TPF: a rational choice for larynx preservation?

For many years, the standard approach for the treatment of resectable squamous cell carcinoma of the head and neck was surgery, with or without subsequent radiotherapy. However, the morbidity associated with this approach, particularly for patients requiring total laryngectomy, can severely impair a patient's quality of life. The finding that patients whose tumors responded to chemotherapy showed a good response to subsequent radiotherapy opened up the possibility of a new organ-preserving management strategy for patients with resectable disease. Randomized studies demonstrated that induction chemotherapy with a cisplatin-5-fluorouracil (5-FU) doublet (PF) prior to radiotherapy enabled larynx preservation in a substantial proportion of patients, compared with surgery plus radiotherapy, without compromising survival. The benefit in terms of larynx preservation when using platinum-based doublet induction chemotherapy followed by radiotherapy, compared with concurrent chemotherapy and radiotherapy, is less clear, although the sequential approach appears to be better tolerated. Adding the taxane docetaxel to PF, to create the TPF triplet regimen, led to significantly higher larynx preservation and laryngectomy-free survival rates than with the PF doublet. TPF is now the accepted standard induction chemotherapy regimen for future clinical trials in resectable disease. Methods for improving postinduction treatment strategies are being explored.     

Induction chemotherapy and larynx preservation: is such practice useful?

BACKGROUND: Surgery followed by irradiation is considered to be the standard treatment but require frequently a total laryngectomy. Chemotherapy followed by irradiation is available in larynx and hypopharynx squamous cell carcinoma (SCC) treatment. Are results obtained in daily induction chemotherapy usefulness identical to results obtained in larynx preservation studies? PATIENTS AND METHOD: We conducted a retrospective study on patients treated at centre Oscar-Lambret, Lille, from 1986 to 1995, by chemotherapy followed by definitive radiotherapy or by surgery and radiotherapy for laryngeal or hypopharyngeal cancer treatment. All patients were naive of previous head and neck SCC and a surgical treatment, requiring total laryngectomy, should be proposed with curative intent. Induction chemotherapy associated cisplatin (100 mg/m2) on day 1 and 5-fluorouracil (5FU)(1,000 mg/m2) on days 1-4 or 1-5. Irradiation was performed for responders (complete or partial > 50%). If case of non-responder, patients underwent surgical treatment followed by irradiation. We compared results obtained with patients enrolled in clinical trial and with patients whom benefited from this protocol out of trial. RESULTS: Hundred-eight patients were evaluable for purposes of this study. Fifty-two patients were included in clinical trial (group 1) while 56 patients (group 2) were not. There was no statistical difference as regard neither to sex nor to node (palpable or not palpable) and metastasis status between the groups. We found a higher frequency of laryngeal tumour in group 2 (31 vs 17; p =.03). We observed more stage III and less stage IV in group 1. For chemotherapy-related toxic reactions, the exclusive statistical difference observed was haematological toxicity grade III and IV after the second cycle (0 pt in group 1 vs 8 pts in group 2; p =.02). After initial treatment, complete response was achieved without statistical difference between the groups (88.2% vs 78%; p =.27). A surgical procedure was performed in 46 cases without difference according to the reference group and functional larynx preservation was 55.8% (29/52) in group 1 and 53.6% (30/56) in group 2. Whatever the group, causes of death were similarly distributed. Cancer was the first cause of death in both groups. The overall survival of the population (108 patients) was 81.5% at one year, 49.6% at 3 years and 35.3% at 5 years with a median survival of 3 years. There was no statistical difference between both groups. Some parameters influenced the overall survival like T (p =.04), response to chemotherapy (p=.006), extra capsular spread (p = 0.03) and response after completion treatment. CONCLUSION: Induction chemotherapy is available for larynx preservation but cannot be considered as a standard treatment. Nevertheless, results should be reproduced in daily practice with experimented teams as found with non included patient's results. The long-term side effects of such protocols should be evaluated. Recent publication, on increase postoperative infection after chemotherapy, should be evaluated in clinical trial. If confirmed, cost effectiveness of such complication must be integrated in larynx preservation protocols. Larynx preservation remains an interesting point of view for patients but stay an optional procedure and not a reference.     

Hypofractioned radiotherapy in prostate cancer: is it the next step?

There are many available options for prostate cancer treatment, including active surveillance, surgery, brachytherapy and external beam radiotherapy. Based on a radiobiological rationale, which considers the prostate tumor as a low α/β tumor, the use of higher and fewer fractions to prostate cancer external beam radiotherapy treatment has been proposed. Instead of the traditional fractions of 1.8–2.0 Gy per day, fractions higher than 2 Gy per day were the subject of a number of studies. In addition, new technologies such as intensity-modulated radiation therapy, image-guided radiation therapy, volumetric-modulated arch therapy and others have emerged as background for changing paradigms. Meanwhile, moderate and ultra-hypofractionation have been the subject of studies in recent years. Some moderate hypofractionation data from randomized controlled trials are ready to use, though other non-inferiority data are still lacking. The data on ultra-hypofractionation are still very new and require further evaluation to determine its long-term safety and efficacy.     

Treatment of locally advanced prostate cancer: is chemotherapy the next step?

PURPOSE: Management of locally advanced prostate cancer remains controversial. Various single and combination modality approaches have been advocated, but an accepted standard of care remains undefined. The purpose of this review is to define the current knowledge in managing locally advanced prostate cancer and to propose new treatment approaches based on current knowledge. MATERIALS AND METHODS: A MEDLINE search to detect all relevant articles on the management of locally advanced prostate cancer was performed. A review of the staging, natural history, and prognosis of this disease was also performed. RESULTS: The lack of a clearly defined treatment approach to patients with locally advanced prostate cancer stems from multiple factors, including ambiguities in clinical staging, inadequate knowledge of the natural history of the cancer, and a dearth of comparative randomized trials evaluating efficacy of different therapies. Single modality treatment, including radical prostatectomy (RP) or external-beam radiotherapy alone, is associated with high rates of failure. The use of adjuvant hormonal ablation therapy in combination with external-beam radiotherapy has shown improvement in progression-free and overall survival, although similar improvements have not been clearly demonstrated for surgical patients treated with hormonal therapy. New advances in chemotherapy for hormone-refractory prostate cancer suggest that response rates may be as high as 50% or more, and current trials are evaluating the addition of chemotherapy to hormonal ablation in either surgery or radiation therapy in locally advanced prostate cancer. CONCLUSION: Optimal management of locally advanced prostate cancer remains undefined. Standard treatment options include RP, external-beam radiotherapy, or hormonal ablation therapy, alone or in combination. New approaches being tested include improved methods for delivering radiation or combining hormonal ablation with surgery or radiation. It is possible that other forms of systemic therapy, including chemotherapy, may become important components of multimodality treatment. Clinical trials designed to test this hypothesis are ongoing.     

Targeted agents and esophageal cancer--the next step?

Esophageal cancer (EC) is an aggressive cancer and is a leading cause of cancer-related death worldwide. In the United States and Western Europe, there has been a decline in the incidence of squamous cell carcinomas coupled with a rapid rise in incidence of adenocarcinoma of the esophagus and gastroesophageal junction. Although the 5-year survival rates have slowly increased over time from 4% to 14%, the outcomes are still dismal. The lack of adequate preventative strategies, inadequate screening techniques, early lymphatic and hematogenous spread, and lack of truly effective therapeutic agents all contribute to the poor outcome. This review will highlight the current status of targeted therapies in EC. This will include a review of agents targeting the vascular endothelial growth factor and epidermal growth factor receptor pathways and trials planned or ongoing to incorporate these and other agents into therapy for advanced disease and into combined modality therapy for early-stage tumors. Further work is required regarding the rational integration of these targeted agents and the optimal selection of patients who will most likely benefit.     

Concomitant chemoradiotherapy for muscle-invasive bladder cancer: the way forward for bladder preservation?

Muscle-invasive bladder cancer is a common malignancy with a high mortality rate. Despite ongoing debates about the optimal primary intervention, radical cystectomy remains the cornerstone of first-line therapy in many institutions. Over the past decade, bladder-preserving strategies involving transurethral resection (TUR), chemotherapy and radiotherapy have evolved. However, the advantage of these approaches over radiation treatment as monotherapy has yet to be fully evaluated. In other tumour models, most notably cervical and anal cancer, radiation and chemotherapy delivered concomitantly have resulted in significant survival advantages. Here, we consider the potential value of this approach in the treatment of invasive bladder cancer. Concomitant chemoradiotherapy is currently the mainstay of several bladder-preserving programmes reported in the medical literature. Overall, local control and survival rates compare favourably with contemporary cystectomy series; however, difficulties in drawing valid conclusions are highlighted. Concomitant chemoradiotherapy may have a role in the management of certain patient subgroups, and the debate should remain open. Further large-scale randomised trials are needed, and information regarding bladder function and quality of life after treatment is lacking at present. The importance of close follow-up and prompt salvage cystectomy is emphasised.     

CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing?

Introduction: The outcome for patients with glioblastoma (GBM) remains poor, and there is an urgent need to develop novel therapeutic approaches. T cells genetically modified with chimeric antigen receptors (CARs) hold the promise to improve outcomes since they recognize and kill cells through different mechanisms than conventional therapeutics.

Areas covered: This article reviews CAR design, tumor associated antigens expressed by GBMs that can be targeted with CAR T cells, preclinical and clinical studies conducted with CAR T cells, and genetic approaches to enhance their effector function.

Expert commentary: While preclinical studies have highlighted the potent anti-GBM activity of CAR T cells, the initial foray of CAR T-cell therapies into the clinic resulted only in limited benefits for GBM patients. Additional genetic modification of CAR T cells has resulted in a significant increase in their anti-GBM activity in preclinical models. We are optimistic that clinical testing of these enhanced CAR T cells will be safe and result in improved anti-glioma activity in GBM patients.     

Beyond BRAF: where next for melanoma therapy?

In recent years, melanoma has become a poster-child for the development of oncogene-directed targeted therapies. This approach, which has been exemplified by the development of small-molecule BRAF inhibitors and the BRAF/MEK inhibitor combination for BRAF-mutant melanoma, has brought new hope to patients. Despite these successes, treatment failure seems near inevitable in the majority of cases—even in individuals treated with the BRAF/MEK inhibitor doublet. In the current review, we discuss the future of combination strategies for patients with BRAF-mutant melanoma as well as the emerging therapeutic options for patients with NRAS-mutant and BRAF/NRAS-wild-type melanoma. We also outline some of the newest developments in the in-depth personalisation of therapy that should allow melanoma treatment to continue shaping the field precision cancer medicine.     

First-line therapy for ovarian carcinoma: what's next?

Based on results from large, randomized trials conducted over the last 25 years, the current standard of care for newly diagnosed advanced (FIGO stage III-IV) ovarian carcinoma is surgical bulk reduction followed by six cycles of paclitaxel plus carboplatin. This approach has resulted in an enhanced response rate and clinical complete response rate, an improved progression-free survival, an increase in survival, and more long-term survivors. Despite these results, the overall frequency of relapse and hence need for second-line therapy is 62%. Ongoing and future studies focus or will focus on four major themes: dose intensity through the use of intraperitoneal chemotherapy in selected patients, addition of a third cytotoxic agent to front line therapy, addition of a targeted or biologic agent to front-line therapy, and the development of effective maintenance or consolidation therapy. The current standard of care for patients who present with limited (FIGO stage I-II) ovarian carcinoma is the use of prognostic factors to classify the patient as at low risk or high risk for recurrence. High risk features include: grade 2 or 3 disease, disease on the surface of the ovary, disease outside the ovary, positive peritoneal cytology, or the presence of ascites. Any one high risk feature makes the patient high risk for recurrence. Patients at low risk require surgical resection only, whereas those at high risk for recurrence require adjuvant therapy. Ongoing studies evaluate the duration of therapy and the potential value of anti-angiogenic agents in those patients at high risk for recurrence. Future directions point to the evaluation of targeted or biologic agents in high risk patients. At present, there is no evidence that any approach constitutes an effective screening test. Studies of serum markers, transvaginal sonography, and serum proteomic profiles have failed to establish any of these techniques as an effective tool for early diagnosis. An overview of current management and its basis will be followed by a discussion of the rationale for both current and potential future trials.     

Is combination therapy the next step to overcome resistance and reduce toxicities in melanoma?

In the last few years, several drugs targeting signalling proteins critical for melanoma entered clinical evaluation. In 2011 vemurafenib (Zelboraf®, F. Hoffman-La Roche Ltd.) was approved for BRAF V600-positive melanoma and showed high overall response rates (48–53%). However recent results from a phase II clinical trial also showed that the median duration of response was 6.7 months and median progression free survival was 6.8 months with tumour relapse. Resistance to targeted agents is quite common and understanding of the underlying molecular mechanisms might predict response or failure. The knowledge of the mechanisms involved in intrinsic and acquired resistance to mutated BRAF is increasing swiftly. Subsequently the elucidation of these mechanisms resulted in the development of rational combination therapies to overcome toxicity and resistance. These combination therapies will be discussed.     

Turning tumour cells into antigen presenting cells: The next step to improve cancer immunotherapy?

Downregulation/loss of the antigen presentation is a major immune escape mechanism in cancer. It allows tumour cells to become ‘invisible’ and avoid immune attack by antitumour T cells. In tumour harbouring properties of professional antigen presenting cells (i.e. tumour B cells in lymphoma), downregulation/loss of the antigen presentation may also prevent direct priming of naïve T cells by tumour cells. Here, we review treatments that may induce/restore antigen presentation by the tumour cells. These treatments may increase the generation of antitumour T cells and/or their capacity to recognise and eliminate tumour cells. By forcing tumour cells to present their antigens, these treatments may sensitise patients to T cell–based immunotherapies, including checkpoint inhibitors.