	The prognosis and treatment outcome of patients with advanced renal cell carcinoma have substantially improved with the multitude of currently available molecularly targeted therapies. The rapid addition of novel therapeutic options has made the treatment algorithm complex and has created a significant challenge for the community oncologist, who is faced with selecting a drug for a given patient from a growing list of agents. The optimal treatment sequence remains to be determined, and effective management of side effects and toxicities is currently the key. These targeted therapies are associated with toxicity profiles that are classically distinct from those associated with conventional chemotherapy agents. In order to help community oncologists optimize patient outcomes, this review summarizes clinical issues associated with specific therapies and the background pivotal data.

	Approximately 58,240 patients were diagnosed with and 13,040 died of cancer of the kidney and renal pelvis in 2010,

 and the incidence of this cancer is reported to be increasing.

 Renal cell carcinoma (RCC), originating within the renal cortex, constitutes about 85% to 90% of primary renal tumors. The most common subtype of RCC is clear cell carcinoma, arising from the proximal tubule, and constitutes approximately 75% to 85% of new diagnoses.

	The past several decades have witnessed a significant increase in the understanding of the biology of RCC, leading to development of many new therapeutic targets and a greater availability of newer drugs for RCC management. A majority of kidney cancers are believed to be related to changes in a gene called von Hippel—Lindau (VHL). A loss of functional 

 gene results in an increased amount of a protein known as hypoxia-inducible factor, which thereafter leads to highly vascular tumors. Overexpression of hypoxia-inducible factor in kidney cancer is also related to stimulation of a receptor called the mammalian target of rapamycin (mTOR). Both the vascular endothelial growth factor (VEGF) and the mTOR pathways clearly provide opportunities for the development of molecularly targeted drugs in RCC (

		Figure. Mechanism of Action of Targeted Therapies in Renal Cell Carcinoma

		Reprinted with permission from Courtney et al. Curr Oncol Rep. 2009;11(3):218-226.

		GF indicates growth factor; GFR, growth factor receptor; HIF, hypoxia-inducible factor; mTORC1, mTORC2, mammalian target of rapamycin complexes 1 and 2; PDK1, phosphoinositide-dependent kinase-1; PI3K, phosphatidylinositol 3-kinase; SDF, stromal cell-derived factor; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau.

	Historical Treatment of Advanced Renal Cell Carcinoma

	Dramatic and sustained remissions had been seen occasionally in RCC patients with medications known to invoke immune responses. Until only about five years ago, immunotherapeutic agents such as interleukin-2 or interferon alfa were the mainstay of initial treatment of RCC. It is thought that immunotherapeutic agents cause killing of tumor cells by activated T cells and natural killer cells. Among the various immunotherapeutic strategies used to treat advanced RCC, high-dose bolus interleukin-2 induced durable remissions in about 15% to 20% of patients, but its use had been limited by severe toxicity and the need for specialized care (eg, admission to an intensive-care unit) during treatment. Therefore, this treatment approach was largely restricted to carefully selected patients with optimal organ function, who could withstand the possibility of severe hypotension.

 Subsequently, lower-dose interleukin-2 regimens were used to decrease toxicity, but they appeared to be less effective. Response rates (about 10%-15%) have also been seen with low-dose interleukin-2 and interferon alfa.

	Better understanding of the molecular biology of RCC led to identification of new therapeutic targets, which in turn led to development of molecular therapies that have now been integrated into the routine treatment algorithm of patients with advanced RCC. These novel therapies targeting the VEGF or the mTOR pathway are both more active as well as less toxic than immunotherapies that were used before.

	The importance of angiogenic pathways in the biology of RCC is now well established. As with many other tumors, RCC must induce new blood vessels in order to receive nutrients and oxygen required for progressive cancer growth. VEGF is the strongest proangiogenic protein, and inhibiting VEGF has been proven to be of clinical value in many malignancies, including metastatic RCC.

	Several angiogenic inhibitors have been approved, and many others are in clinical development for RCC. Two different approaches proven to have clinical activity in blocking the VEGF pathway in RCC are inhibition by small-molecule tyrosine kinase (TK) inhibitors (eg, sunitinib, sorafenib, pazopanib) and binding with an antibody (bevacizumab). Small-molecule TK inhibitors block the intracellular domain of the VEGF receptor, while bevacizumab binds with circulating VEGF and prevents activation of the VEGF receptor.

 In contrast to older immunotherapies, these newer agents demonstrated both significantly superior efficacy and better safety profiles, and thus changed the management landscape of metastatic RCC. Although all phase III pivotal studies showed prolongation in progression-free survival (PFS) and a strong trend toward improved overall survival (OS), only one of these studies increased OS to the level of statistical significance.

	The mTOR pathway, which has a central role in the regulation of cell growth, is dysregulated in multiple cancer types. This pathway stimulates protein synthesis after receiving input from multiple signals including growth factors, hormones, nutrients, and other stimulants. The mTOR pathway is involved in additional critical cellular functions (eg, protein degradation), as well as in angiogenesis, and is most dysregulated in patients with poor prognostic factors such as high nuclear grades.

 Use of mTOR pathway inhibitors represents a relatively novel therapeutic approach in the targeted treatment of malignancies. So far, two mTOR inhibitors, temsirolimus and everolimus, have been approved and widely characterized for treatment of advanced RCC. These agents lead to G1 growth arrest after binding to a protein complex and inhibiting mTOR, and have been shown to be effective in both first-line and second-line advanced RCC.

 The first-line trial showed improved overall survival; the second-line trial was halted by the Data & Safety Monitoring Board after 191 progression events were observed, with progression occurring in 65% (90/138) of placebo patients compared with 37% (102/272) of everolimus-treated patients. Patients on placebo crossed over to the active drug after the trial was halted. The significantly improved PFS in the everolimus arm remained consistent throughout trials in all three Memorial Sloan-Kettering Cancer Center risk groups.

 Clearly mTOR inhibitors are proven and highly active agents in advanced RCC and also have proven effects on OS, the hardest endpoint to achieve.

	With the availability of 4 VEGF inhibitors and two mTOR inhibitors for advanced RCC, it becomes challenging to choose therapeutic options for a patient. Complicating this choice is the fact that none of these agents has been compared head-to-head in a clinical trial, and a cross-study comparison of efficacy endpoints may lead to erroneous conclusions. The only thing that can be stated definitely about efficacy is that out of four phase III trials of VEGF inhibitors in advanced RCC, one has shown a survival improvement while the other three trials have not shown survival improvements. In contrast, among the two phase III trials of mTOR inhibitors, one has shown survival improvement and one was stopped after an interim analysis showed a high-magnitude difference in PFS.

	Because the efficacy of these different agents is likely to be similar, the choice of therapy in advanced RCC is more likely to be individualized by physicians on the basis of the patients’ comorbidities and the side effects they can tolerate. There are clearly differences in side effects between the VEGF inhibitors and the mTOR inhibitors, and understanding these differences may help when making personalized decisions. Although all VEGF inhibitors could lead to serious cardiovascular and thromboembolic events, the most serious event related to mTOR inhibitor class is drug-induced pneumonitis. The baseline comorbidities (eg, hypertension, heart disease, or cerebrovascular disease vs preexisting pulmonary dysfunction) are likely the most important factors in choosing between the two classes of agents. Even among VEGF inhibitors, there are some differences between oral VEGF TK inhibitors and bevacizumab. In the following three sections, I discuss the side effects associated with these three broad categories of medications used in advanced RCC: oral small-molecule VEGF TK inhibitors, bevacizumab, and mTOR inhibitors.

	The most extensive data regarding the side effects from oral VEGF TK inhibitors come from patients treated with sunitinib and sorafenib.

	Small-molecule VEGF TK inhibitors are associated with hypertension and, less commonly, renal disease. A systematic review analyzed the incidence of hypertension in more than 4500 patients treated with sorafenib in nine prospective studies.

 New-onset hypertension was reported in 23% of patients and was considered severe or life-threatening in 6%. In a separate analysis of approximately 5000 patients from 13 clinical trials treated with sunitinib, the incidence of all-grade and high-grade hypertension was 22% and 7%, respectively.

 This meta-analysis also found a significant risk of renal dysfunction. Both of these studies concluded that there is significant risk of developing hypertension with these drugs.

	The Investigational Drug Steering Committee of the National Cancer Institute convened an interdisciplinary cardiovascular toxicities expert panel to evaluate the risk of hypertension and renal dysfunction with VEGF inhibitors and to make recommendations. The panel recommended conducting a formal risk assessment for potential cardiovascular complications in patients receiving VEGF inhibitors,

 and also suggested proper agent selection, dosing, and scheduling of follow-up so that the complications associated with excessive or prolonged elevation in blood pressure could be avoided.

	VEGF TK inhibitors are also associated with a slight but definite increased risk of arterial thromboembolic events. In a systematic review that included more than 10,000 patients treated with sunitinib or sorafenib in 10 trials, the incidence of arterial thromboembolic events was 1.4%, which was threefold the risk found in the control population.

 The phase III pazopanib trial also reported similarly elevated risk of arterial thromboembolic events compared with placebo.

	VEGF TK inhibitors have also been reported to increase the risk of cardiotoxicity. In retrospective series and clinical trials, sunitinib has been associated with a decline in left ventricular ejection fraction in up to 28% of treated patients and clinical heart failure in up to 15% of treated patients. Among the patients treated in the pivotal randomized trial leading to sunitinib approval for treatment of advanced RCC, 21% of patients experienced a decline in left ventricular ejection fraction, and this decline was symptomatic in 10% of the patients.

 Presence of hypertension and a history of coronary artery disease are believed to increase this risk of cardiac toxicity.

	Another adverse event frequently observed in patients treated with VEGF TK inhibitors is thyroid dysfunction, most commonly hypothyroidism. In a single institution series of 73 patients treated with sunitinib, 56 patients (77%) had abnormal thyroid function tests consistent with hypothyroidism, and 47 had clinical signs or symptoms possibly related to hypothyroidism.

 Thyroid hormone replacement was given to 17 patients, 9 of whom had an improvement in symptoms. In addition to hypothyroidism, some reports have also described transient thyrotoxicosis with sunitinib. Although thyroid dysfunction also occurs in patients treated with sorafenib, it appears to be less frequent. Because of the high prevalence of hypothyroidism, regular surveillance of thyroid-stimulating hormone levels is warranted during sunitinib therapy.

	A variety of cutaneous effects are also seen with oral VEGF TK inhibitors. The most common skin manifestation is a hand-foot skin reaction, which differs in its clinical presentation from the classical acral erythema caused by conventional chemotherapeutics. Patients treated with VEGF TK inhibitors who develop cutaneous effects have localized tender lesions, appearing as blisters or hyperkeratosis in areas of trauma or friction. Hyperkeratosis is frequent, developing in more than one-half of affected patients, and typically presents as yellowish, painful, hyperkeratotic plaques localized to the pressure sole areas such as heels or metatarsals. The frequency of cutaneous effects appears to be higher with sorafenib (30%-60%) than with sunitinib (10%-20%). Cutaneous side effects are recognized to increase with cumulative exposure to the drugs. An international consensus panel recommends that preexisting hyperkeratotic areas and calluses should be removed with a manicure and/or pedicure, using appropriately sterilized instruments, and exposure of hands and feet to hot water should be avoided, as this is believed to exacerbate symptoms.

	Elevations of the pancreatic enzymes lipase and amylase have been reported with VEGF TK inhibitors, although overt pancreatitis is rare. Blood glucose levels may be reduced in diabetic patients, and thus should be monitored in patients who are treated with VEGF TK inhibitors and have the comorbidity of diabetes. Antidiabetic medications may need to be adjusted.

	Severe and occasionally fatal hepatotoxicity has also been observed. Therefore, patients treated with these agents should be monitored for evidence of liver toxicity, and treatment should be interrupted or discontinued if evidence of toxicity is observed.

	Skeletal muscle wasting is a common phenomenon in patients with advanced cancer. However, it is also known to be an adverse effect associated with the use of VEGF TK inhibitors. The loss of muscle mass contributes to asthenia and fatigue, and is mostly progressive with cumulative exposure.

	Among the three broad groups of medications classified in this discussion, the agent with the most data on adverse events is bevacizumab. Hypertension is a frequent side effect of bevacizumab, and guidelines for pretreatment assessment, monitoring, and management of elevated blood pressure in patients receiving bevacizumab are available.

 Although the effects of bevacizumab on hypertension, cardiac toxicity, arterial and venous thromboembolic events, and albuminuria appear similar to those of oral VEGF TK inhibitors, a few of the side effects more commonly seen with oral VEGF TK inhibitors are not seen with bevacizumab. These include thyroid dysfunction, cutaneous effects, pancreatic and liver enzyme elevations, and skeletal wasting. On the other hand, hemorrhage and gastrointestinal perforations are known to occur with bevacizumab; these complications are not commonly seen with oral VEGF TK inhibitors.

	mTOR inhibitors have specific class-associated adverse events, making it critical to recognize and manage them appropriately. In a recent review article, Rodriguez-Pascual et al

 describe the most relevant emergent toxicities and their management and conclude that most of the toxicities, if recognized and managed appropriately, should resolve with minimal impact on patients’ quality of life or on the antitumor efficacy of the anticancer therapy.

	Among the side effects observed with temsirolimus, the most frequent ones are asthenia, rash, anemia, nausea, and anorexia.

 Severe adverse events have mostly been uncommon; the incidence of the most frequent grade 3 or 4 adverse events of anemia, asthenia, and hyperglycemia was 20%, 11%, and 11%, respectively.

 A smaller proportion of patients developed hyperlipidemia. The most frequent severe adverse events in patients treated with everolimus included lympho-penia and hyperglycemia, occurring in 15% and 12% of patients, respectively.

 A smaller incidence of stomatitis (3%) has also been observed. Attention to routine hematology and blood glucose/cholesterol levels, especially in patients who have preexisting diabetes or hypercholesterolemia, will help in the overall management of these patients.

	With the intravenous mTOR inhibitor temsirolimus, hypersensitivity reactions have also been reported and may be severe or life-threatening.

 Therefore, premedication with diphenhydramine is recommended with each dose of temsirolimus.

	The class-specific side effect associated with mTOR inhibitors is pneumonitis. Low-grade pneumonitis is much more common than severe pneumonitis. Radiographic findings consistent with drug-induced pneumonitis have been detected in 36% of patients receiving temsirolimus in an independent review of serial radiographic studies.

 X-ray findings include ground glass opacity or consolidation, and more than 50% of these findings are asymptomatic. Common management includes antibiotics and/or glucocorticoids. Clinical suspicion of symptomatic drug-induced lung toxicity generally justifies treatment discontinuation and consideration of an alternate agent.

	Like temsirolimus, everolimus has also been associated with pneumonitis. Clinical pneumonitis was suspected in 37 (14%) of the 274 patients who received everolimus in the pivotal phase III trial.

 Most of these cases were low grade (grade 1-2); 10 (3.6%) had grade 3 pneumonitis, and none had grade 4 pneumonitis. Dedicated radiologic review of available serial radiographic studies found a higher percentage of new radiographic findings, even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9% vs 15.2%). The most common radiographic findings included focally consolidative areas at the lung bases or ground glass opacity. Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in patients treated with everolimus. Monitoring and management guidelines have been suggested for patients who develop symptoms or radiographic changes while receiving everolimus, based on the grade of pneumonitis (

		Table. Suggested Guidance for mTOR-Associated Pneumonitis

					Asymptomatic; radiographic findings only

					Continue drug therapy; observe patient closely (eg, repeat chest X-ray/CT scan every 2 cycles)

					Symptomatic but not interfering with ADLs

					Reduce everolimus dose to 5 mg daily until improvement to grade 1 or less and interrupt everolimus therapy if improvement to grade 1 or less does not occur within 3 weeks; administer glucocorticoids only if cough is troublesome; obtain chest CT scan and pulmonary function tests each cycle

					Symptomatic and interfering with ADLs; oxygen indicated

					Interrupt everolimus therapy until improvement of pneumonitis to grade 1 or less; administer glucocorticoids after infection is excluded

					Life threatening; ventilatory support indicated

					Permanently discontinue everolimus therapy; prescribe systemic glucocorticoids after infection is excluded

		ADLs indicates activities of daily living; CT, computed tomography; mTOR, mammalian target of rapamycin.

	Baseline lung function appears to be a risk factor for development of pulmonary side effects with mTOR inhibitors. Therefore, before starting therapy with an mTOR inhibitor, an evaluation for preexisting pulmonary issues should be considered. Patients with moderate-to-severe chronic obstructive pulmonary disease or those who are unlikely to tolerate a pulmonary challenge should preferably be offered treatments other than mTOR inhibitors.

	Retrospective analyses suggest lack of cross-resistance among drugs targeting the VEGF pathway and those that inhibit mTOR. The RECORD-3 trial is trying to determine the optimal sequence of a VEGF inhibitor and an mTOR inhibitor. This large phase III trial plans to randomize patients with untreated advanced RCC to sunitinib followed by everolimus versus everolimus followed by sunitinib (Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients With Metastatic Renal Cell Carcinoma [RECORD-3]; 

http://clinicaltrials.gov/ct2/show/NCT00903175

	There is a biologic hypothesis that synergism might be possible among VEGF and mTOR inhibitors, though combinations may also result in additive toxicity. Results of a recent phase II trial of everolimus and bevacizumab as first-line as well as second-line treatment have been published.

 The regimen was well tolerated by most patients, with the toxicity profile as expected based on the known toxicities of these two agents. Grade 3-4 proteinuria was more frequent than expected (25%) and led to treatment discontinuation in 6 patients. The study concluded that the combination of bevacizumab and everolimus is active and well tolerated in the treatment of advanced clear cell renal cancer, either as first-line treatment or after treatment with sunitinib and/or sorafenib. Cancer and Leukemia Group B is now planning to test the benefits of this combination regimen as later-line therapy after previous treatments with 1 or multiple oral VEGF TK inhibitors.

 The primary endpoint is OS, and the trial implements a futility rule based on interim evaluation of PFS.

	Many adjuvant trials have been undertaken in an attempt to reduce the risk of recurrence among patients who undergo surgical resection for locally advanced renal cancer. However, no clear benefit has been identified to date. A recent meta-analysis identified 12 trials in the adjuvant setting, which used hormone therapy, biochemotherapy, chemotherapy, vaccine, or immunotherapy.

 The meta-analysis confirmed the evidence that no studied systemic therapy so far provides improvement in survival for patients who undergo surgical resection of RCC. This may change with the advent of adjuvant trials of targeted agents in resected renal cancer. Various adjuvant trials with oral VEGF inhibitors or mTOR inhibitors are currently ongoing and will determine whether an adjuvant therapeutic strategy with a molecularly targeted therapy adds value in the care of these patients.

	Other experimental approaches for treatment of RCC include immunomodulatory drugs (eg, lenalidomide), vaccines, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation.

	Akhil Kumar, MD, is the owner of Oncology Consultants in Miramar, Florida.

	The author has reported no financial interest with an entity that would pose a conflict of interest with the subject matter of this article.

	Akhil Kumar, MD, 5253 SW 157th Ln, Miramar, FL 33027. E-mail: 

			Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010 [published correction appears in 

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			Belldegrun A, Webb DE, Austin HA 3rd, et al. Effects of interleukin-2 on renal function in patients receiving immunotherapy for advanced cancer. 

			Atkins MB. Management of advanced renal cancer.

			Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. 

			Figlin RA, Seligson DB, Wu H, et al. Characterization of the mTOR pathway in renal cell carcinoma and its use in predicting patient selection for agents targeting this pathway. 

			Hudes G, Carducci M, Tomczak P, et al; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. 

			Motzer RJ, Escudier B, Oudard S, et al; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. 

			Wu S, Chen JJ, Kudelka A, Lu J, Zhu X. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. L

			Zhu X, Stergiopoulos K, Wu S. Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. 

			Maitland ML, Bakris GL, Black HR, et al; Cardiovascular Toxicities Panel, Convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. 

Articles

In order to help community oncologists optimize patient outcomes, this review summarizes clinical issues associated with specific therapies and the background pivotal data.

Targeted Therapies in Advanced Renal Cell Cancer: A Critical Review

Extracorporeal photopheresis (ECP) is a form of apheresis and photodynamic therapy in which blood is treated ex vivo with a photoactivable drug (ie, one that is activated with ultraviolet light). The whole process takes approximately 3 to 4 hours to complete and involves leukapheresis, separation of the buffy coat, photoactivation, and finally reinfusion. ECP has been approved by the FDA for cutaneous T-cell lymphoma (CTCL) since 1988.

	The history of the photoactivable drug methoxsalen (8-methoxypsoralen) dates to ancient Egypt. Medicinal properties were observed in 

, a plant commonly known as Bishop’s weed, which was found next to the Nile River. The injudicious use of the weed, which the Egyptians used to treat skin ailments, caused skin damage. This damage is now understood to be activated by ultraviolet radiation (UVA) and is the result of phototoxic mechanisms that are dependent on the psoralen content of Bishop’s weed. The results are clinical changes such as erythema, bullae in the skin 24 to 72 hours later, and hyperpigmentation. Methoxsalen’s exact mechanism of action is not known, but in the presence of UVA methoxsalen intercalates with the patient’s DNA and produces adducts, thereby deranging DNA synthesis in those cells. A second mechanism, which is being recognized more often and is the subject of ongoing research, is the immune effects on macrophages, dendritic cells, and helper T cells. This second mechanism is thought to be more likely contributing to the benefits seen with ECP in graft-versus-host disease (GVHD).

	Oral methoxsalen provides clinical benefit to patients with psoriasis, vitiligo, and CTCL. In CTCL, ECP is approved for the palliative treatment of the skin manifestations of CTCL that are unresponsive to other forms of treatment. Additional disease areas in which ECP has been shown to provide benefit are GVHD and autoimmune diseases such as multiple sclerosis.

	GVHD occurs when immune cells transplanted from a nonidentical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient. The leading cause of GVHD is allogeneic hematopoietic cell transplantation (HCT), though solid organ transplants, blood transfusions, and maternal-fetal transfusions also reportedly cause GVHD.

	GVHD has been classically divided into acute and chronic subtypes based on the time of onset from the HCT. Acute GVHD occurs when the disease presents within the first 100 days of HCT and chronic GVHD refers to the disease having onset after the first 100 days. However, this division at day 100 post-HCT is artificial, and there has been a shift toward defining acute and chronic GVHD based on the clinical manifestations, rather than the arbitrary cutoff of a particular date posttransplantation.

	Clinically significant acute GVHD occurs in 9% to 50% of patients who receive an allogeneic HCT from a genotypically HLA-identical sibling, despite intensive prophylaxis with immunosuppressive agents such as methotrexate, cyclosporine, tacrolimus, corticosteroids, or antithymocyte globulin. Patients with acute GVHD commonly demonstrate a classic maculopapular rash, liver toxicity, diarrhea, and affects on the hematopoietic system.

	Chronic GVHD occurs in more than 50% of long-term survivors of HLA-identical sibling transplants and can occur after previous or ongoing acute GVHD. It may also appear in patients without a history of acute GVHD (ie, de novo chronic GVHD). The target organs affected by chronic GVHD differ from those observed with acute disease. The skin involvement with chronic GVHD resembles lichen planus or the cutaneous manifestations of scleroderma. Patients may also have dry oral mucosa with ulcerations and sclerosis of the gastrointestinal tract, and a rising serum bilirubin concentration. Lung involvement also commonly occurs with chronic GVHD. With chronic GVHD, there is a marked immunodeficiency due to direct immunosuppressive effects and the consequences of the agents administered to treat the disease. Since chronic GVHD also causes a delay in the recovery of immune function, patients remain immunodeficient as long as the disease is active. In chronic GVHD, helper T cells react against major histocompatibility complex and generate excessive help. This enhanced help activates a subpopulation of selfreactive (possibly host) B cells, thereby causing autoantibody formation. Autoantibodies found in patients with chronic GVHD are similar to those observed in systemic lupus erythematosus and other rheumatologic disorders, implicating autoimmunity and autoimmune disease-related gene polymorphisms as important components of chronic GVHD.

		Table 1: Complete Resolution Rates with ECP in Different Grades of Acute GVHD

	The management of a patient who has developed acute GVHD primarily includes steroids, and the durable remission rate with steroids in acute GVHD ranges from 24% to 40%.

 The second-line agents, such as cyclosporine, are generally less successful. A prospective phase II trial of ECP in steroidrefractory GVHD or steroid-dependent GVHD showed complete resolution of GVHD in 82% of patients with cutaneous involvement, 61% with liver involvement, and 61% with gut involvement 

 Patients were treated on 2 consecutive days (1 cycle) at 1- to 2-week intervals until improvement and thereafter every 2 to 4 weeks until maximal response. An analysis of the relationship of response of acute GVHD to transplant-related mortality and survival was also conducted. The 4-year survival for those in whom acute GVHD had a complete resolution was 59%, which compares very favorably to the 11% of those who did not achieve complete resolution of acute GVHD. Overall, the study confirmed that ECP allows for accelerated tapering of corticosteroids, which had a significantly favorable impact on transplant-related mortality 

		Figure 1: Relationship of Complete Resolution with ECP to Long-Term Survival

		ECP indicates extracorporeal photophoresis; CR, complete resolution.

	The treatment of chronic GVHD is determined in part by the severity of the disease. The severity is graded as either limited or extensive and is based on the clinical severity and target organs affected. Treatment is individualized and commonly includes combination of steroids with other immunosuppressants, such as cyclosporine or azathioprine. Patients with limited chronic GVHD have a favorable prognosis even without therapy, while those who have extensive GVHD, particularly those with multiorgan involvement, have poor longterm outcomes. There are numerous studies that have shown significant clinical benefit of ECP in chronic GVHD.

 The phase II study by Alcindor and colleagues included 25 patients with chronic GVHD who were treated with ECP either weekly or on 2 consecutive days once every 2 weeks. Skin improvement was shown in 71% of patients and response rates were similar in patients who were treated early (<18 months from transplant) versus late (>18 months from transplant). Steroid sparing or tapering of immunosuppression was seen in more than 80% of the patients. A correlation of the response rates with various baseline clinical characteristics is provided in 

		Table 2: Correlation Between Response to ECP and Baseline Clinical Characteristics

		ECP indicates extracorporeal photophoresis.

	The data in both acute and chronic GVHD largely are case series or single-center phase II studies. Though these data have the limitation of selection bias, the responses seen are generally very impressive in patients who are refractory to conventional measures. There are also several advantages of ECP when compared to conventional therapies. There is selective benefit in GVHD without the increased rates of infection and malignant disease relapse associated with the use of conventional immunosuppressants. In responding patients, ECP treatment can lead to a reduction and, often, a cessation of treatment with corticosteroids and other immunosuppressive agents. ECP is associated with few acute side effects from the therapy itself; these effects include occasional hypotensive episodes, mild pyrexia, and general tiredness and lethargy. There are no reported long-term side effects of this treatment, despite more than 5 years of follow-up in many patients. Analysis of survival data reveals increased survival in patients who respond. This confirms that the benefit of controlling GVHD is not lost through toxicity of the therapy or disease relapse, which are major problems with alternative therapies.

			Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graftversus- host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. 

			Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. 

			Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graftversus- host disease: secondary treatment. 

			Antin JH, Chen HR, Couriel DR, et al. Novel approaches to the therapy of steroid-resistant acute graft-versus-host disease. 

			Greinix HT, Knobler RM, Worel N, et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. 

			Alcindor T, Gorgun G, Miller KB, et al. Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease. 

			Gonzalez Vicent M, Ramirez M, Sevilla J, Abad L, Diaz MA. Analysis of clinical outcome and survival in pediatric patients undergoing extracorporeal photopheresis for the treatment of steroid-refractory GVHD. 

			Jagasia MH, Savani BN, Stricklin G, et al. Classic and overlap chronic graft-versus-host disease (cGVHD) is associated with superior outcome after extracorporeal photopheresis (ECP). 

Extracorporeal photopheresis takes approximately 3 to 4 hours to complete and involves leukapheresis, separation of the buffy coat, photoactivation, and finally reinfusion.

Using Extracorporeal Photopheresis in the Treatment of Graft-Versus-Host Disease

“Luminal A genetic signature in node-negative, estrogen receptor- (ER-) positive breast cancer predicts a very high disease-free survival rate of more than 95% at 8.5 years with adjuvant hormonal therapy alone, and thus, in general, should not be offered adjuvant chemotherapy” said Daniel F. Hayes, MD, Stuart B. Padnos Professor of Breast Cancer Research at University of Michigan at this year’s Annual Meeting of the American Society of Clinical Oncology.

Hayes, who is also a co-director of the Breast Care Center and the clinical director of the Breast Cancer Program at University of Michigan, was discussing research presented by Aleix Prat, MD from University of North Carolina.

Hayes added that among the various gene signatures available, most are similar in identifying either the low-risk or the high-risk breast cancers. However, some differences among various gene signatures are seen in predicting breast cancers with intermediate risk for relapse.

Prat, the lead investigator of the research paper, stated that among the ER+ breast cancer, all of the different intrinsic molecular subtypes are represented, although the luminal subtypes predominate. His group evaluated the prognostic ability and biologic significance of 6 independent gene-expression signatures, including Oncotype DX, Mamma print, PAM50, Rotterdam 76-gene signature, endocrine sensitivity index (SET), and the estrogen-induced gene set. Each signature was evaluated as a continuous variable, as well as grouped according to respective published literature. A total of 1417 patients, comprising 686 node-negative and 731 node-positive, were identified and contributed to the study. All patients were evaluated with a combination of gene signature, and had early stage ER+ tumors treated only with adjuvant tamoxifen. As expected, approximately 85% of patients had the luminal subtypes, with 46% being luminal A and 39% being luminal B.

As per Prat, most signatures discriminated the relatively good prognosis Luminal A tumors from the poorer prognosis Luminal B or the HER2-enriched as well as the basal-like tumors. All the signatures were prognostic in all patients as well as in patients with node-negative or node-positive disease. When the signatures were combined together, there was a small increase in prognostic capacity for node-negative disease, while the increase in prognostic capacity for node-positive disease with the combination of various signatures was minimal.

Prat concluded that despite tracking similar biology, a group of patients with very high disease-free survival of more than 95% was identified only in node-negative disease, thus suggesting that clinical features are still important in addition to the molecular features. He also stated that though different gene signatures are similar, they are not exactly the same, and differences are especially seen in patients predicted to have intermediate risk. It is in this group of patients that combination of gene signatures may provide additional advantage in accurately predicting the outcomes. Prat also added that the performance of gene signatures in node-positive appears minimal, and thus from a clinical perspective, these signatures should specifically aid in identifying patients with node-negative Luminal A breast cancers that might be considered for adjuvant endocrine therapies alone.

Prat A, Parker JS, Fan C, et al. Concordance among gene-expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen. 

Luminal A genetic signature in node-negative, estrogen receptor- (ER-) positive breast cancer predicts a very high disease-free survival rate

Deciphering the Challenge of the Genomic Era in Breast Cancer

“Treatment with lapatinib and capecitabine as initial therapy in an attempt to delay whole brain radiation (WBR) is a reasonable approach in a well-informed patient with brain metastasis and HER2+ breast cancer” said Nancy U. Lin, MD, regarding data from the LANDSCAPE trial presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) meeting.

“With an incidence of 30%-40%, central nervous system (CNS) metastases are common complications of HER2+ metastatic breast cancer, and the current standard practice is WBR. The whole brain irradiation can lead to neurological toxicity, and systemic treatments are universally held off during the time of WBR, and thus the frequently concomitant extra-CNS disease can worsen during this time," said Lin, who is an assistant professor of medicine at Harvard Medical School and holds active staff privileges at the Dana Farber Cancer Institute, Boston, Massachusetts.

As responses on CNS localization have been reported with the lapatinib + capecitabine combination after WBR, the LANDSCAPE trial evaluated this combination as first-line treatment for brain metastases in HER2+ metastatic breast cancer. "The aim to avoid or delay WBR, as well as provide an opportunity to treat both the CNS and the extra-CNS disease at the same time” said Thomas D. Bachelot, MD, PhD, the lead investigator of the LANDSCAPE trial, and an oncologist from Centre Léon Bérard, Lyon, France.

Patients in the LANDSCAPE trial were treated with 1250 mg of lapatinib/day combined with 2000 mg/m

/day of capecitabine days 1-14, every 21 days. The ASCO presentation detailed a remarkable CNS overall response rate of 67% among 43 efficacy-evaluable patients. Twenty one percent of patients had more than an 80% reduction in the size of CNS lesions, and 43% of patients also had a RECIST response in their extra-CNS disease. The median time to progression and median time to WBR were 5.5 months and 8.6 months, respectively. Additionally, the median survival had not been reached with a median follow-up of 14.1 months, with a 6-month survival of more than 90%, and 1-year survival of more than 70%.

Bachelot concluded that the combination has high activity in the initial treatment of patients with brain metastasis and HER2+ breast cancer, but needs to be further evaluated in phase III studies.

Lin said caveats of the trial were that, even though the inclusion criterion allowed patients with ECOG PS 0-2, approximately 5% of patients had an ECOG PS of 2, and thus this study was largely limited to patients with good performance status. Lin also commented that the treatment with lapatinib + capecitabine is associated with its own toxicities, including approximately 20% incidence of grade 3/4 diarrhea and another 20% incidence of grade 3/4 hand-foot syndrome. Nevertheless, Lin agreed that the combination has value in the management of patients with CNS metastasis in HER2+ breast cancer and may have the promise to reserve WBR in the future in a salvage setting.

Bachelot TD, Romieu G, Campone M, et al.LANDSCAPE: An FNCLCC phase II study with lapatinib (L) and capecitabine (C) in patients with brain metastases (BM) from HER2-positive (+) metastatic breast cancer (MBC) before whole-brain radiotherapy (WBR). 

Lapatinib and capecitabine is a reasonable approach in a well-informed patient with brain metastasis and HER2+ breast cancer

Akhil Kumar, MD

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