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Neoadjuvant Chemotherapy for Bladder CancerOccult distant micrometastasis at the time of radical cystectomy leads predominantly to distant failures in patients with locally advanced muscle-invasive transitional cell carcinoma of the bladder. Cisplatin-based combination chemotherapy enhances survival in patients with metastatic urothelial cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power. However, randomized clinical trials have demonstrated a survival benefit for neoadjvuant cisplatin-based combination chemotherapy, which should be considered a standard of care. In addition, neoadjuvant therapy may assist in the rapid development of novel systemic therapy regimens, since pathologic complete remission appears to be a powerful prognostic factor for long-term outcomes. Patients who are either unfit for or refuse radical cystectomy may benefit from neoadjuvant chemotherapy with or without radiation to enable bladder preservation.
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Hematopoietic Stem Cell Transplantation in the ElderlyHematopoietic stem cell (HSC) transplantation may improve outcomes of patients with hematologic malignancies not curable with conventional therapies. In some clinical settings, transplantation represents the only curative option. The feasibility and efficacy of this approach in older patients are undefined, since this population has been excluded from nearly all clinical trials. Advances in supportive care, HSC harvesting, and safer conditioning regimens have made this therapy available to patients well into their 6th and 7th decades of life. Recent evidence suggests that elderly patients with good performance status and no comorbidities could, in fact, not only survive the transplant with reasonable risk, but also benefit in the same measure as younger patients.
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Hematopoietic Stem Cell Transplantation in the ElderlyHematopoietic stem cell (HSC) transplantation may improve outcomes of patients with hematologic malignancies not curable with conventional therapies. In some clinical settings, transplantation represents the only curative option. The feasibility and efficacy of this approach in older patients are undefined, since this population has been excluded from nearly all clinical trials. Advances in supportive care, HSC harvesting, and safer conditioning regimens have made this therapy available to patients well into their 6th and 7th decades of life. Recent evidence suggests that elderly patients with good performance status and no comorbidities could, in fact, not only survive the transplant with reasonable risk, but also benefit in the same measure as younger patients.
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Hematopoietic Stem Cell Transplantation in the ElderlyHematopoietic stem cell (HSC) transplantation may improve outcomes of patients with hematologic malignancies not curable with conventional therapies. In some clinical settings, transplantation represents the only curative option. The feasibility and efficacy of this approach in older patients are undefined, since this population has been excluded from nearly all clinical trials. Advances in supportive care, HSC harvesting, and safer conditioning regimens have made this therapy available to patients well into their 6th and 7th decades of life. Recent evidence suggests that elderly patients with good performance status and no comorbidities could, in fact, not only survive the transplant with reasonable risk, but also benefit in the same measure as younger patients.
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Limited-Stage Small-Cell Lung Cancer: Therapeutic OptionsAlmost 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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Novel Concepts in Radioimmunotherapy for Non-Hodgkin's LymphomaTositumomab/iodine-131 tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin) are radioimmunoconjugates targeting the CD20 antigen. Both agents are approved in the United States for use in relapsed or refractory, indolent or transformed, B-cell lymphoma. These agents are well tolerated and have the highest levels of single-agent activity observed in these histologies. This review will summarize the key trials that led to approval of both I-131 tositumomab and ibritumomab tiuxetan, and then focus on four novel therapeutic concepts in radioimmunotherapy: retreatment, therapy of de novo indolent lymphoma, therapy of aggressive histologies, and incorporation in high-dose therapy programs utilizing autologous stem cell support.
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Novel Concepts in Radioimmunotherapy for Non-Hodgkin's LymphomaTositumomab/iodine-131 tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin) are radioimmunoconjugates targeting the CD20 antigen. Both agents are approved in the United States for use in relapsed or refractory, indolent or transformed, B-cell lymphoma. These agents are well tolerated and have the highest levels of single-agent activity observed in these histologies. This review will summarize the key trials that led to approval of both I-131 tositumomab and ibritumomab tiuxetan, and then focus on four novel therapeutic concepts in radioimmunotherapy: retreatment, therapy of de novo indolent lymphoma, therapy of aggressive histologies, and incorporation in high-dose therapy programs utilizing autologous stem cell support.
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Is There a Role for Hemopoietic Stem-Cell Transplantation in CTCL?The role of autologous and allogeneic stem-cell transplantation (SCT) in the treatment of cutaneous T-cell lymphoma (CTCL) is reviewed. Patients most likely to benefit are those with advanced-stage disease, multiple relapses, and short remissions; chemosensitive disease is also a prerequisite for these treatments. Autologous SCT produces high response rates in patients with peripheral T-cell lymphoma, but these are generally of short duration. This therapy is relatively safe to administer, with little transplant-related mortality. In contrast, allogeneic SCT may be highly toxic and result in transplant-related mortality, but it has the potential to produce long-lasting responses. Prospective studies of these treatments in patients with CTCL are required. Nevertheless, selected patients could be considered for allogeneic SCT, preferably early in their disease when their performance status is still good.
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Systemic Monotherapy vs Combination Therapy for CTCL: Rationale and Future StrategiesThere are few approved therapies for cutaneous T-cell lymphoma (CTCL). The retinoids are the major biologic response modifiers used in CTCL, producing good response rates but few complete responses. For patients with early-stage disease, the oral retinoids can be combined with other therapies, such as psoralen plus ultraviolet A or interferon α, to improve response rates. Combined-modality therapy with oral retinoids, combined chemotherapy, electron-beam therapy, and topical mustargen has also proved effective. For the treatment of advanced-stage disease, the targeted therapy denileukin diftitox (Ontak) provides a nonimmunosuppressive alternative to conventional chemotherapy or radiation therapy. Of the conventional chemotherapies that have been tested in CTCL, gemcitabine (Gemzar) has demonstrated good efficacy in producing responses, particularly in patients with tumors. This agent can be used in combination with a maintenance therapy of bexarotene (Targretin) to manage the plaques and patches of mycosis fungoides. Several other targeted therapies are now also in testing, for example, alemtuzumab (CamPath), HuMax-CD4, several histone deacetylase inhibitors, and the transition-state inhibitor forodesine. These drugs, in combination with currently used therapies, may increase the number and combinations of therapies available for the treatment of this chronic condition to optimize long-lasting responses in CTCL.
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Novel Targets and Therapies for Metastatic Renal Cell CarcinomaFor the past 20 years, the systemic treatment of metastatic renal cell carcinoma (RCC) has been limited primarily to cytokines, with few patients showing benefit. However, recent advances in understanding the pathobiology of RCC have led to the identification of novel therapeutic targets for this disease. Drugs specifically designed to inhibit these targets have been developed, with several showing superior efficacy over traditional cytokine therapy. Moreover, these agents are well tolerated and have improved the span of progression-free, and in some cases, overall survival. As a result, between December 2005 and January 2006, two of these targeted therapies—sunitinib (Sutent) and sorafenib (Nexavar)—were approved by the US Food and Drug Administration for the treatment of advanced RCC. The authors review the clinical trials that have focused on these two drugs as well as those concentrating on two other promising agents, bevacizumab (Avastin) and temsirolimus. The ways in which these novel drugs are changing the standard of care for metastatic RCC and the future directions of RCC clinical trials are also discussed.
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Primary Carcinoid Tumors of the Lung: A Role for RadiotherapyPrimary neuroendocrine neoplasms of the lung represent a clinical spectrum of tumors ranging from the relatively benign and slow-growing typical carcinoid to the highly aggressive small-cell lung carcinoma. The rarity of carcinoids has made the role of radiation therapy in their management controversial. This review considers the results of published studies to generate treatment recommendations and identify areas for future research. Surgery remains the standard of care for medically operable disease. Histology plays the most important role in determining the role of adjuvant radiation. Resected typical carcinoids likely do not require adjuvant therapy irrespective of nodal status. Resected atypical carcinoids and large-cell neuroendocrine carcinomas have a significant risk of local failure, for which adjuvant radiation likely improves local control. Definitive radiation is warranted in unresectable disease. Palliative radiation for symptomatic lesions has demonstrated efficacy for all histologies. Collaborative group trials are warranted.
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From Radiotherapy to Targeted Therapy: 20 Years in the Management of Non-Small-Cell Lung CancerNon-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Before 1980, radiotherapy was considered the only real recourse in advanced disease. In 1995, a landmark meta-analysis of trials conducted in the 1980s and early 1990s demonstrated a survival benefit with platinum-based chemotherapy. Newer chemotherapy agents and improved supportive care measures have allowed more patients to benefit from chemotherapy with reduced toxicity. Concurrent platinum-based chemotherapy and radiotherapy has improved the survival in stage III disease, and recently chemotherapy has also demonstrated improved survival in resected early-stage disease. The majority of patients still present with advanced unresec disease for whom the prognosis remains poor, but for key subpopulations the outlook has improved markedly since the emergence of targeted therapies directed against the epidermal growth factor receptor and vascular endothelial growth factor receptor pathways. Patient selection and the incorporation of targeted therapies with cytotoxic chemotherapy are the focus of many ongoing studies, and there is an abundance of new agents undergoing clinical trials. Together, these developments have moved us away from the nihilism of 20 years ago into an era of unprecedented optimism in taking on the many remaining challenges of managing NSCLC in the 21st century.
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Topotecan in Combination With Cisplatin for the Treatment of Stage IVB, Recurrent, or Persistent Cervical CancerTopotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.
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Topotecan in Combination With Cisplatin for the Treatment of Stage IVB, Recurrent, or Persistent Cervical CancerTopotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.
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Topotecan in Combination With Cisplatin for the Treatment of Stage IVB, Recurrent, or Persistent Cervical CancerTopotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.
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Topotecan in Combination With Cisplatin for the Treatment of Stage IVB, Recurrent, or Persistent Cervical CancerTopotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.
Latest:
Topotecan in Combination With Cisplatin for the Treatment of Stage IVB, Recurrent, or Persistent Cervical CancerTopotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.
Latest:
Topotecan in Combination With Cisplatin for the Treatment of Stage IVB, Recurrent, or Persistent Cervical CancerTopotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.
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New Questions About Transplantation in Multiple MyelomaMultiple myeloma is now the most common indication for autologous stem cell transplantation (ASCT) in North America, with over 5,000 transplants performed yearly (Center for International Blood and Marrow Transplant Research [CIBMTR] data). While the role of ASCT as initial therapy in multiple myeloma has been established by randomized studies, newer therapies are challenging the traditional paradigm. The availability of novel induction agents and newer risk stratification tools, and the increasing recognition of durability of remissions are changing the treatment paradigm. However, even with arduous therapy designed to produce more complete remissions—for example, tandem autologous transplants—we have seen no plateau in survival curves. A tandem autologous procedure followed by maintenance therapy may be performed in an attempt to sustain remission. Sequential autologous transplants followed by nonmyeloablative allotransplants are pursued with the hope of "curing" multiple myeloma. We examine how the key challenges of increasing the response rates and maintaining responses are being addressed using more effective induction and/or consolidation treatments and the need for maintenance therapies after ASCT. We argue that given the biologic heterogeneity of multiple myeloma, risk-adapted transplant approaches are warranted. While the role of curative-intent, dose-intense toxic therapy is still controversial, conventional myeloablative allogeneic transplants need to be reexamined as an option in high-risk aggressive myeloma, given improvements in supportive care and transplant-related mortality.
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Management of Anemia in Patients With Hematologic MalignanciesAnemia is common in patients with hematologic malignancies, and it has negative effects on their quality of life. The current clinical practice guidelines recommend erythropoietic therapy in patients with cancer- or chemotherapy-related anemia, but anemia is often undertreated in patients with hematologic malignancies. Several randomized controlled trials have shown that treatment with erythropoiesis-stimulating proteins such as epoetin alfa (Procrit), epoetin beta, and darbepoetin alfa (Aranesp) increases hemoglobin levels, reduces the need for red blood cell transfusions, and improves quality of life in patients with hematologic malignancies and anemia receiving chemotherapy. Furthermore, preliminary data from a recent open-label study suggest that early treatment of mild anemia in patients with hematologic malignancies treated with chemotherapy produces marked improvements in quality of life and productivity. Increasing patients' hemoglobin levels may also improve their cognitive function. These findings support the use of erythropoietic therapy to manage anemia in patients with hematologic malignancies who are treated with chemotherapy.
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Guidelines for the Use of Erythropoietic Growth Factors in Patients With Chemotherapy-Induced AnemiaThe use of erythropoietic growth factors to treat chemotherapy-induced anemia (CIA) has been increasing as clinicians become more aware of the ability of these drugs to improve the quality of life of patients with cancer. The cost associated with erythropoietic growth factor therapy makes its appropriate use a practical issue for physicians and hospitals. Clinical practice guidelines can benefit physicians by increasing practice efficiency, reducing medical errors, increasing the quality of medical care, and decreasing reimbursement problems. The American Society of Clinical Oncology and the American Society of Hematology, the European Organisation for Research and Treatment of Cancer, and the National Comprehensive Cancer Network (NCCN) have all published guidelines for using erythropoietic growth factors to treat CIA, and this article reviews and summarizes those guidelines. Of the three guidelines for the use of erythropoietic growth factors in CIA, the NCCN guidelines are based on the most recent data. Current evidence indicates that erythropoietic growth factors can increase hemoglobin levels, reduce the need for red blood cell transfusions, and improve quality of life; the effect of erythropoietic therapy on outcomes in patients with CIA is still being investigated.
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Commentary (Goldman)-Chronic Myeloid Leukemia: Changing the Treatment ParadigmsMolecular discoveries and clinical advances over the past few decades have made the treatment of chronic myeloid leukemia (CML) one of the great success stories of modern medicine. Before the 1980s, the focus was on maintaining normal white blood cell counts with agents such as hydroxyurea and busulfan. With the use of interferon, treatment strategies turned more toward cytogenetic remission. In 1998, targeted therapy was introduced to this setting with the first studies of imatinib mesylate. Since then, treatment objectives have shifted toward the attainment of molecular remission. In this review, we consider the variety of approaches to treating CML, efforts to minimize treatment failures, and possible future directions in therapy.
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Commentary (Harari): Anti-EGFR Therapy UpdateSince initial characterization over 40 years ago, strong preclinical and clinical data have clearly established the epidermal growth factor receptor (EGFR) as a worthy molecular target for intervention in cancer therapy. The receptor is expressed, overexpressed, or mutated in many human tumors, including head and neck, colorectal, pancreatic, non-small-cell lung, ovarian, esophageal, gastric, breast, prostate, bladder, and renal cancers. Experiments in several model systems have confirmed that EGFR signaling is involved in regulating several key biologic processes, including cell proliferation, epithelial development, organogenesis, apoptosis, angiogenesis, and differentiation. Furthermore, EGFR function has been shown to be altered and/or dysregulated in a variety of spontaneous tumors.
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Treatment of Stage I-III Non-Small-Cell Lung Cancer in the ElderlyElderly patients with stage I-III non-small-cell lung cancer (NSCLC) constitute a peculiar patient population and need specific therapeutic approaches. Limited resections are an attractive alternative for elderly patients with resectable NSCLC because of the potential reduction in postoperative complications. Curative radiation therapy is an acceptable alternative for elderly patients who are unfit for or refuse surgery. Hypofractionated stereotactic body radiation therapy is of particular interest for this population because of its favorable tolerance.
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Treatment of Stage I-III Non-Small-Cell Lung Cancer in the ElderlyElderly patients with stage I-III non-small-cell lung cancer (NSCLC) constitute a peculiar patient population and need specific therapeutic approaches. Limited resections are an attractive alternative for elderly patients with resectable NSCLC because of the potential reduction in postoperative complications. Curative radiation therapy is an acceptable alternative for elderly patients who are unfit for or refuse surgery. Hypofractionated stereotactic body radiation therapy is of particular interest for this population because of its favorable tolerance.
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New Treatments for Multiple MyelomaIn 2004, multiple myeloma was diagnosed in more than 15,000 peoplein the United States and will account for approximately 20% of deathsdue to hematologic malignancies. Although traditional therapies suchas melphalan (Alkeran)/prednisone, combination chemotherapy withVAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), andhigh-dose chemotherapy with stem cell transplantation have shownsome success, median survival remains between 3 to 5 years. Treatmentoptions for patients with multiple myeloma have increased in recentyears, with the promise of improvement in survival. New agents, suchas the proteasome inhibitor bortezomib (Velcade), the antiangiogenicand immunomodulator thalidomide (Thalomid) and its analogs, suchas lenalidomide (Revlimid), together with other small molecules, includingarsenic trioxide (Trisenox), and other targeted therapies, havebeen studied alone and in combination with other antineoplastic therapies,either as induction therapy prior to stem cell transplantation or inpatients with relapsed disease. Bortezomib recently was approved inthe United States for the treatment of multiple myeloma in patientswho have received at least one prior therapy. The use of bortezomibbasedregimens as front-line therapy as well as the use of other agentsin multiple myeloma remain under investigation, and approvals forboth thalidomide and lenalidomide are hoped for soon, with the overallprospect of patient outcome continuing to be increasingly positive.
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New Treatments for Multiple MyelomaIn 2004, multiple myeloma was diagnosed in more than 15,000 peoplein the United States and will account for approximately 20% of deathsdue to hematologic malignancies. Although traditional therapies suchas melphalan (Alkeran)/prednisone, combination chemotherapy withVAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), andhigh-dose chemotherapy with stem cell transplantation have shownsome success, median survival remains between 3 to 5 years. Treatmentoptions for patients with multiple myeloma have increased in recentyears, with the promise of improvement in survival. New agents, suchas the proteasome inhibitor bortezomib (Velcade), the antiangiogenicand immunomodulator thalidomide (Thalomid) and its analogs, suchas lenalidomide (Revlimid), together with other small molecules, includingarsenic trioxide (Trisenox), and other targeted therapies, havebeen studied alone and in combination with other antineoplastic therapies,either as induction therapy prior to stem cell transplantation or inpatients with relapsed disease. Bortezomib recently was approved inthe United States for the treatment of multiple myeloma in patientswho have received at least one prior therapy. The use of bortezomibbasedregimens as front-line therapy as well as the use of other agentsin multiple myeloma remain under investigation, and approvals forboth thalidomide and lenalidomide are hoped for soon, with the overallprospect of patient outcome continuing to be increasingly positive.
Latest:
New Treatments for Multiple MyelomaIn 2004, multiple myeloma was diagnosed in more than 15,000 peoplein the United States and will account for approximately 20% of deathsdue to hematologic malignancies. Although traditional therapies suchas melphalan (Alkeran)/prednisone, combination chemotherapy withVAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), andhigh-dose chemotherapy with stem cell transplantation have shownsome success, median survival remains between 3 to 5 years. Treatmentoptions for patients with multiple myeloma have increased in recentyears, with the promise of improvement in survival. New agents, suchas the proteasome inhibitor bortezomib (Velcade), the antiangiogenicand immunomodulator thalidomide (Thalomid) and its analogs, suchas lenalidomide (Revlimid), together with other small molecules, includingarsenic trioxide (Trisenox), and other targeted therapies, havebeen studied alone and in combination with other antineoplastic therapies,either as induction therapy prior to stem cell transplantation or inpatients with relapsed disease. Bortezomib recently was approved inthe United States for the treatment of multiple myeloma in patientswho have received at least one prior therapy. The use of bortezomibbasedregimens as front-line therapy as well as the use of other agentsin multiple myeloma remain under investigation, and approvals forboth thalidomide and lenalidomide are hoped for soon, with the overallprospect of patient outcome continuing to be increasingly positive.
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Adjuvant Chemotherapy for Resected Non–Small-Cell Lung CancerBecause of the high rate of distant disease recurrence, the 5-yearsurvival of patients who have undergone complete surgical resectionof localized non–small-cell lung cancer (NSCLC) is approximately 50%.Initial results from early studies of adjuvant postoperative chemotherapyreported an adverse effect of alkylating agent and older chemotherapyregimens on survival. Cisplatin-based combinations were the first toshow a survival advantage. A 1995 meta-analysis of these studies suggesteda 13% reduction in the hazard ratio for death (HR = 0.87), leadingto a 5% survival benefit at 5 years. Still, these trials involved limitednumbers of patients (N = 1,394), and the results failed to reach statisticalsignificance (P = .08). Of the five largest subsequent randomizedtrials of platinum-based adjuvant therapy, three showed a significantsurvival advantage. Although it is impossible to determine the reasonsfor the differing outcomes of these studies, several key features distinguishthem, and the data suggest that medically fit patients with resectedstage IB or II NSCLC should be offered chemotherapy with a platinum/new drug combination.
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ACR Appropriateness Criteria® Nonsurgical Treatment for Locally Advanced Non–Small-Cell Lung Cancer: Good Performance Status/Definitive IntentThe treatment of inoperable stage III non–small-cell lung cancer (NSCLC) remains a challenge due to high rates of distant metastasis, local recurrence, and toxicity associated with definitive therapy.
