At a median of 4.9 months of therapy with the investigational agent nilotinib (Tasigna, formerly AMN107), 92% of patients with treatment-resistant chronic phase Ph+ chronic myeloid leukemia (CML) achieved a complete hematologic response with normalization of white blood cell counts, and 35% had a complete cytogenetic response. All patient had shown resistance or intolerance to optimized imatinib (Gleevec) therapy
Molecular 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.
A combination of radiation and suicide-gene therapy is eliminating the spread of prostate cancer; and providing a long-term vaccine against the disease, according to a study presented at the American Society of Clinical Oncology's annual prostate cancer meeting in San Francisco recently.
Molecular 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.
Molecular 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.
Although 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.
This report of a case of cytokine-refractory metastatic, clear-cell renal cell carcinoma (RCC) presents some current issues related to use of targeted therapy in the community. Due to the different mechanisms of cytostatic vs cytotoxic agents, traditional response assessments may not always apply in deciding when to either continue or stop treatment. While community physicians may increasingly focus more on duration of response, symptom relief, and how well patients tolerate treatment, there is a clear need for validated surrogate markers of biologic activity and response, as well as randomized trials that directly compare some of the targeted therapies being applied in advanced RCC.
Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.
Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.
Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.
Since 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.
Cleveland?Gene therapy and pharmacologic therapy, administered separately and combined, rescued retinal function in blind mice that were bred without an enzyme crucial to the detection of light.
Baltimore?Uveitis is a vision-threatening disease for which current therapy?namely, oral corticosteroids, antimetabolites, T-cell inhibitors, and alkylating agents?is not consistently effective. In addition, the side effects produced by these treatments are well known.
In part 2, we address risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.
Elderly 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.
Elderly 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.
Elderly 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.
Researchers have developed a new approach to drug discovery that takes advantage of the gene expression signatures of tumors to generate potential drug matches. A proof-of-principle of this technique revealed a potential new combination therapy for children with acute lymphocytic leukemia (ALL).
In 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.
Research into the genetics of ocular disease is paying off with discoveries of new genes associated with both common and rare eye conditions. Gene therapy, however, could be 5 to 10 years away for many eye diseases. In this first of a two-part series, researchers explain the progress in age-related macular degeneration (AMD), Leber's congenital amaurosis, and familial exudative vitreoretinopathy (FEVR). In the second half of the series, gains in glaucoma, myopia, and retinitis pigmentosa will be covered as well as a promising therapy for AMD—RNA interference.
Kauh and colleagues nicely outlinethe major problems facingclinicians who treat humanimmunodeficiency virus (HIV)-positivepatients with squamous cell carcinomaof the anus. This is a highly curabledisease with combined-modality therapy,though the HIV-positive populationpresents unique challenges. Weagree with the approaches outlined bythe authors and would also like to emphasizeseveral principles in the managementof anal cancer.
Drs. Laskin and Sandler havedone an excellent job of summarizingthe results of chemotherapyin the treatment of stageIV non–small-cell lung cancer. Theyhave pointed out that a meta-analysispublished in 1995 showed that chemotherapyprovided a modest survivaladvantage compared to supportivecare alone. In addition, they have citedstudies that have shown the treatmentis cost-effective and that it relieveslung cancer–related symptoms.They have thoroughly discussed thefact that multiple phase III trials testingnewer chemotherapy doubletsshow slightly different toxicity profiles with virtually identical efficacy,and that giving more than four coursesof therapy with regimens that consistof three or more drugs does notprovide significant benefit.
The identification of key signaltransduction pathways and, inparticular, specific proteins thatare involved in the regulation of cancercell growth has provided unprecedentedopportunities for researchersinterested in targeted cancer treatment.The identification of molecular target-specific therapy offers the potentialof maximal therapeutic benefitwhile minimizing toxicity to normalcells. The accomplishment that led tothe sequencing and analysis of theentire human genome in 2001 has providedresearchers with the basic criticaltools to begin to identify anddifferentiate cancer from normal tissueat the genetic level.[1,2] Whilethe implications of this landmarkachievement are still being realized,it has become evident that the identificationof critical genes and proteinsinvolved in cell division and growthare just the beginning. The complexrelationships between multiple signaltransduction pathways, the surroundingtumor microenvironment, andpathways involved in immune-systemregulation have gained new appreciation.The ability to manipulate thesemultiple interactive systems with targetedtherapies represents a new treatmentparadigm in oncology.
Lung cancer continues to be themost common cause of cancerdeaths in the United States forboth men and women. Unfortunately,the majority of patients presentwith local or distant disease at thetime of diagnosis. Surgical resectioncontinues to offer the best chance forlong-term survival; however, less than25% of patients have surgically resectabledisease. Even after surgicalresection for early-stage disease a significantnumber of patients will developrecurrent disease, with themajority being distant in nature. Developmentof distant disease usuallyproves to be the terminal event inmost patients. Multiple treatmentmodalities have been investigated asadjuvant therapy to decrease the incidenceof distant disease after completesurgical resection. Untilrecently, no modality has shown asurvival advantage in patients afterresection for non–small-cell lung cancer(NSCLC).
Squamous cell anal cancer remains an uncommon entity; however,the incidence appears to be increasing in at-risk populations, especiallythose infected with human papillomavirus (HPV) and human immunodeficiencyvirus (HIV). Given the ability to cure this cancer using synchronouschemoradiotherapy, management practices of this disease arecritical. This article considers treatment strategies for HIV-positive patientswith anal cancer, including the impact on chemoradiation-inducedtoxicities and the role of highly active antiretroviral therapy in the treatmentof this patient population. The standard treatment has beenfluorouracil (5-FU) and mitomycin (or cisplatin) as chemotherapy agentsplus radiation. Consideration to modifying the standard treatment regimeis based on the fact that patients with HIV tend to experience greatertoxicity, especially when CD4 counts are below 200; these patients alsorequire longer treatment breaks. Additional changes to the chemotherapydosing, such as giving 5-FU continuously and decreasing mitomycin dose,are evaluated and considered in relation to radiation field sizes in an effortto reduce toxicity, maintain local tumor control, and limit need forcolostomy. The opportunity for decreasing the radiation field size andusing intensity-modulated radiation therapy (IMRT) is also considered,particularly in light of the fact that IMRT provides dose-sparing whilemaximizing target volume dose to involved areas. The impact of the immunesystem in patients with HIV and squamous cell carcinoma of theanus and the associated response to therapy remains unknown. Continuedstudies and phase III trials will be needed to test new treatment strategiesin HIV-infected patients with squamous cell cancer of the anus todetermine which treatment protocols provide the greatest benefits.
Because 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.
ORLANDO - Thalidomide (Thalomid) added to intensive front-line therapy for multiple myeloma proved superior to intensive therapy alone in a randomized trial led by Bart Barlogie, MD, PhD, director, University of Arkansas Myeloma Institute for Research & Therapy, Little Rock, and lead investigator of the trial. He reported the findings at the American Society of Clinical Oncology 41st Annual Meeting (abstract 6502). The researchers also found that cytogenetic abnormalities were strongly associated with response and survival. Thalidomide benefited only patients without the abnormalities. The phase III trial randomized 668 newly diagnosed patients to receive Total Therapy 2, which involves several rounds of stem cell transplants and chemotherapy, with or without thalidomide, given from the beginning of treatment and continued until recurrence.
About 172,570 new cases ofnon–small-cell lung cancer(NSCLC) are expected to bediagnosed in 2005 in the United States,and almost as many will die of thedisease. Patients with effusions or metastaticdisease are candidates for combinationchemotherapy. The regimensof choice are platinum-based combinationchemotherapy schedules. Giventhat most patients will experience diseaseprogression despite their initialtreatment, they may be eligible for second-line chemotherapy, provided theyhave an acceptable performance status.
We applaud Dr. Cappuzzo andcolleagues for an excellentreview of an emerging fieldin lung cancer treatment. Since 2000,three drugs (docetaxel [Taxotere],pemetrexed [Alimta], and erlotinib[Tarceva]) have been approved by theUS Food and Drug Administration(FDA) for second-line therapy in non–small-cell lung cancer (NSCLC) basedon the results of phase III trials (seeTable 1).[1-4] It is also possible thatsimilar approval will be sought for otherdrugs (eg, topotecan [Hycamtin]),[5]and gefitinib (Iressa) remains an optionfor treatment in the third-line setting.
