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Journal: Expert review of anticancer therapy

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The majority of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) will recur. The treatment of patients with recurrent/metastatic (R/M) HNSCC) is rapidly evolving. Areas covered: This article will comprehensively review the current systemic treatment of R/M HNSCC. Expert Commentary: For the time being, the EXTREME regimen (cetuximab in combination with platinum and 5-fluorouracil) still remains standard of care in previously untreated R/M HNSCC patients who are candidates for combination chemotherapy. Single agents with well documented activity in HNSCC include methotrexate, cisplatin, 5-FU, docetaxel, and paclitaxel. The anti-PD-1 monoclonal antibody nivolumab can be considered the current standard of care in patients with R/M HNSCC progressing after platinum-based therapy based on the results of CheckMate 141 showing a survival benefit over standard of care drugs, such as single agent weekly cetuximab, methotrexate, or docetaxel. Multiple randomized phase III trials comparing anti-PD(L)-antibodies either as single agent or in combination with chemotherapy or an anti-CTLA-4 with the EXTREME as fist line treatment are ongoing or planned. The outcome of these trials might change the current treatment paradigm in previously untreated R/M HNSCC. Immunotherapeutic agents under active investigation include Toll-like receptor 8 agonists and inhibitors of IDO1.

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Because of their efficacy against numerous cancers, immune-checkpoint inhibitors (ICIs), anti-cytotoxic T-lymphocyte antigen-4 (CTLA4) and anti-programmed cell-death (PD-1) monoclonal antibodies, are being used ever more often in oncology. However, some patients were excluded from clinical trials because of their comorbidities, despite their potentially higher cancer frequencies, as is the case for immunocompromised patients. Areas covered: We analyzed reported preclinical and clinical information and evaluated the risk/benefit ratio for 4 immunocompromised populations: people living with human immunodeficiency virus (PLHs), solid-organ-transplant recipients, recipients of hematopoietic stem-cell allografts and patients with autoimmune diseases. Expert commentary: Information available in the literature is fragmentary and scarce, making it difficult to evaluate the risk/benefit ratio. It can, nonetheless, be noted that ICI use in PLHs seems possible. For solid-organ-transplant recipients, the risk for the graft seems elevated. For the other 2 populations, it is difficult to conclude at this time.

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Chemotherapy and radiation therapy are two mainstream strategies applied in the treatment of cancer that is not operable. Patients with hematological or solid tumor malignancies substantially benefit from chemotherapeutic drugs and/or ionizing radiation delivered to the site of malignancy. However, considerable adverse effects, including lung inflammation and fibrosis, are associated with the use of these treatment modalities. Areas covered: As we move towards the era of precision health, we are compelled to understand the molecular basis of chemoradiation-induced pathological lung remodeling and to develop effective treatment strategies that mitigate the development of chronic lung disease (i.e. fibrosis) in cancer patients. The review discusses chemotherapeutic agents that are reported to induce or associate with acute and/or chronic lung injury. Expert commentary: There is a need to molecularly understand how chemotherapeutic drugs induce or associate with respiratory toxicities and whether such characteristics are inherently related to their anti-tumor effect or are collateral. Once such mechanisms have been identified and/or fully characterized, they may be able to guide disease-management decisions including effective intervention strategies for the adverse effects. In the meantime, radiation oncologists should be judicious on the dose of radiation delivered to the lungs, the volume of lung irradiated, and concurrent use of chemotherapeutic drugs.

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Recently there have been a number of advances in imaging pancreatic neuroendocrine tumors (panNETs), as well as other neuroendocrine tumors (NETs), which have had a profound effect on the management and treatment of these patients, but in some cases are also associated with controversies. Areas covered: These advances are the result of numerous studies attempting to better define the roles of both cross-sectional imaging, endoscopic ultrasound, with or without fine needle aspiration, and molecular imaging in both sporadic and inherited panNET syndromes; the increased attempt to develop imaging parameters that correlate with tumor classification or have prognostic value; the rapidly increasing use of molecular imaging in these tumors and the attempt to develop imaging parameters that correlate with treatment/outcome results. Each of these areas and the associated controversies are reviewed. Expert Commentary: There have been numerous advances in all aspects of the imaging of panNETs, as well as other NETs, in the last few years. The advances are leading to expanded roles of imaging in the management of these patients and the results being seen in panNETs/GI-NETs with these newer techniques are already being used in more common tumors.

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Several recent phase III studies have attempted to improve the dismal survival seen in glioblastoma patients, with disappointing results despite prior promising phase II data. Areas covered: A literature review of prior phase II and phase III studied in glioblastoma was performed to help identify possible areas of concern. Numerous issues in previous phase II trials for glioblastoma were found that may have contributed to these discouraging outcomes and discordant results. Expert Commentary: These concerns include the improper selection of therapeutics warranting investigation in a phase III trial, suboptimal design of phase II studies (often lacking a control arm), absence of molecular data, the use of imaging criteria as a surrogate endpoint, and a lack of pharmacodynamic testing. Hopefully, by recognizing prior phase II trial limitations that contributed to failed phase III trials, we can adapt quickly to improve our ability to accurately discover survival-prolonging treatments for glioblastoma patients.

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Nowadays follicular lymphoma (FL) is considered a virtually incurable disease. Nevertheless, an improvement of prognostic criteria must be pursued in order to achieve new treatment strategies based on a personalized approach. Areas covered: Prognostic scores, old and recent, as well as innovative and experimental therapeutic approaches are constantly evaluated when it comes to discussing the proper approach to FL, due to its extremely variable presentation at diagnosis. For asymptomatic, low-tumor burden FL, a “watch & wait” policy is currently the first-choice approach, although possible alternatives are discussed. Early stage FL may be treated with local radiotherapy although the role of minimal residual disease in possible additional agents should be determined. The first line treatment for symptomatic FL is chemo-immunotherapy followed by two years maintenance therapy with anti-CD20 monoclonal antibodies. A deeper knowledge of FL biology has opened new perspectives regarding the timing of therapy and has offered new targets for the development of novel agents that aim to change the therapeutic scenario of FL management. Expert commentary: The introduction of novel agents could question the incurability of FL and change the therapeutic goal from prolonging the complete remission state to eradicating the disease in young/fit patients, as well as improving quality of life in elderly/unfit patients. In the near future, combining new biologic agents and adoptive cell therapies could help in achieving these aims.

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Endometrial cancer is the most common gynecologic malignancy in the developed world, and its incidence is increasing. Mortality from this cancer has not improved in recent decades and is primarily driven by high-grade carcinomas that are more likely to present at an advanced stage and ultimately are more likely to recur. The prognosis for recurrent endometrial cancer is poor, especially for the 50% of these women that present with extrapelvic disease recurrence. As a standard of care, recurrent disease has been treated with platinum-based chemotherapy; however, new therapies are emerging as we identify drivers of proliferation and metastasis at the cellular and molecular levels. Areas Covered: We review currently available data for the management of recurrent endometrial cancer, with a focus on systemic treatment of recurrent disease. We discuss the available evidence for first-line, second-line, and subsequent systemic therapy and discuss emerging therapeutic targets including their biologic plausibility and early clinical data. Expert Commentary: Endometrial cancer, though prevalent, remains underfunded and understudied. Recurrent and metastatic disease remains difficult to treat, and prospective randomized data are limited. Our ability to reduce mortality due to this cancer is dependent on identifying new and effective therapeutic strategies for recurrent disease.

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In the majority of cases, multiple myeloma is a disease occurring in elderly patients. In the last decades, a major improvement in myeloma patients' outcome has been achieved with the introduction of several new drugs. However, this positive outcome was less likely to occur in elderly patients. Areas covered: An overall increase of myeloma cases in elderly patients is expected in the next years. This patient population is highly heterogeneous in terms of physiological functions and ability to resist stressing conditions such as myeloma and its treatment. While physicians cannot prevent the stress arising from the disease itself, the intensity of therapeutic approaches can be tuned according to patients' predicted tolerance. In this review, we focus on the assessment of patients' fitness and on available significant data on treatment efficacy and tolerability in elderly patients. Expert commentary: Fit, elderly patients should undergo full-dose therapy to maximize the depth of response, while intermediate and frail patients benefit from reduced-dose regimens in order to avoid toxicity and preserve quality of life. Ongoing trials will provide further evidence to individualize treatment on the basis of geriatric assessment and disease characteristics.

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Owing to improvements in clinical care and systemic therapy, more patients are being diagnosed with, and living longer with, spinal metastases (SM). In parallel, tremendous technological progress has been made in the field of radiation oncology. Advances in both software and hardware are able to integrate three- (and four-) dimensional body imaging with spatially accurate treatment delivery methods. This is able to improve the efficacy, shorten the overall treatment schedule and potentially reduce treatment-related toxicity. Areas covered: In this review, we will look at the progress made by stereotactic body radiotherapy (SBRT) in the management of SM. We will review the technological factors which have enabled the widespread use of SBRT. The efficacy of SBRT, in various clinical scenarios, and associated toxicities will be reviewed. Lastly, we will discuss about patient selection, and provide a five-year roadmap. Expert commentary: Spine SBRT is a safe and efficacious treatment option. Practice guidelines recommend the use of SBRT in oligo-metastatic patients especially those with radio-resistant cancer types, and in scenarios involving re-irradiation. SBRT offers patients dose-intensification over a short schedule which may allow less time off systemic therapy. The results of the phase III trials are eagerly awaited.

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Deregulation of the fibroblast growth factor (FGF)/FGF receptor (FGFR) network occurs frequently in tumors due to gene amplification, activating mutations and oncogenic fusions. Thus, the development of FGF/FGFR-targeting therapies is the focus of several basic, preclinical and clinical studies. Areas covered: This review will recapitulate the status of current FGF/FGFR-targeted drugs. Expert commentary: Non-selective FGF/FGFR inhibitors have been approved for cancer treatment but evidence highlights various complications affecting their use in the clinical practice. It appears mandatory to identify FGF/FGFR alterations and appropriate biomarkers that may predict and monitor response to treatment, to establish the contribution of the FGF/FGFR system to the onset of mechanisms of drug resistance and to develop effective combinations of FGF/FGFR inhibitors with other targeted therapies.