Particle therapy in lung cancer: Where do we stand?

BACKGROUND: From a theoretical point of view, charged particles should lead to superior results compared to photons. In this review, we searched for clinical evidence that protons or C-ions are really beneficial to patients with lung cancer. METHODS: A systematic literature review based on an earlier published comprehensive review was performed and updated until November 1st 2007. RESULTS: Ten fully published series, all dealing with non-small cell lung cancer (NSCLC), mainly stage I, were identified. No phase III trials were found. On proton therapy, 2-5 year local tumor control rates varied between 87% and 57%. The 2 year/5 year overall survival and 2 year/5 year cause specific survival varied between 31-74%/23% and 58-86%/46%, respectively. Late side effects were observed in about 10% of the patients. For C-ion therapy, the local tumor control rate was 77%, while 95% when using a hypofractionated radiation schedule. The 5 year overall survival and cause specific survival rates were 42% and 60%, respectively. Slightly better results were reported when using hypofractionation, 50% and 76%, respectively. The reported late side effects for C-ions were 4%. CONCLUSION: The results with charged particles, at least for stage I disease, seem to be promising. A gain can be expected in reduction of late side effects, especially after treatment with C-ions. Available data demonstrate that particle therapy in general is a safe and feasible treatment modality. Although current results are promising, more evidence is required before particle therapy can become internationally the standard treatment for (subsets of) lung cancer patients.     

Targeted therapy in advanced non-small cell lung cancer (NSCLC): Where do we stand?

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.     

Antiangiogenic agents in the management of non-small cell lung cancer: Where do we stand now and where are we headed?

Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, BIBF 1120, sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751, and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.     

Postoperative radiation therapy for lung cancer: where do we stand?

Lung cancer is the leading cause of cancer mortality in the United States. Local recurrence after surgery for operable disease has long been recognized as a hindrance to long-term survival. Postoperative radiation therapy was logically explored as a means to improve local control and survival. Multiple randomized trials were conducted, many showing improved local control, but none demonstrated a statistically significant survival benefit. In fact, a meta-analysis showed a rather large survival detriment, presumably from treatment-related complications. Radiation therapy has evolved over the years, and more modern treatment planning and delivery has the potential to treat sites deemed at high risk of recurrence while limiting the dose to critical intrathoracic structures, which should decrease the risk of treatment-related complications. Recent studies have supported this supposition. Similarly, since cancer is often a systemic disease, local control will become a more pressing issue as systemic micrometastatic disease is eradicated with effective chemotherapy. Unfortunately, randomized trials testing the effectiveness of modern postoperative radiation therapy in the chemotherapy era have not been performed. Clinicians must therefore counsel patients regarding the risk of disease recurrence after surgery, the potential but unproven benefit of postoperative radiation therapy, and the possibility of treatment-related complications.     

Pleural lavage cytology: Where do we stand?

Although a malignant pleural effusion is considered a manifestation of an advanced stage disease not amenable to curative resection in patients with non-small cell lung cancer, the same is not true in the case of the presence of malignant cells in the pleural cavity without an accompanying effusion, discovered incidentally during the operation with pleural lavage cytology (PLC). PLC is a diagnostic technique used to detect tumor cells and translate this finding to a prognostic index. Various reports have attempted to utilize the results of PLC and draw inferences regarding the origins of malignant cells in the pleural cavity, the association of these results with various disease characteristics and, most importantly, their impact on disease recurrence and survival. However, due to non-consistent techniques and protocols used to acquire the samples for cytological evaluation and assess their significance, results are inhomogeneous. Nevertheless, the entrance of malignant cells in the pleural cavity follows the rules posed by the natural disease process when discovered before pulmonary resection takes place, while surgical manipulations certainly play an important role in the case malignant cells are checked over after pulmonary resection. In addition, although the prognostic significance of a positive PLC result is indisputable and significantly decreases long-term survival in the majority of studies, this factor has not yet been incorporated into the TNM staging system. Lastly, some authors have advocated the use of some form of adjuvant treatment for those patients found with positive PLC results, based on the assumption that a curative resection followed by multiple pleural washings will not remove the entirety of the population of malignant cells present in the pleural space.     

Vascular-targeting agents and radiation therapy in lung cancer: where do we stand in 2005?

With recent Food and Drug Administration approval of the anti-vascular endothelial growth factor (VEGF) antibody for the treatment of colon cancer, it may be possible to achieve similar progress in the treatment of locally advanced lung cancer. Antiangiogenic therapies in the clinic are a reality, and it is important to demonstrate that they can be used safely with conventional modalities, including radiation therapy (RT). Strategies under scrutiny in preclinical and clinical studies include the use of endogenous inhibitors of angiogenesis, use of agents that target VEGF and VEGF receptor signaling, targeting endothelial-related integrins during angiogenesis, and targeting the preexisting immature vessels growing within tumors (ie, vascular targeting). Regardless of the approach, it is necessary to address whether angiogenesis is a consistent phenomenon within the lung parenchyma around a cancer and a relevant target and whether inhibiting angiogenesis will improve current lung cancer therapies without increasing toxicity. Vascular-targeting agents (VTAs) are an interesting class of agents that have the potential to enhance RT, but their clinical promise has yet to be realized. In preclinical models, these agents selectively destroy the tumor vasculature, initiating a rapid centralized necrosis within established tumors. Characteristically, after treatment with VTAs, a rim of viable tumor cells remains at the periphery of the tumor, which remains well perfused and should therefore be relatively sensitive to radiation-induced cytotoxicity. This review will focus on VTAs in the treatment of lung cancer and includes a discussion of combination studies with RT in the laboratory and some of the hurdles in the clinical application of these agents.     

Adjuvant endocrine therapy in postmenopausal women with early breast cancer: Where are we now?

Tamoxifen has been the standard of care for adjuvant endocrine therapy of early breast cancer. In postmenopausal women, data now suggest that alternative agents (aromatase inhibitors [AIs]) may have improved long-term risk:benefit profiles and thus have the potential to improve outcome. The 'Arimidex', Tamoxifen, alone or in combination (ATAC) trial has shown that anastrozole provides improved disease-free survival (DFS) and time to recurrence, significantly reduced time to distant metastases and superior overall tolerability compared with tamoxifen when used as initial adjuvant therapy. Results have already led to a reconsideration of current recommendations for adjuvant therapy. Other ongoing trials include studies that are evaluating the benefits of sequencing of endocrine agents both within the standard 5-year adjuvant treatment period and as additional therapy in the post-adjuvant period. Three recently reported trials have suggested that switching from tamoxifen to an AI after 2-3 years of treatment leads to better outcomes than 5 years of tamoxifen. Finally, the NCIC MA 17 trial has shown that switching to an AI after 5 years of tamoxifen improves DFS compared with placebo. These are momentous discoveries that have improved our biological understanding and will inevitably change the management of breast cancer in the near future.     

Where do we stand with 5-fluorouracil?

For nearly four decades, 5-fluorouracil (5-FU) has been the mainstay of treatment for colorectal cancer. Due to the lack of other agents with significant activity, tremendous efforts have been undertaken to increase the efficacy of 5-FU by investigating alternative schedules of delivery and biomodulation. However, bolus 5-FU in combination with folinic acid (FA), either as the Mayo Clinic or Roswell Park protocol, still represents the standard treatment for adjuvant and first-line palliative chemotherapy of colorectal cancer. In a recent meta-analysis, infusional protocols of 5-FU demonstrated increased response rates (14% to 22%) and a marginal, but significant survival benefit of 3 weeks (11.3 to 12.1 months). In view of the much higher costs and complicated management of infusional 5-FU regimens, this marginal survival benefit does not yet allow protracted 5-FU application to be defined as standard therapy. However, protracted 5-FU infusion in combination with radiation can be considered standard therapy as adjuvant treatment of rectal cancer, since it has demonstrated a significant increase in survival. In the future, oral 5-FU prodrugs may be substituted for infusional 5-FU. Furthermore, current data indicate that 5-FU will also be an essential component of combination chemotherapy protocols with the new active agents oxaliplatin, irinotecan, and raltitrexed. Preclinical studies show synergistic antitumor activity of 5-FU with these agents, which corresponds well with clinical response rates of 50% in untreated and 15% to 25% in 5-FU-refractory patients. Moreover, 5-FU-based pro-drug-active drug systems serve as excellent models for tumor-targeted gene therapy.     

Ethnicity and breast cancer in the UK: Where are we now?

Outcomes from breast cancer for women in the UK have improved significantly over recent decades. These gains are largely attributable to a combination of earlier diagnosis and access to treatments delivered to patients by the National Health Service irrespective of cost. Ethnic minority groups make up almost fifteen percent of the UK population and there is concern however that these groups may have poorer outcomes from the disease. In this short report we seek to summarise what the current evidence tells us about the patterns of breast cancer incidence and outcomes in ethnic minority women in the UK in order to raise awareness about this topic and provide consideration for what future research is needed to address the gaps that may exist.     

Adjuvant treatment in non-small cell lung cancer: Where are we now?

Lung cancer is the most common cancer worldwide, accounting for 1.2 million new cases annually. Despite aggressive local management of patients diagnosed with early-stage disease (stages I-IIIA), more than half of patients who have undergone surgical resection will die from complications caused by recurrent lung cancer. Over the past 5 years, results from several large trials assessing the use of adjuvant platinum-based chemotherapy in non-small cell lung cancer have become available. This article reviews the data from the most prominent of these trials and focuses on how the combination of cisplatin and etoposide has been evaluated for use in the adjuvant setting. Cisplatin-based therapy has now been shown to provide a significant survival benefit in several trials and recent meta-analyses. These data have changed the paradigm for how early-stage lung cancer is managed.     

Personalized therapy for hepatocellular carcinoma: Where are we now?

Following the approval of sorafenib, a large number of molecular targeted agents have been tested clinically for advanced hepatocellular carcinoma (HCC), but all have failed to demonstrate significant efficacy in clinical trials. Multiple reasons for this phenomenon have been discussed in the literature, with one reason being the lack of patient selection on the basis of molecular profile in clinical trials. The concept of drug testing in selected populations has been recently suggested by retrospective analyses of HCC clinical trials in which a particular subgroup of patients, either enriched by clinical factors or by tissue biomarkers, derived more benefits from the novel drug. In addition, recent advances in genomic medicine have enhanced the understanding of genetic and epigenetic events occurring in HCC, raising the possibility of personalizing targeted agents in accordance with the genetic make-up of the tumors. The development of ‘personalized’ treatment for HCC is, however, hindered by the lack of fresh biopsy of advanced HCC, the low incidence of genetic driver mutations in HCC and the tumor heterogeneity. These limitations may be overcome by sequencing cell-free DNA in plasma, frequently known as liquid biopsy, and revolution in the concept of the design of clinical trials. In this review article, we aim to: (1) give a summary of the recent sequencing results of HCC and the related implications for drug development; (2) highlight potential individual targeted agents and existing research on biomarker selection in clinical trials; and (3) discuss future directions, including the potential of liquid biopsy and umbrella clinical trials, to enhance personalized drug testing for HCC.     

Where do we stand with hepatoblastoma? A review

Hepatoblastoma (HB) is the most common pediatric liver malignancy, comprising approximately 1% of all pediatric cancers. The disparate clinical staging systems and histologic classifications that were developed during the last decades, nevertheless, reflect the remaining difficulties and uncertainties in characterizing HB. Furthermore, the combination of surgery and (neo)adjuvant chemotherapy has improved patient outcomes dramatically. A poor prognosis is associated with large tumor size, multifocality, extrahepatic disease, and metastatic spread. The exact etiology of HB remains unknown, but the cytogenetic alterations, phenotypic features, and biologic aspects that accompany this neoplasm yield more and more insight into its pathogenesis. New cell-biologic and molecular-biologic insights may lead to the development of new treatment modalities, especially for patients with a bad prognosis. This review summarizes the different aspects of this intriguing tumor and discusses the current status of research and treatment for patients with HB.     

Recent translational research: antiangiogenic therapy for breast cancer – where do we stand?

The central importance of angiogenesis and our understanding of how new blood vessels are formed have led to the development of novel antiangiogenic therapies. Although the number of agents in development has grown exponentially, only one phase III trial in breast cancer has been completed. In that study the addition of bevacizumab to capecitabine did not extend the progression-free survival of patients with refractory disease as compared with capecitabine monotherapy. Early enthusiasm for antiangiogenic therapy must give way to clinical reality. Our challenge now is to exploit better the activity of antiangiogenic agents seen in the early clinical studies.     

Prevention of ER-negative breast cancer: where do we stand?

Oestrogen receptor-negative and triple-negative breast cancers are types of aggressive tumours that account for approximately 30 and 15% of total breast cancers, respectively. Selective oestrogen receptor modulators and aromatase inhibitors are unable to treat and prevent these subtypes of mammary tumours. Thus, it is worth identifying new pathways, biomarkers, and agents that are effective in the treatment and prevention of these subtypes. Several classes of drugs have been studied, and many are still currently under investigation. We have attempted to conduct a state-of-the-art study on this important issue.     

Use of radiomics in the radiation oncology setting: Where do we stand and what do we need?

Radiomics is a field that has been growing rapidly for the past ten years in medical imaging and more particularly in oncology where the primary objective is to contribute to personalised and predictive medicine. This short review aimed at providing some insights regarding the potential value of radiomics for cancer patients treated with radiotherapy. Radiomics may contribute to each stage of the patients’ management: diagnosis, planning, treatment monitoring and post-treatment follow-up (toxicity and response). However, its applicability in clinical routine is currently hindered by several factors, including lack of automation, standardisation and harmonisation. A major effort must be carried out to automate the workflow, standardise radiomics good practices and carry out large-scale studies before any transfer to daily clinical practice.     

Stereotactic body radiation therapy (SBRT) for high-risk prostate cancer: Where are we now?

Purpose

Stereotactic body radiation therapy (SBRT) is increasingly being used for the management of localized prostate cancer. This trend combined with declining use of brachytherapy (BT) has pushed issues and questions regarding the use of SBRT to the forefront. A systematic literature review was conducted to review the current evidence of biochemical disease-free survival (bDFS) and toxicity of SBRT in high-risk (HR) prostate cancer.

Small cell lung cancer: Where do we go from here?

Small cell lung cancer (SCLC) is an aggressive disease that accounts for approximately 14% of all lung cancers. In the United States, approximately 31,000 patients are diagnosed annually with SCLC. Despite numerous clinical trials, including at least 40 phase 3 trials since the 1970s, systemic treatment for patients with SCLC has not changed significantly in the past several decades. Consequently, the 5‐year survival rate remains low at <7% overall, and most patients survive for only 1 year or less after diagnosis. Unlike nonsmall cell lung cancer (NSCLC), in which major advances have been made using targeted therapies, there are still no approved targeted drugs for SCLC. Significant barriers to progress in SCLC include 1) a lack of early detection modalities, 2) limited tumor tissue for translational research (eg, molecular profiling of DNA, RNA, and/or protein alterations) because of small diagnostic biopsies and the rare use of surgical resection in standard treatment, and 3) rapid disease progression with poor understanding of the mechanisms contributing to therapeutic resistance. In this report, the authors review the current state of SCLC treatment, recent advances in current understanding of the underlying disease biology, and opportunities to advance translational research and therapeutic approaches for patients with SCLC. Cancer 2015;121:664–672. © 2014 American Cancer Society.