Neoadjuvant chemotherapy and chemoradiotherapy for non-small cell lung cancer: current status and future prospects

Of the patients with non-small cell lung cancer, 60% present with localised or locally advanced disease. Although they may be considered potentially curable, the vast majority will die, usually from systemic disease. So far, adjuvant (postoperative) therapy has failed to demonstrate benefit. In contrast, chemotherapy has demonstrated clear advantages when administered prior to, or concurrently with radiotherapy in Stage III disease or prior to surgery in Stage III disease. Chemotherapy administered prior to surgery, termed neoadjuvant therapy, in Stage I and II disease has been demonstrated to be feasible. Several trials employing currently available agents have yielded promising results. Whether these regimens will result in an unequivocal benefit is the subject of several ongoing studies in the US and Europe. Current research is focusing on the role of newer drugs including novel antitubulin agents, growth factor receptor antagonists, eicosanoid modulators and various other agents.     

Pharmacotherapy of gestational trophoblastic disease

Gestational trophoblastic neoplasms are the most responsive of all solid tumours to chemotherapy leading to an overall cure rate of > 90%. Nonmetastatic disease (FIGO Stage I) and low-risk metastatic disease (FIGO Stages II and III; WHO score < 7) can be treated with single-agent methotrexate or actinomycin D protocols resulting in a survival rate approaching 100%. Metastatic high-risk disease (FIGO Stage IV or WHO score > 7) should be treated with initial intensive multimodality therapy with combination chemotherapy, consisting of etoposide, high-dose methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) and adjuvant radiotherapy and surgery when indicated. Despite this aggressive approach, ～ 30% of patients with high-risk disease will fail initial therapy or relapse from remission. Salvage chemotherapy with drug regimens containing platinum agents and etoposide, usually in conjunction with bleomycin or ifosfamide, as well as surgical resection of sites of resistant disease, will ultimately result in a survival rate of 80 – 90% for metastatic high-risk disease.     

Pharmacotherapy of gestational trophoblastic disease

Gestational trophoblastic neoplasms are the most responsive of all solid tumours to chemotherapy leading to an overall cure rate of > 90%. Non-metastatic disease (FIGO Stage I) and low-risk metastatic disease (FIGO Stages II and III; WHO score < 7) can be treated with single-agent methotrexate or actinomycin D protocols resulting in a survival rate approaching 100%. Metastatic high-risk disease (FIGO Stage IV or WHO score > 7) should be treated with initial intensive multimodality therapy with combination chemotherapy, consisting of etoposide, high-dose methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) and adjuvant radiotherapy and surgery when indicated. Despite this aggressive approach, approximately 30% of patients with high-risk disease will fail initial therapy or relapse from remission. Salvage chemotherapy with drug regimens containing platinum agents and etoposide, usually in conjunction with bleomycin or ifosfamide, as well as surgical resection of sites of resistant disease, will ultimately result in a survival rate of 80 - 90% for metastatic high-risk disease.     

Neoadjuvant therapy for resectable and borderline resectable adenocarcinoma of the pancreas

For over 25 years, the standard of care for resectable pancreatic adenocarcinoma has been upfront surgery followed by delivery of post-operative therapy. Until recently however, there has been no consensus as what constituted a standard adjuvant regimen. Data from large phase III studies now support single agent gemcitabine, administered over 6 cycles, as standard. Nevertheless, the overall survival of patients undergoing upfront surgical resection followed by adjuvant therapy remains poor, with no significant improvements in median, or long term survival over the last 3 decades. Surgery as the first intervention for potentially curative pancreatic cancer has some distinct disadvantages and neoadjuvant therapy provides a mechanism to better select patients for subsequent surgical intervention. Current data suggest this approach spares patients from a morbid surgical procedure when it will be of no benefit and improves outcomes for those who do undergo surgery. Furthermore, with the increasing recognition of borderline resectable pancreatic cancer, neoadjuvant treatment should be considered as alternative to upfront surgery for this distinct clinical entity. This has the potential to maximize the chances of a margin-negative resection and minimize the number of patients harboring aggressive disease from undergoing a fruitless surgical procedure. Importantly, as the number of targeted agents available for clinical use expands, more rational, personalized neoadjuvant therapies may emerge.     

Current chemotherapy options for thymic epithelial neoplasms

Thymomas and thymic carcinoma are rare neoplasms. Surgical resection is the cornerstone of effective therapy. Stage I disease is effectively treated by complete surgical resection. The role of radiation therapy in completely resected stage II disease remains controversial. Adjuvant radiation therapy is useful for local control and may improve survival in patients with incompletely resected tumours. Cisplatin-based chemotherapy regimens play an important role in the treatment of advanced stage III/IV or recurrent disease thymomas, but have proven less effective for thymic carcinoma. Phase II trials of multimodality therapy incorporating neoadjuvant chemotherapy, surgery and postoperative radiation therapy show promise for unresectable disease. This review discusses recent clinical data and the potential role for agents targeting the epidermal growth factor receptor, angiogenesis and apoptotic pathways.     

Current chemotherapy options for thymic epithelial neoplasms

Thymomas and thymic carcinoma are rare neoplasms. Surgical resection is the cornerstone of effective therapy. Stage I disease is effectively treated by complete surgical resection. The role of radiation therapy in completely resected stage II disease remains controversial. Adjuvant radiation therapy is useful for local control and may improve survival in patients with incompletely resected tumours. Cisplatin-based chemotherapy regimens play an important role in the treatment of advanced stage III/IV or recurrent disease thymomas, but have proven less effective for thymic carcinoma. Phase II trials of multimodality therapy incorporating neoadjuvant chemotherapy, surgery and postoperative radiation therapy show promise for unresectable disease. This review discusses recent clinical data and the potential role for agents targeting the epidermal growth factor receptor, angiogenesis and apoptotic pathways.     

Genomic profiling associated with recurrence in patients with rectal cancer treated with chemoradiation

PURPOSE: Stage II and III adenocarcinoma of the rectum has an overall 5-year survival rate of approximately 50%, and tumor recurrence remains a major problem despite an improvement in local control through chemotherapy and radiation. The efficacy of chemoradiation therapy may be significantly compromised as a result of interindividual variations in clinical response and host toxicity. Therefore, it is imperative to identify those patients who will benefit from chemoradiation therapy and those who will develop recurrent disease. In this study, we tested whether a specific pattern of 21 polymorphisms in 18 genes involved in the critical pathways of cancer progression (i.e., drug metabolism, tumor microenvironment, cell cycle regulation, and DNA repair) will predict the risk of tumor recurrence in rectal cancer patients treated with chemoradiation. PATIENTS AND METHODS: A total of 90 patients with Stage II or III rectal cancer treated with chemoradiation were genotyped using polymerase chain reaction (PCR)-based techniques for 21 polymorphisms. RESULTS: A polymorphism in interleukin (IL)-8 was individually associated with risk of recurrence. Classification and regression tree analysis of all polymorphisms and clinical variables developed a risk tree including the following variables: node status, IL-8, intracellular adhesion molecule-1, transforming growth factor-beta, and fibroblast growth factor receptor 4. CONCLUSION: Genomic profiling may help to identify patients who are at high risk for developing tumor recurrence, and those who are more likely to benefit from chemoradiation therapy. A larger prospective study is needed to validate these preliminary data using germline polymorphisms on tumor recurrences in rectal cancer patients treated with chemoradiation.     

Goserelin acetate in combination with radiotherapy for prostate cancer

Improvements in longer-term survival rates have been demonstrated for locally advanced prostate cancer patients treated with adjuvant androgen deprivation therapy (ADT), and in subsets of men with clinically localized disease treated with ADT combined with external-beam radiotherapy (RT). In these studies, ADT was administered in the form of surgery (orchiectomy) or with a class of drugs called luteinizing hormone-releasing hormone agonists. Goserelin acetate is a member of this class, and 10 of 11 major Phase III trials demonstrating better outcomes with ADT and RT used goserelin acetate. The reduction in deaths from prostate cancer noted in the mid-1990s may largely be due to the early use of these agents in men with intermediate-to-high-risk disease.     

Treating systemic prostate cancer: emerging drug targets and therapies

Prostate cancer is the most common cancer among men and is the second most common cause of cancer death. Although more patients are now diagnosed with localised prostate cancer since the advent of prostate specific antigen (PSA) screening, 30 - 40% will develop recurrent disease even following definitive therapy with either surgery or radiation. Patients who develop recurrent disease may be treated with androgen deprivation strategies, however within 1 - 2 years, most patients will develop androgen independent prostate cancer (AIPC). While chemotherapy has been shown to have palliative benefit in this situation, there is no evidence of prolonged survival. Given the shear numbers of patients with this disease and its inexorable progression to AIPC for which no life prolonging therapy exists, there clearly is a need for improved treatment strategies for systemic prostate cancer. Research in this area includes testing combinations of previously studied chemotherapeutic agents as well as the identification and testing of novel agents. It is these drugs that are designed to target strategic pathways to improve survival and increase quality of life in these patients. In this paper, we will not review traditional chemotherapeutic agents but discuss several key potential areas of targeted therapy for prostate cancer.     

The role of antiangiogenetic agents in the treatment of breast cancer

Angiogenesis is known to be essential for the development and progression of cancer. Vascular endothelial growth factor (VEGF) is a critical mediator in tumor angiogenesis for many solid malignancies, including breast cancer. Increased levels of VEGF have been associated with poor clinical outcomes, including reduced survival. VEGF has become an attractive target for cancer therapy in view of its pivotal role in angiogenesis. The primary approaches for inhibiting angiogenesis have focused on inhibiting the activity of VEGF, either by targeting the VEGF ligand itself with monoclonal antibodies (mAbs) or by interfering with the signaling events downstream of VEGF through the use of tyrosine kinase inhibitors (TKIs). Bevacizumab is a recombinant, humanized monoclonal IgG1, anti-VEGF antibody that has demonstrated significant clinical benefit in several solid tumors. Bevacizumab has been approved for use in combination with paclitaxel for the first line treatment of patients with metastatic breast cancer (MBC) based on the results of the randomized phase III E2100 trial in which it improves response rate and time to progress when administered with weekly paclitaxel until disease progression. Several trials to define the role of bevacizumab in different setting of disease and in combination with different chemotherapy regimens and targeted therapy in breast cancer patients are ongoing. Other small molecule inhibitors of VEGF tyrosine kinase activity (TKIs) such as sunitinib, vandetanib and sorafenib are being tested in MBC. This review will focus on bevacizumab and on the developements of the main antiangiogenic agents in the treatment of breast cancer.     

Which drug combination for colorectal cancer?

In Westernised countries, colorectal cancer (CRC) is second only to lung cancer as a cause of death from malignancy, with only 60% of patients alive at 5 years. In Stage II/III CRC, where the standard treatment is 5-fluorouracil (5-FU)/leucovorin, a recent clinical trial has shown that with the addition of oxaliplatin, fewer patients have relapsed or died at 40 months follow-up. The benefit was more pronounced in patients with Stage III than II CRC, and the addition of oxaliplatin to 5-FU/leucovorin should be considered in Stage III CRC. In metastatic CRC, where the standard treatment is 5-FU/leucovorin/irinotecan, a recent clinical trial has shown that the addition of bevacizumab, a mAb, to vascular endothelial growth factor, prolonged progression-free and overall survival. Bevacizumab is likely to become part of the standard therapy for metastatic CRC.     

Which drug combination for colorectal cancer?

In Westernised countries, colorectal cancer (CRC) is second only to lung cancer as a cause of death from malignancy, with only 60% of patients alive at 5 years. In Stage II/III CRC, where the standard treatment is 5-fluorouracil (5-FU)/leucovorin, a recent clinical trial has shown that with the addition of oxaliplatin, fewer patients have relapsed or died at 40 months follow-up. The benefit was more pronounced in patients with Stage III than II CRC, and the addition of oxaliplatin to 5-FU/leucovorin should be considered in Stage III CRC. In metastatic CRC, where the standard treatment is 5-FU/leucovorin/irinotecan, a recent clinical trial has shown that the addition of bevacizumab, a mAb, to vascular endothelial growth factor, prolonged progression-free and overall survival. Bevacizumab is likely to become part of the standard therapy for metastatic CRC.     

Emerging drugs for head and neck cancer

Head and neck cancer is a challenging disease. The treatment is quite complex and significant toxicity is seen with the combination of chemotherapy, radiation therapy and surgery. The present standard of care is chemoradiotherapy for most sites in the head and neck area for patients with locally advanced, unresectable disease and in patients treated for organ preservation. The recent approval of cetuximab, an EGF receptor inhibitor, for head and neck cancer in combination with radiotherapy represent an opportunity to improve the outcome for these patients, and the inclusion of this antibody within the chemoradiotherapy approaches will be studied in Phase III trials. In addition, a significant shift is occurring with the inclusion of more aggressive chemotherapy upfront, prior to chemoradiotherapy. This approach, known as sequential chemoradiotherapy, is the basis of many recently completed Phase III trials. Docetaxel, cisplatin and 5-fluorouracil appears to be the most effective induction chemotherapy regimen and is the new induction ‘standard’ that is being used by many cancer centres and intergroups going forward. It is also a new platform that will be used to add new targeted agents to induction chemotherapy.     

Emerging drugs for head and neck cancer

Head and neck cancer is a challenging disease. The treatment is quite complex and significant toxicity is seen with the combination of chemotherapy, radiation therapy and surgery. The present standard of care is chemoradiotherapy for most sites in the head and neck area for patients with locally advanced, unresectable disease and in patients treated for organ preservation. The recent approval of cetuximab, an EGF receptor inhibitor, for head and neck cancer in combination with radiotherapy represent an opportunity to improve the outcome for these patients, and the inclusion of this antibody within the chemoradiotherapy approaches will be studied in Phase III trials. In addition, a significant shift is occurring with the inclusion of more aggressive chemotherapy upfront, prior to chemoradiotherapy. This approach, known as sequential chemoradiotherapy, is the basis of many recently completed Phase III trials. Docetaxel, cisplatin and 5-fluorouracil appears to be the most effective induction chemotherapy regimen and is the new induction 'standard' that is being used by many cancer centres and intergroups going forward. It is also a new platform that will be used to add new targeted agents to induction chemotherapy.     

Duration of therapy in metastatic breast cancer: management using Herceptin

Despite progressive developments in therapeutic interventions, including surgery, radiotherapy and chemotherapy, there has been no major improvement in the survival of women with metastatic breast cancer (MBC). Based on knowledge of tumor growth patterns, approaches addressing this issue have included increasing chemotherapy dose or dose density and extending the duration of therapy. However, only the latter approach has resulted in improved clinical benefit, although not survival; and its use is restricted by the cumulative toxicity of chemotherapeutic agents. Therefore, the best hope for improved survival lies with new classes of anticancer drug and particularly biological agents. This review focuses on the first oncogene-targeted therapy for human epidermal growth factor receptor-2 (HER2)+ MBC patients. The humanized anti-HER2 monoclonal antibody Herceptin has proven clinical benefits in HER2+ MBC patients, most importantly improved survival, and is rapidly becoming a standard of care for these patients. In contrast to the fixed number of cycles used for chemotherapeutic agents, Herceptin is administered until disease progression, with some data suggesting that continuation beyond disease progression should be investigated. The preclinical and clinical findings on which the current recommended duration of Herceptin therapy are based are reviewed and alternative strategies are discussed.     

Review article: management of peptic ulcer bleeding-the roles of proton pump inhibitors and Helicobacter pylori eradication

Peptic ulcer bleeding is associated with substantial morbidity and mortality. The goals of management are to control any active bleeding and prevent re-bleeding and then to heal the ulcer and prevent its recurrence. Initial management strategies are guided by the patient's clinical condition and endoscopic findings. Thus, treatment may consist of endoscopic and medical therapy and, sometimes, surgery. Control of acid secretion, preferably with proton pump inhibitor therapy in the initial management continues to evolve; it has also been used as both an adjunct to endoscopic therapy and as primary treatment. These agents have been found to be effective in some trials in the reduction of re-bleeding and the need for surgery, although there is no clear benefit demonstrated for overall mortality. Proton pump inhibitors have been administered either intravenously or orally in different trials. The long-term management of patients with peptic ulcer, after the initial bleeding episode, should include patient stratification based upon risk factors for ulcer recurrence (i.e. Helicobacter pylori infection, use of aspirin or nonsteroidal anti-inflammatory drugs). Elimination or modification of these risk factors reduces the risk of ulcer recurrence and, hence, of recurrent ulcer bleeding.     

Epidermal growth factor receptor inhibitors: an update on their development as cancer therapeutics

Therapeutic agents targeting the epidermal growth factor receptor (EGFR) have recently been approved for use in patients based on the results of large-scale phase II studies involving patients with advanced refractory non-small-cell lung cancer (NSCLC). Disappointingly, results from phase III trials of gefitinib in combination with standard chemotherapy regimens for the treatment of NSCLC were negative. While results from phase III trials with other agents such as erlotinib and cetuximab will be reported in the next 12 to 18 months, the early results raise a number of questions regarding the development of these agents, including patient selection (e.g., disease, stage, prior therapy, EGFR or other biomarker expression) and combinations with standard treatment regimens as well as hormonal agents, radiation or other novel agents which will require further elucidation. Early data suggest a number of potential roles for these agents in the modulation of resistance and in combination with other inhibitors of signal transduction.     

New directions in the management of advanced pancreatic cancer: a review

Complete surgical resection is the only potentially curative option for pancreatic cancer. However, most patients have advanced/metastatic disease at the time of diagnosis, or will relapse after surgery. Systemic chemotherapy is only palliative. Gemcitabine-based therapy is an acceptable standard for unresectable locally advanced/metastatic pancreatic cancer, but average median survival is only 6 months. The addition of other chemotherapies (including other antimetabolites, platinum, and topoisomerase I inhibitors) or targeted therapies (farnesyl transferase inhibitors, metalloproteinase inhibitors, cetuximab and bevacizumab) to gemcitabine has failed to improve outcome. The combination of gemcitabine and erlotinib, a small-molecule tyrosine kinase inhibitor of the human epidermal growth factor receptor, was recently approved by the US/European authorities for use in advanced disease. In a phase III trial, the combination demonstrated a significant improvement in overall survival compared with gemcitabine monotherapy. Positive efficacy results have also been observed in a phase III trial, favoring the addition of capecitabine to gemcitabine compared with gemcitabine alone. This review focuses on the recent developments in systemic treatment, and discusses how novel agents might be incorporated into future treatment strategies for pancreatic cancer.     

Pergolide. A review of its pharmacological properties and therapeutic potential in Parkinson's disease

When used to treat patients with Parkinson's disease pergolide acts at dopamine receptors in the corpus striatum to improve locomotor activity, reducing the tremor, gait disturbances, bradykinesia or akinesia and rigidity experienced by such patients. Treatment with pergolide often allows substantial reductions in concomitant levodopa dosage, and occasionally levodopa can be completely replaced by pergolide therapy in short term use. Pergolide has a long duration of action, thus reducing the wearing-off and end-of-dose phenomena frequently seen with long term levodopa therapy, suppressing fluctuations in levodopa response, and increasing total 'on' time. Despite a lack of well controlled studies comparing this drug with other dopamine agonist agents, pergolide appears to result in adverse effects and anti-Parkinson responses similar to those of bromocriptine and lisuride. Thus, pergolide would appear to be at least as useful as other dopamine agonists such as bromocriptine or lisuride for the management of patients with Parkinson's disease when administered in combination with levodopa. Future research should be directed towards establishing which patients are most likely to benefit from pergolide therapy, and clarifying the relative efficacy and safety of the anti-Parkinsonian drugs available to the clinician. If pergolide does provide clinical benefit when substituted for levodopa-adjunct drugs that are producing less than optimal control, this will be an advantage in a disease area which at present has few therapeutic options.     

Novel oral anticoagulants and their role in clinical practice

The complexities of oral anticoagulation with warfarin have led to the search for more practical alternative agents. Novel direct factor IIa inhibitors and direct factor Xa inhibitors currently in development can be administered at a fixed dose and do not require routine coagulation monitoring and ongoing dosage adjustment to ensure their effectiveness and safety. A number of phase III trials of these agents for the prevention of venous thromboembolism associated with orthopedic surgery and acute medical illness, for the treatment of venous thromboembolism, and for stroke prevention in patients with atrial fibrillation have been completed, with almost universally positive results. If these novel agents are approved for use in the United States, the future of oral anticoagulant therapy will allow a more nuanced approach to drug selection than has been available in the past. Attention to drug interactions and renal function will be required, as methods to measure the presence of these agents are not precise, cannot quantify the degree of anticoagulant present, and are influenced by the changes in serum drug concentrations during the dosing interval. In the future, patient preferences and the pharmacokinetic and pharmacodynamic characteristics of individual drugs will be able to be matched to optimize therapy. These new agents represent a new paradigm for anticoagulation that promises to improve patient care in the long term.