acidosis. The TKIs, imatinib and dasatinib, can result in acute or chronic renal failure. Rituximab, an anti-CD20 monoclonal antibody, can cause acute renal failure following initiation of therapy because of the onset of acute tumor lysis syndrome. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, can result in proteinuria. Discerning the renal adverse effects resulting from these agents is essential for safe treatment strategies, particularly in those with pre-existing renal disease.

Background: Salivary duct carcinoma (SDC) is a rare malignancy with a poor prognosis. Human epidermal growth factor receptor-2 (Her-2/neu) is overexpressed in SDC and, hence, HER-2/neu targeted therapy could be an option., Methods: A 72-year-old man presented with parotid swelling and cervical lymphadenopathy. He underwent a parotidectomy, modified radical neck dissection, and postoperative chemoradiation with cisplatin. A year later, he developed metastatic disease in the contralateral neck that was treated surgically with right axillary lymphadenopathy. He received radiation to both sites, concurrent with carboplatin. Two years later, he underwent resection of a lung metastasis. He then had progression in the axillary and mediastinal lymph nodes and received 5 cycles of docetaxel and trastuzumab followed by maintenance trastuzumab., Results: The patient had a partial response and restaging studies 9 months after therapy discontinuation did not show progression., Conclusion: Trastuzumab-based therapy is a potential therapeutic option for patients with SDC., (Copyright © 2013 Wiley Periodicals, Inc., A Wiley Company.)

Pulmonary toxicity is rarely seen with most commonly used targeted therapies. The endothelial growth factor receptor (EGFR) small-molecule tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib can cause interstitial lung disease (ILD). BCR-ABL tyrosine kinase inhibitors imatinib and dasatinib can cause pleural effusions. Infusion-related bronchospasm is common with the monoclonal antibodies to EGFR cetuximab and panitumumab, and case reports of bronchiolitis and pulmonary fibrosis have been described. Up to one-sixth of patients taking mammalian target of rapamycin (mTOR) inhibitors get a reversible interstitial pneumonitis. Bevacizumab, the monoclonal antibody to vascular endothelial growth factor (VEGF), has been associated with hemoptysis and pulmonary embolism particularly in patients with squamous cell lung cancer. Infusion-related bronchospasms, acute respiratory distress syndrome (ARDS), and interstitial pneumonitis can be seen with the anti-lymphocyte monoclonal antibodies rituximab, ofatumumab, and alemtuzumab. While most pulmonary toxicities from these therapies are mild and resolve promptly with dose reduction or discontinuation, it is important for the clinician to recognize these potential toxicities when faced with treatment-related complications. Discerning these pulmonary adverse effects may help in making decisions on diagnostic testing and therapy, particularly for those with pulmonary and cardiovascular co-morbidities.

Cancer is a disease of the elderly with the majority of new diagnoses and deaths from cancer occurring in persons greater than 65 years of age. A major goal of cancer therapy, in the elderly is the preservation of functional independence and quality of life. The advent of targeted therapies has raised the hope that older patients with cancer could be treated as effectively as younger patients and without added toxicities. However, caution must be exercised while addressing the use of these therapies in the elderly population and only after taking into consideration the risks, benefits and prognosis of patients on an individual basis. This article reviews the current literature on the efficacy, cost-effectiveness and toxicity of the currently approved targeted agents in the elderly population., (Published by Elsevier Ireland Ltd.)

Background: Concurrent chemoradiotherapy with cisplatin is the standard therapy for patients with unresectable locally advanced head and neck squamous cell carcinoma. However, cisplatin administration in patients on hemodialysis is complicated by the need to perform hemodialysis immediately after the infusion. Concurrent chemoradiation with cetuximab has been approved in definitive treatment of locally advanced head and neck cancer. Although cetuximab is not excreted via the kidneys, its use in patients on hemodialysis has not been reported., Methods and Results: We present the case of a 65-year-old man undergoing hemodialysis, with stage IVA squamous cell carcinoma of the hypopharynx. Given the logistics of performing hemodialysis immediately postcisplatin, he received concurrent chemoradiotherapy with cetuximab. He tolerated treatment well with minor side effects., Conclusion: Cetuximab can be safely used in patients with renal impairment. This is the first reported case of the use of cetuximab in a patient undergoing hemodialysis.

Cyclins and cyclin-dependent kinases (CDK) form a key part of the regulatory proteins that govern the cell cycle. Aberrancy in their function can lead to uncontrolled growth and proliferation of the cells which forms the basis of many human diseases, especially cancers. Seliciclib (CYC202, R-roscovitine) is a second-generation CDK inhibitor that competes for ATP binding sites on these kinases, reducing tumor growth and inducing cell death. It is a direct inhibitor of cyclin E/CDK2 and also has inhibitory effects on cyclin H/CDK7 and cyclin T/CDK9. Seliciclib leads to growth arrest and apoptosis of cell lines through activation of the p53 gene, inhibition of RNA processing and blockage of the RNA polymerase II-dependent transcription, and reduction of anti-apoptotic proteins. Seliciclib has good oral bioavailability, although its absorption is slowed by food. It is distributed rapidly to the body tissues and metabolized rapidly to a carboxylated derivative that is excreted by the kidneys. The major adverse effects of seliciclib are electrolyte disturbances (hypokalemia, hyponatremia), gastrointestinal side effects (nausea, emesis, anorexia), fatigue, transient hyperglycemia, elevation of liver enzymes and reversible elevation of serum creatinine. At present, it is in Phase II trials for non-small cell lung cancer and nasopharyngeal carcinoma.

Small-cell lung cancer is a chemo-sensitive disease with a response rate ranging from 70 to 90% for first-line treatment; however, relapses are very common and as a result long-term survival is poor. Chemotherapy has demonstrated a benefit over the best supportive care, even in patients who have relapsed after initial treatment with a platinum-based regimen. Agents currently being used in salvage therapy include topotecan, cyclophosphamide, doxorubicin and vincristine regimen. In the last 5 years, several drugs have shown promise in initial evaluation; however, randomized phase III trials would be needed to answer this question. Our understanding of the biology of small-cell lung cancer has improved dramatically over the past few years and this has translated into the developments of new therapeutic targets for this disease. Agents affecting several targets, including bcl-2, matrix metalloproteinases, epidermal growth factors and angiogenesis, are being studied currently and have the potential to change the treatment paradigms of this otherwise fatal malignancy. This review focuses on the various current and future options, including cytoxic and targeted agents, for salvage therapy in patients with this disease.

Cytotoxic chemotherapy has helped improve the outcomes in patients with advanced non-small cell lung cancer (NSCLC), but we seem to have reached a plateau with respect to the benefit obtained. Also, a large subset of elderly patients and those with a poor performance status cannot tolerate these drugs at recommended doses. There is a growing need to incorporate newer drugs with different mechanisms of action and better safety profile. The epidermal growth factor receptor family (EGFR) and vascular endothelial growth factor (VEGF) have been identified as potential targets and agents acting specifically against these targets have been developed with the hope of improving outcomes. Although recent data with the small molecule EGFR tyrosine kinase inhibitors have been disappointing, there have been instances of dramatic responses thereby raising questions about the ideal patient to whom these drugs should be administered. Cetuximab, the anti-EGFR antibody has shown promising results. Bevacizumab, the anti-VEGF antibody was the first drug to demonstrate a survival benefit in first line treatment when added to chemotherapy. This review will briefly discuss the important trials using these targeted agents in advanced NSCLC.

The epidermal growth factor receptor (EGFR) plays an important role in the carcinogenesis of many human malignancies and is therefore an attractive target against which anticancer therapy may be effective. At present, there are two ways in which this may be achieved clinically: antibodies against EGFR and inhibitors of the EGFR tyrosine kinase. This review describes presently approved agents cetuximab (monoclonal EGFR antibody), gefitinib and erlotinib (EGFR tyrosine kinase inhibitors) in detail. Efficacy data for these agents in various human malignancies is presented. Various other agents that are in the early stages of development at present have also been mentioned.

Abstract: Background: Previous meta-analysis on three drugs combination for treatment of advanced non-small cell lung cancer (NSCLC) did not demonstrate an improvement in survival, however many of the trials included in this meta-analysis used older and less effective cytotoxic drugs. We conducted this analysis to compare the relative efficacy of third generation triplet therapy with that of standard double therapy in the treatment of advanced NSCLC. Methods: A MEDLINE search was performed using the search terms “lung cancer” and “randomized trials”. Trials not utilizing a third generation cytotoxic chemotherapeutic agent (paclitaxel, docetaxel, vinorelbine, gemcitabine) were excluded. Pooled odds ratios (OR) for the objective response and toxicity rates were calculated using the Mantel-Haenszel estimate. Pooled median ratios for median survival were calculated using the weighted sum of the log-ratio of median ratios of individual study. Results: We analyzed six randomized comparative trials involving 1932 patients. Patients receiving triplet therapy had a significantly higher response rate (OR: 1.33; 95% CI, 1.50–2.23; P <0.001). Incidence of grade III/IV hematological toxicity was higher with triplet therapy. Non-hematological toxicities, with the exception of neuropathy, were similar. Median survival of triplet therapy was not significantly different from doublet (MR: 1.10; 95% CI: 0.91–1.35; P =0.059). Conclusions: Triplet therapy with third generation cytotoxic drugs is associated with higher tumor response rate at the expense of increased toxicity. Although triplet therapy had a better overall survival compared to doublet therapy, this did not reach statistical significance. [Copyright &y& Elsevier]