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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.
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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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Optimal Combination With PUVA: Rationale and Clinical Trial UpdateCutaneous T-cell lymphoma (CTCL) is relatively benign in its early stages, but survival rates decrease dramatically as the disease progresses. As no curative therapies are currently available, the goal of therapy is preventing or delaying progression from early disease stages while minimizing long-term toxicity. No single agent, including psoralen plus ultraviolet A (PUVA), can control disease progression fully, so combination therapy is needed to improve response rates. In addition, low-dose combination therapy may improve treatment safety and tolerability. A combination of PUVA and interferon (IFN)α in early disease has been shown to be effective and well tolerated. Likewise, small studies of PUVA and bexarotene (Targretin) indicate good efficacy for this combination. Reduced doses of these combinations may also be effective as maintenance therapies following complete remission. Other treatment combinations shown to be effective in early disease stages include bexarotene with IFNα, and bexarotene with denileukin diftitox (Ontak). In advanced stages of CTCL, liposomal-encapsulated doxorubicin or extracorporeal photopheresis may be combined with bexarotene or IFNα.
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Management of Early-Stage Lung Cancer: Past, Present, and Future Adjuvant TrialsThe standard of care with regard to adjuvant chemotherapy of lung cancer has changed remarkably over the past 3 years. Until the initial report of the International Adjuvant Lung Trial in 2003, there was no real evidence from any individual randomized clinical trial (RCT) that adjuvant chemotherapy improves survival in resectable non-small-cell lung cancer. However, five RCTs that have now been reported indicate that adjuvant chemotherapy is effective, at least in certain subgroups of resectable patients. Moreover, numerous meta-analyses have also reported a positive effect from adjuvant treatment. Nonetheless, because of methodologic issues and conflicting results, the question of who should be treated and what constitutes optimal adjuvant therapy remains controversial. This article reviews the recent randomized trials that have contributed to a change in the state of the art, as well as some of the methodologic problems that may have confounded their proper interpretation. It also considers newer approaches to adjuvant therapy, with a particular focus on strategies that incorporate our growing knowledge of molecular medicine and predictive factors to the field of adjuvant chemotherapy of lung cancer.
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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.
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Commentary (Roy/Rai)-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 (Roy/Rai)-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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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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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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Historic Evidence and Future Directions in Clinical Trial Therapy of Solid TumorsAlthough improved survival is the "gold standard" for proving clinical benefit of oncologic therapy, the US Food and Drug Administration (FDA) has accepted significant results in clinical trials using surrogate endpoints as the basis for drug approval. One surrogate is the amount of tumor reduction, or tumor response. Although tumor shrinkage would seem to be a necessary precondition for improved survival, clinical studies of a variety of oncologic agents have not consistently demonstrated a correlation between the two in patients with renal cell carcinoma. Moreover, tumor response may not be an appropriate endpoint for evaluating the effects of the new targeted therapies, whose putative mechanisms are generally cytostatic rather than cytotoxic. Clinical trials suggest that some patients with other solid tumors, such as lung cancer, may derive clinical benefit from treatment that helps stabilize their disease. There is also controversy as to whether the Response Evaluation Criteria in Solid Tumors (RECIST) provides the most appropriate instrument for assessing tumor burden. Ultimately, use of a variety of endpoints as well as different trial designs may provide an adequate basis for investigating the benefits/risks of newer therapies.
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Historic Evidence and Future Directions in Clinical Trial Therapy of Solid TumorsAlthough improved survival is the "gold standard" for proving clinical benefit of oncologic therapy, the US Food and Drug Administration (FDA) has accepted significant results in clinical trials using surrogate endpoints as the basis for drug approval. One surrogate is the amount of tumor reduction, or tumor response. Although tumor shrinkage would seem to be a necessary precondition for improved survival, clinical studies of a variety of oncologic agents have not consistently demonstrated a correlation between the two in patients with renal cell carcinoma. Moreover, tumor response may not be an appropriate endpoint for evaluating the effects of the new targeted therapies, whose putative mechanisms are generally cytostatic rather than cytotoxic. Clinical trials suggest that some patients with other solid tumors, such as lung cancer, may derive clinical benefit from treatment that helps stabilize their disease. There is also controversy as to whether the Response Evaluation Criteria in Solid Tumors (RECIST) provides the most appropriate instrument for assessing tumor burden. Ultimately, use of a variety of endpoints as well as different trial designs may provide an adequate basis for investigating the benefits/risks of newer therapies.
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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.
