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Clinical Status and Optimal Use of Rituximab for B-Cell LymphomasRituximab (IDEC-C2B8 [Rituxan]) is a chimeric anti-CD20 monoclonal antibody (MoAb) that was recently approved by the FDA for the treatment of patients with low-grade or follicular B-cell non-Hodgkin’s lymphoma. Its potential efficacy in other B-cell malignancies is currently being explored. This article reviews the mechanisms of action of rituximab, as well as preclinical data and results of the clinical trials that led to its approval. Also discussed are the mechanics of administering rituximab on the recommended weekly ´ 4 outpatient schedule. Finally, the article describes ongoing and planned trials of rituximab in other dosage schedules, in other B-cell neoplasms, and in conjunction with chemotherapy. As the first MoAb to gain FDA approval for the treatment of a malignancy, rituximab signals the beginning of a promising new era in cancer therapy. [ONCOLOGY 12(12):1763-1770, 1998]
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Recent Progress in Radioimmunotherapy for CancerRadioimmunotherapy allows for the delivery of systemically targeted radiation to areas of disease while relatively sparing normal tissues. Despite numerous challenges, considerable progress has been made in the application of radioimmunotherapy to a wide variety of human malignancies. The greatest successes have occurred in the treatment of hematologic malignancies. Radioimmunotherapy, with or without stem-cell transplant support, has produced substantial complete remission rates in chemotherapy-resistant B-cell lymphomas. Nonmyeloablative regimens have shown so much promise that they are now being tested as initial therapy for low-grade B-cell lymphomas. Although solid tumor malignancies have been less responsive to radioimmunotherapy, encouraging results have been obtained with locoregional routes of administration, especially when the tumor burden is small. Greater tumor-to-normal tissue ratios are achievable with regional administration. Even with intraperitoneal and intrathecal administration, bone marrow suppression remains the dose-limiting toxicity. Ongoing research into new targeting molecules, improved chelation chemistry, and novel isotope utilization is likely to extend the applications of this strategy to other tumor types. The potential for radioimmunotherapy will be enhanced if this modality can be optimally adapted for integration with other agents and if the administration method can be tailored to the type and distribution of malignancy. [ONCOLOGY 11(7):979-987, 1997]
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Concomitant Cisplatin, Vinorelbine, and Radiation in Advanced Chest MalignanciesNewer chemotherapy drugs have shown encouraging activity in advanced non-small-cell lung cancer. Based on these improved outcomes, as well as the high rate of distant relapse in patients with locally advanced disease, several recent studies have evaluated the use of systemic therapy in patients with earlier-stage disease.
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Concomitant Cisplatin, Vinorelbine, and Radiation in Advanced Chest MalignanciesNewer chemotherapy drugs have shown encouraging activity in advanced non-small-cell lung cancer. Based on these improved outcomes, as well as the high rate of distant relapse in patients with locally advanced disease, several recent studies have evaluated the use of systemic therapy in patients with earlier-stage disease.
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Concomitant Cisplatin, Vinorelbine, and Radiation in Advanced Chest MalignanciesNewer chemotherapy drugs have shown encouraging activity in advanced non-small-cell lung cancer. Based on these improved outcomes, as well as the high rate of distant relapse in patients with locally advanced disease, several recent studies have evaluated the use of systemic therapy in patients with earlier-stage disease.
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Expert on Emergence of Osimertinib, New Discoveries in Lung Cancer CareRoy S. Herbst, MD, PhD, presented a late breaking abstract on behalf of his colleagues regarding the ADAURA trial, which analyzed osimertinib as an adjuvant therapy to treat patients with non-small cell lung cancer.
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Prophylactic Cranial Irradiation in Small-Cell Lung Cancer: Is It Ever Indicated?Prophylactic cranial irradiation (PCI) is being reintroduced into multimodality treatment protocols of patients with small-cell lung cancer (SCLC). The history of its use brings interesting insights into clinical evaluations of treatment strategies and design of relevant and informative trials. The critical issues of effectiveness and overall health gains of prophylactic cranial irradiation have been addressed in a series of recently completed clinical trials. These trials tested prophylactic cranial irradiation in small-cell lung cancer patients achieving good response to induction therapy and confirmed the ability of standard prophylactic cranial irradiation schedules to significantly reduce the lifetime risk of brain metastases. A subset of these trials evaluated neurotoxicity in a formal and prospective manner. No sustained or significant detriment in neuropsychometric function could be linked to the use of prophylactic cranial irradiation. In addition, all the large trials have shown a consistent survival advantage in favor of the prophylactic cranial irradiation arm. None of the individual sample sizes were large enough to statistically confirm this survival benefit, but a meta-analysis is in progress and will report on this aspect of evidence shortly. Issues that remain to be answered are the optimal dose and schedule of prophylactic cranial irradiation as well as the timing of this administration. These questions form the nucleus of the next generation of collaborative trials that are being designed.[ONCOLOGY 12(Suppl 2):19-24, 1998]
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Efficiency of In Vivo Purging With Rituximab Followed by High-Dose Therapy With Autologous Peripheral Blood Stem Cell Transplantation in B-Cell Non-Hodgkin’s Lymphomas: A Single-Institution StudyHigh-dose therapy (HDT) with peripheral blood stem cell transplantation is a treatment option for patients with advanced follicular, marginal, and mantle cell lymphoma. In this setting, frequent contamination of peripheral blood stem cell harvests by
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Efficiency of In Vivo Purging With Rituximab Followed by High-Dose Therapy With Autologous Peripheral Blood Stem Cell Transplantation in B-Cell Non-Hodgkin’s Lymphomas: A Single-Institution StudyHigh-dose therapy (HDT) with peripheral blood stem cell transplantation is a treatment option for patients with advanced follicular, marginal, and mantle cell lymphoma. In this setting, frequent contamination of peripheral blood stem cell harvests by
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Efficiency of In Vivo Purging With Rituximab Followed by High-Dose Therapy With Autologous Peripheral Blood Stem Cell Transplantation in B-Cell Non-Hodgkin’s Lymphomas: A Single-Institution StudyHigh-dose therapy (HDT) with peripheral blood stem cell transplantation is a treatment option for patients with advanced follicular, marginal, and mantle cell lymphoma. In this setting, frequent contamination of peripheral blood stem cell harvests by
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Efficiency of In Vivo Purging With Rituximab Followed by High-Dose Therapy With Autologous Peripheral Blood Stem Cell Transplantation in B-Cell Non-Hodgkin’s Lymphomas: A Single-Institution StudyHigh-dose therapy (HDT) with peripheral blood stem cell transplantation is a treatment option for patients with advanced follicular, marginal, and mantle cell lymphoma. In this setting, frequent contamination of peripheral blood stem cell harvests by
Latest:
Efficiency of In Vivo Purging With Rituximab Followed by High-Dose Therapy With Autologous Peripheral Blood Stem Cell Transplantation in B-Cell Non-Hodgkin’s Lymphomas: A Single-Institution StudyHigh-dose therapy (HDT) with peripheral blood stem cell transplantation is a treatment option for patients with advanced follicular, marginal, and mantle cell lymphoma. In this setting, frequent contamination of peripheral blood stem cell harvests by
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Small-Cell Lung Cancer: Therapeutic ChangesAlmost 40% of patients with newly diagnosed small-cell lung cancer (SCLC) have disease confined to the ipsilateral hemithorax and within a single radiation port, ie, limited-stage disease. The median survival for this group of patients after treatment is approximately 15 months, with one in every four patients surviving 2 years. Current optimal treatment consists of chemotherapy with platinum/etoposide, given concurrently with thoracic radiation. Surgery may represent an option for very early-stage disease, but its added value is uncertain. Prophylactic cranial irradiation (PCI) is used for patients with limited-stage SCLC who have achieved a complete response following initial therapy, as it decreases the risk of brain metastases and provides an overall survival benefit. Newer targeted agents are currently being evaluated in this disease and hold the promise of improving current outcomes seen in patients with early-stage disease.
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Consolidation TherapyWe previously reported the efficacy of concurrent cisplatin (Platinol)/etoposide (PE) and radiotherapy in stage IIIB non–small-cell lung cancer in which biopsy confirmation of T4 (noneffusion) or N3 status was required (S9019). In view of the activity of docetaxel (Taxotere) as second-line therapy and potential molecular mechanisms of action favoring taxane sequencing, we designed the present study to maintain a core of concurrent PE/radiotherapy, but to substitute docetaxel consolidation for the two additional cycles of PE.
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Evolving Chemoradiation Treatment Strategies for Locally Advanced Non-Small-Cell Lung CancerSurvival for patients with stage III nonSMQ-8211-SMQsmall-cell lung cancer hasgradually improved in recent years, with median survival times increasingfrom less than 10 months to more than 18 months. These increasesare thought to result primarily from advances in chemoradiation. Thisarticle reviews major advances in the development of chemoradiationfor patients with locally advanced nonSMQ-8211-SMQsmall-cell lung cancer. Resultsfrom cooperative group trials suggest that concurrent chemoradiationis superior to sequential therapy and may replace sequential therapy asthe new standard of care in patients with good performance status.Technological advances such as 18F-fluorodeoxyglucose positron emissiontomography (PET) staging can be used to improve patient selectionand predict survival. Locoregional control may be improved byaltering radiation fractionation or delivery (eg, hyperfractionation, highdoseinvolved-volume radiotherapy, 3D conformal radiotherapy). Novelagents and regimens in combination with radiation are being investigatedto further improve therapeutic outcomes.
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Continuing Challenges in Treating Indolent B-Cell LymphomaChristopher R. Flowers, MD, reviewed challenges of treating indolent B-cell lymphoma.
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Diagnosis and Management of Mycosis FungoidesMycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is a low-grade cutaneous lymphoma characterized by skin-homing CD4+ T cells. It is notable for highly symptomatic progressive skin lesions, including patches, plaques, tumors, and erytheroderma, and has a poorer prognosis at later stages. Diagnosis remains difficult owing to MF’s nonspecific skin presentation and identification of the optimal treatment strategy is challenging given the paucity of controlled trials and numerous and emerging treatment options. Management includes topical therapy with the addition of systemic therapy for patients with later-stage disease including tumors; erythroderma; and nodal, visceral, or blood involvement. Topical therapies include mechlorethamine (nitrogen mustard), carmustine (BCNU), steroids, bexarotene gel (Targretin Gel), psoralen plus ultraviolet A (PUVA), ultraviolet B (UVB), and either localized or total skin electron radiotherapy. Systemic therapies include interferon, retinoids, oral bexarotene (Targretin), denileukin diftitox (Ontak), vorinostat (Zolinza), extracorporeal photochemotherapy (photopheresis), and cytotoxic chemotherapy. Herein, we outline clinically relevant aspects of MF, including clinical presentation, pathology, diagnosis, and staging. We describe in detail existing and emerging therapeutics and offer specific recommendations for management of each stage of MF.
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Management of Anal Cancer in 2010 Part 2: Current Treatment Standards and Future DirectionsThe treatment of anal squamous cell cancer with definitive chemoradiation is the gold-standard therapy for localized anal cancer, primarily because of its sphincter-saving and colostomy-sparing potential.
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Lung Cancer After 70: Is it a Different Disease?Despite the fact that elderly patients comprise over 50% of the non-small cell lung cancer (NSCLC) population, our knowledge regarding the efficacy and safety of chemotherapy in this group is suboptimal. The “elderly” (defined as individuals ≥70 years of age) experience physiologically normal aging of their bone marrow and kidneys, which inherently increases toxicity to therapy. Standard practice has often been to discourage the use of combination chemotherapy in these patients; however, general consensus guidelines emphasize that performance status should primarily guide the choice of treatment. Elderly patients with advanced NSCLC treated with platinum doublet therapy demonstrate similar efficacy (but increased toxicity) to their younger counterparts. Patients with metastatic disease in which a targeted and/or biological agent(s) was added to chemotherapy experienced benefits similar to those treated with standard platinum doublets, but with increased morbidity and mortality. In the future, effective testing of molecular targeted therapies will have to include elderly patients among research cohorts or risk excluding a large population of eligible patients. Overall, elderly patients with advanced NSCLC, while experiencing greater toxicity, demonstrate the same response rates and survival benefits as their younger peers.
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Proton Therapy for Lung Cancer: New Data to ConsiderThe role of radiation therapy (RT) in lung cancer is long established; some of the earliest Radiation Therapy Oncology Group reports dealt with non-small cell lung cancer (NSCLC).[1,2] More recently, the advent of stereotactic body RT (SBRT) techniques has provided significant local control rates after focused treatment of selected small metastases and inoperable early stage lesions.[3,4] Our center has been in the forefront of examining SBRT and its role in central [5] or bilateral [6] lesions, its effect on PET imaging [7] and pulmonary function testing,[8] and subsequent frequency of brachial plexopathy,[9] chest wall toxicity,[10] or pneumonitis.[11] Still, even this highly conformal technique comes with potentially significant dose to adjacent normal tissue. This is in the context of an emerging appreciation for the pulmonary consequences of elevated mean lung dose,[12] or V5 after pneumonectomy.[13] For each lung cancer patient requiring RT, an effective mechanism to deliver dose to the tumor while minimizing dose to uninvolved lung is called for. Enter protons.
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Proton Therapy for Lung Cancer: New Data to ConsiderThe role of radiation therapy (RT) in lung cancer is long established; some of the earliest Radiation Therapy Oncology Group reports dealt with non-small cell lung cancer (NSCLC).[1,2] More recently, the advent of stereotactic body RT (SBRT) techniques has provided significant local control rates after focused treatment of selected small metastases and inoperable early stage lesions.[3,4] Our center has been in the forefront of examining SBRT and its role in central [5] or bilateral [6] lesions, its effect on PET imaging [7] and pulmonary function testing,[8] and subsequent frequency of brachial plexopathy,[9] chest wall toxicity,[10] or pneumonitis.[11] Still, even this highly conformal technique comes with potentially significant dose to adjacent normal tissue. This is in the context of an emerging appreciation for the pulmonary consequences of elevated mean lung dose,[12] or V5 after pneumonectomy.[13] For each lung cancer patient requiring RT, an effective mechanism to deliver dose to the tumor while minimizing dose to uninvolved lung is called for. Enter protons.
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Proton Radiation Therapy for Lung Cancer: Is There Enough Evidence?Proton radiation for cancer offers the ability to conform the high-dose region of radiation therapy to the tumor while reducing the dose of radiation to adjacent normal tissues. In lung cancer, this equates to greater sparing of uninvolved lung, heart, esophagus, and spinal cord. Sparing these normal tissues permits the delivery of higher-radiation doses to the tumor. Studies that compare the distribution of radiation doses for lung cancer show that proton radiation is superior, even when factors such as respiratory motion are considered. Clinical experience confirms the feasibility of proton radiation for early-stage non-small-cell lung cancers, and clinical trials are being conducted in locally advanced tumors: To date, evidence indicates that proton radiation should be further explored.
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Current Advances in Non–Proteasome Inhibitor–Based Approaches to the Treatment of Relapsed/Refractory Multiple MyelomaMultiple myeloma (MM) remains incurable despite the current approaches used in initial therapy, including more effective induction therapy, one or more autologous stem-cell transplants, and consolidation/maintenance strategies.
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Intensity-Modulated Radiation Therapy for Anal Cancer: An Obvious yet Complicated TransitionPrimary surgery with an abdominoperineal resection (APR) was historically the standard of care for localized anal squamous cell carcinoma. APR achieved 40%-70% survival rates at five years, with local failures from 27%-47%.[1,2] With modern technology and radiation dose escalation, external beam radiation therapy (EBRT) studies have improved complete response rates, decreased morbidity, and improved sphincter preservation rates. Nigro et al added 5-fluorouracil (5FU) and mitomycin C (MMC) to concurrent EBRT [3,4] and impressive complete response rates inspired other groups to investigate the role of chemotherapy as a component of sphincter-preserving therapy. The European Organization for Research and Treatment of Cancer (EORTC) and United Kingdom Coordinating Committee on Cancer Research (UKCCCR) studies reported improved local control and colostomy-free survival when chemotherapy (5FU/MMC) was administered in conjunction with radiation.[5,6] The five-year survival rate for patients receiving standard chemoradiation approaches 70%; however, 20%-40% experience grade 3-4 toxicity, and administration with MMC causes profound hematologic toxicity.
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Managing the Patient With Borderline Resectable Lung CancerDespite recent therapeutic advances, lung cancer continues to be one of the leading causes of cancer-related mortality. Of the various histologic subtypes, non–small-cell lung cancer (NSCLC) is the most common-accounting for approximately 85% of all lung cancers-and will be the focus of this article. In general, the treatment of lung cancer may include surgery, radiation therapy, systemic therapy (eg, chemotherapy with or without targeted therapy), or a combination of the above. Surgery continues to offer the best chance of long-term cure. The initial treatment of stage I and II NSCLC usually entails surgical resection, whereas stage IV disease is primarily treated with systemic agents, in light of the lack of curative potential with surgery and/or radiation therapy alone. It is locally advanced NSCLC, including stage IIIA and IIIB disease, that continues to pose a therapeutic dilemma, given its heterogeneous nature.
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Evolving Role of Novel Targeted Agents in Renal Cell CarcinomaThe treatment of metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. An improved understanding of the biology of RCC has resulted in the development of novel targeted therapeutic agents that have altered the natural history of this disease. In particular, the hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin (mTOR) signal transduction pathway have been exploited. Sunitinib malate (Sutent), sorafenib tosylate (Nexavar), bevacizumab (Avastin)/interferon alfa, and temsirolimus (Torisel) have improved clinical outcomes in randomized trials by inhibiting these tumorigenic pathways. Combinations and sequences of these agents are being evaluated. Other novel multitargeted tyrosine kinase inhibitors (pazopanib and axitinib) and mTOR inhibitors (everolimus) are in clinical development. Recently reported and ongoing clinical trials will help further define the role of these agents as therapy for metastatic RCC.
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Systemic Therapy in Renal Cell Carcinoma: Advancing ParadigmsRenal cell carcinoma (RCC) had historically been regarded as a disease that was refractory to therapy once surgical options had been exhausted.
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Role of Chemotherapy in the Treatment of Gastroesophageal CancersEsophageal, gastroesophageal junction, and gastric cancers are underpublicized but are frequently lethal, and gastroesophageal junction adenocarcinomas are increasingly common diseases in the United States and around the world. Although often grouped together in studies of chemotherapy, clear distinctions can be made in the locoregional therapy of these diseases. Esophageal squamous cell carcinomas may be treated with surgery or radiation with concurrent chemotherapy, whereas esophageal adenocarcinomas and gastroesophageal junction adenocarcinomas are often treated with all three treatment modalities. Over the past several years, it has become increasingly evident that gastric cancer is a disease that is potentially sensitive to chemotherapy. In the perioperative setting—at least in the Western world—chemotherapy and sometimes radiation are applied. However, the optimal chemotherapy for advanced gastric or esophageal cancer remains unsettled, and there is no single standard regimen. Several new chemotherapy agents have demonstrated activity in these diseases, but the best chemotherapy remains to be determined. This paper will review the role of chemotherapy in gastroesophageal cancers.
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Emerging Role of Immunotherapy in the Management of Prostate CancerThere has been a resurgence of interest in developing noncytotoxic immune therapies for patients with either hormone-naive biochemically relapsed post-primary therapy or castrate metastatic prostate cancer. The rationale for developing an immunotherapeutic approach has been based on the overexpression and underglycosylation of a wide variety of altered "self" molecules including prostate-specific antigen (PSA), acid phosphatase (ACP), prostate stem cell antigen (PSCA), and prostate-specific membrane antigen (PSMA), which can serve as targets for immune recognition and attack. In addition, such a strategy could theoretically make use of the patient's immune system to fight the tumor particularly if their disease is of reasonably low volume. A variety of immunotherapeutic approaches have been explored through phase I, II, and now phase III trials demonstrating that immunologic tolerance could be broken, as evidenced by the development of high-titer antibodies and T-cell responses specific for the tumor. What appears to be revolutionizing the immunotherapy field is the combination of vaccines with cytokines or immune modulators, which not only potentiate immune reactivity in vivo but foster dramatic antitumor responses. This review explores the challenges now faced in establishing a role for immune therapies for prostate cancer treatment.
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HPV and the Immune System in Head and Neck Cancers: Therapeutic ConsiderationsA review of the role of immune therapy in HPV-associated head and neck squamous cell carcinoma, along with the evidence and perspective behind differing therapeutic considerations.
