	Various immunotherapeutic strategies to treat advanced melanoma have been under investigation for more than a decade—primarily vaccines and adoptive cell transfer (ACT) therapy. Most of these novel approaches appear relatively safe, but with differing levels of efficacy. Researchers continue to believe that some form of immunotherapy, either alone or combined with other therapeutics, may prove to be effective in late-stage melanoma. Data are accumulating in support of novel therapeutic immunotherapy regimens and schedules; these data are often incongruent with the dogma of the past few decades on how the host immune response becomes activated to cancer.

	Several early-phase clinical trials have shown that autologous and allogeneic tumor cell—based vaccines can be given safely with few adverse effects. One of the first such vaccines tested extensively in clinical trials was onamelatucel-L, a polyvalent whole–tumor cell vaccine derived from 3 human melanoma cell lines. Although early trials failed to show significant clinical benefit, a few complete and durable responses provided the impetus for two multicenter, phase III randomized trials in 1998.

 As part of the design of the onamelatucel-L trials, patients with stage IV melanoma were required to undergo definitive surgical removal of all metastatic disease prior to enrollment. Both trials closed prematurely, after an interim analysis revealed no probable efficacy over placebo.

 Evidence supports a hypothesis of first removing the bulk of disease, and long-term responses have indeed been observed in patients who had complete surgical resection of regional nodal disease without any adjuvant immunotherapy.

	Over the years, several other tumor cell—based trials

 have yielded interesting clinical outcomes. Overall, however, the application of strict response criteria finds that response rates remain exceedingly low. The next generation of whole—tumor cell vaccines has incorporated advances in gene transfer technology with the immunobiology of the cancer cell and host immune system. Initial preclinical studies have shown that a melanoma whole–tumor cell vaccine transduced with the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene confers a potent and long-lasting anti-tumor immune response.

 The secretion of GM-CSF by the transduced melanoma cells attract immune cells, such as antigen-presenting cells and T-lymphocytes, to the vaccine site.

 Several phase I/II clinical trials using this approach have been completed, with a few objective clinical responses noted.

 These early studies, however, involve small numbers of patients. Further clinical trials that enroll more patients are needed before strong conclusions can be made about the efficacy of this vaccine approach.

Peptide- and Dendritic Cell-Based Vaccines

	Rosenberg and associates performed one of the first clinical trials to use peptides derived from melanoma cells.

 The researchers used a modified immune-dominant peptide of the gp100 antigen, g209-2M, to vaccinate 11 patients with stage IV melanoma. They found that 10 (91%) of the patients showed a consistently high level of immunization against the native g209-217 peptide, but not against g280-288, the control peptide. Although many patients developed an immunologic response to the peptide vaccine, all patients went on to develop progressive disease. This study, however, provided a central proof-of-principle that patients with advanced melanoma could mount an immune response against their own self-antigens, an exciting concept not appreciated previously. The trial also highlighted that an immunologic response does not necessarily equate with a clinical response.  

	Although the vaccines are seemingly effective at enhancing a tumor-antigen—specific immune response, clinical outcomes have been uniformly disappointing. A recent analysis of 28 different peptide-based vaccines in stage IV patients revealed an objective response rate (ORR) of just 2.9%.

 Other studies using a peptide-based vaccination strategy have produced only limited responses.

	Another novel approach to melanoma immunotherapy involves using autologous dendritic cells (DCs) as potent antigen-presenting cells that interact with other immune cells and activate an antigen-specific immune response. The first published clinical trial of DC vaccination was in 1995; this has been followed by 98 additional clinical trials in 15 different countries involving >1000 patients.

 Of these 98 trials, 28 focused on patients with advanced stages of melanoma. The trials have shown that DC-based vaccines are safe, producing few severe adverse effects. Yet, their record of effectiveness has been disappointing, with an ORR of <5% in most trials. A recent DC-based vaccination trial by Schadendorf and colleagues from the German Dendritic Cell Study Group produced similar results.

	One approach to immunotherapy is to use viral vectors as carriers of cDNA encoding for the gene of interest. The advantage of using recombinant viruses to carry gene encoding for an antigen is that viruses efficiently infect cells, particularly DC.

 Although the use of viral vectors is appealing for multiple reasons, several induce a tremendous antiviral-neutralizing antibody response to first and subsequent vaccinations, severely limiting the effectiveness of this approach. One exception may be the use of fowlpox viral vectors, which appear not to produce neutralizing antibodies. Other studies have used adenovirus, vaccinia, canarypox, or fowlpox viruses, encoding various melanoma antigens, such as gp100, MART-1, tyrosine, or MAGE. Only occasional immunological or clinical responses have been observed.

	In a recent study, recombinant vaccinia and fowlpox virus encoding the antigen NY-ESO-1, used in a prime-boost vaccination setting, induced humoral and/or cellular responses in a majority of patients.

 Kaufman and colleagues have examined several combinations of a recombinant vaccinia virus in patients with unresectable melanoma,

evaluating the vaccines’ toxicity, therapeutic efficacy, and ability to generate melanoma-specific immunity. Despite using a plethora of viral vectors that encoded various melanoma-associated antigens and co-stimulatory molecules, results have been disappointing. Rosenberg and associatesdescribed using various viral vaccines to treat 160 patients, with only 2 demonstrating any clinical response.

	Together, the various viral vaccination strategies have an ORR of only 1.9%. A recent phase I trial showed that intra-tumoral plasmid IL-12 gene electroporation was highly efficient at delivering plasmid-DNA across 7 dosing groups. IL-12 protein levels increased up to 18-fold above mean baseline in patients with stages IIIB/C and IV melanoma.

 Daud and colleagues used electroporation with a plasmid vector containing the IL-12 gene to treat accessible metastatic lesions in 24 patients. Of the evaluable patients, 10 (53%) exhibited stable disease (SD) or distant-tumor regression; 4 of the 19 patients (21%) with distant lesions showed distant clinical response. A total of 3 patients had complete remission (CR) lasting beyond study follow-up, and 2 of these received no subsequent systemic therapy; the third received dacarbazine after plasmid IL-12 treatment but prior to exhibiting complete tumor regression. In addition, 6 patients exhibited SD at distant sites that lasted 4 to 20 months.

	Grinshtein and associates recently examined the effectiveness of neoadjuvant vaccination in a murine melanoma model at improving tumor-free survival following surgery.

 They found that vaccinating mice in the neoadjuvant setting was far superior to vaccination in the adjuvant setting, providing nearly 100% protection against relapse. Further, neoadjuvant vaccination appeared to increase the overall number of antigen-specific T-cells and tumor-infiltrating lymphocytes within the tumor.

	ACT therapy for melanoma patients initially involves isolating highly active, melanoma-antigen—specific autologous T-cells from a patient and growing large numbers of the cells in vitro. The reactive T-cells are then infused back into the patient. ACT therapy is usually administered along with high-dose IL-2, which appears to be a promising approach for advanced melanoma.

 Initial studies using cloned melanoma-antigen—specific T-cells, with or without IL-2, failed to observe an objective anti-tumor response.

 Another method uses tumor-infiltrating lymphocytes (TIL), which has the hypothetical advantage of containing a diverse effector population comprised of CD4 and CD8 T-cells. In clinical studies using TIL in conjunction with high-dose IL-2, 33% of patients experienced objective tumor regression. Unfortunately, these clinical responses were transient, with the transferred TIL cells failing to persist.

	To enhance the efficacy of ACT therapy using TILs, a lymphodepleting, non-myeloablative preconditioning chemotherapy regimen consisting of cyclophosphamide and fludarabine was administered prior to the highly reactive melanoma-antigen—specific TIL cells in combination with high-dose IL-2.

 The initial study involved 13 patients whose melanoma had progressed despite multiple treatments, including high-dose IL-2. Objective clinical response was observed in 6 patients, and 4 demonstrated mixed response, with some lesions regressing and others progressing.

 In a recent follow-up study, cancer regression in patients with refractory metastatic melanoma with large, vascularized tumors was noted in a striking 18 of 35 patients (51% response rate); 4 patients had complete regression of all metastatic disease.

 It is clear that highly reactive cytotoxic T-cells can mediate the destruction of large, bulky tumors and render stage IV melanoma patients disease-free, albeit rarely.

	Dudley and colleagues recently reported on two different sequencing trials in patients with stage IV melanoma that involved administering non-myeloablative chemotherapy with whole body radiotherapy. They used the previously described lymphodepleting preparative regimen of cyclophosphamide and fludarabine plus either 2 Gy or 12 Gy of total body irradiation (TBI) prior to ACT therapy.

 While non-myeloablative chemotherapy alone was associated with an ORR of 49%, the addition of 2 Gy of TBI increased the ORR to 52%, and ORR increased to 72% with the use of 12 Gy of TBI. This study yields the highest ORRs to date for the immunotherapeutic treatment of patients with stage IV melanoma.

	Targeted therapy for patients with metastatic melanoma has expanded rapidly over the past decade, with several novel agents currently being examined in early-phase clinical trials. Regulatory T-cells seem to play an important role in host immune tolerance, autoimmunity, and suppression of the immune response to cancer.

 The use of targeted therapeutics against melanoma remains an active area of research, and we continue to learn about these agents through important clinical trials.

	The development of denileukin diftitox, an immunotoxin specific for the IL-2 receptor, has become standard therapy for patients with cutaneous T-cell lymphoma, producing an ORR of 30% to 40%.

 Recently, Dannull and associates showed that denileukin diftitox induced elimination of regulatory T-cells (Tregs), and, followed by vaccination with RNA-transfected DC, significantly improved the stimulation of tumor-specific T-cell responses in renal cell carcinoma patients.

 In contrast, a study by Attia and colleagues concluded that denileukin diftitox does not eliminate the absolute number of Tregs or decrease their suppressive activity.

 Another more recent report showed that the transient depletion of T-cells with denileukin diftitox contributed to significant tumor regression and partial response (PR) in 5 (31%) out of 16 patients.

	Numerous studies have substantiated the central role of cellular signaling through the RAF/MEK/ERK/MAPK pathway and its involvement in melanocytic tumorigenesis. Sorafenib is an orally administered multikinase inhibitor that targets not only BRAF serine/threonine kinases, which are frequently mutated in melanoma, but also several tyrosine kinase receptors associated with tumor angiogenesis and progression. Despite strong pre-clinical data, a recent randomized phase II trial found that sorafenib monotherapy demonstrated little or no anti-tumor activity in advanced-melanoma patients.

 There appeared to be no correlation between modest anti-tumor activity and the presence of an oncogenic V600E BRAF mutation within exon 15.

	Other studies investigated sorafenib along with chemotherapeutic agents that had previously demonstrated some activity against melanoma, such as carboplatin and paclitaxel, in patients with advanced melanoma. This combination induced 1 CR (<1%), 27 PRs (26%), and 61 SDs (58%).

 In a phase I study of patients with advanced melanoma, sorafenib combined with dacarbazine induced PR in 3 of 10 evaluable patients and SD in 5 patients.

 Further investigations are underway that combine sorafenib with other cytotoxic agents.

Antisense oligonucleotides are short sequences of cDNA engineered to bind to specific gene sequences and prevent the translation of mRNA, with resultant abrogation of protein synthesis. It has been shown that one mechanism of melanoma cell survival depends on overexpression of the BCL2 gene, which produces an anti-apoptotic protein that blocks the release of cytochrome C. Down-regulation of the BCL2 protein results in a higher level of chemotherapy-induced apoptosis in human cancer xenografts.

	A recent randomized phase III trial accruing 771 patients compared dacarbazine alone to dacarbazine plus oblimersen (Genasense), a BCL2 antisense oligonucleotide.

 At 24 months of follow-up, a trend toward improved overall survival (OS) was observed for the combination arm compared with the dacarbazine monotherapy arm (

). Dacarbazine plus oblimersen produced significant improvement in median progression-free survival, and rates of overall response, CR, and durable response.

	Interestingly, the 508 patients in the study with normal levels of lactate dehydrogenase (LDH) demonstrated significantly improved OS with the combined therapy. This indicates that LDH is an effective pretreatment biomarker and confirms an overall poor prognosis for patients with elevated LDH levels prior to treatment. The authors also suggest obtaining serum LDH levels to identify patients that are unlikely to benefit from oblimersen-dacarbazine treatment. Although the survival differences are marginal, they show that oblimersen demonstrates significant clinical activity in melanoma. To maximize the likelihood that oblimersen and similar agents will show statistically significant activity or improvements in survival, future trials with these drugs should probably be limited to patients with normal LDH levels.

	Another novel approach to the treatment of patients with metastatic melanoma involves using different antibodies to reduce the sensitivity of activated T-cells to negative regulatory signals. One mechanism of immune regulation is via CTLA-4 protein expression on activated T-cells, which transduces signals that inhibit T-cell activation and proliferation, as well as IL-2 production, back to the T-cell. It has been shown that the CTLA-4 receptor is present on Tregs, though recent data is contradictory as to whether CTLA-4 blockade leads to the depletion or impairment of Tregs.

CP-675206 is an IgG2 antibody with high affinity for CTLA-4 on the surface of T-cells. Ribas and colleagues recently conducted a phase I clinical trial involving 34 patients with stage IV melanoma.

 Patients received a single dose of CP-675206;4 (12%) had objective responses, 2 showed CR, 2 had PR, and 4 experienced SD. Autoimmune side effects were considerable and included vitiligo, dermatitis, thyroiditis, hypophysitis, and colitis.

More recently, a phase I/II trial investigated two dosing schedules of CP-675206 in patients with stage IV melanoma.

 One group (n = 43) received 10 mg/kg per month, and the other group (n = 41) received 15 mg/kg per month. ORR was similar in both groups, at 9.3% in the low-dose group and 9.8% in the high-dose arm (

). Each arm produced 1 CR and 3 PRs. Median survival was 9.97 months in the low-dose arm and 11.53 months in the high-dose arm, and 12-month survival rates were 32% and 46%, respectively. The most common adverse effects were minor to moderate diarrhea, rash, and pruritis. The relative ease of administration and the reduced frequency of adverse effects for patients in the 15 mg/kg arm led investigators to recommend the regimen for future studies.

Another anti-CTLA-4 antibody, MDX-010 (ipilim-umab), has also been tested in early-phase clinical trials. Hersh and colleaguespresented preliminary results from a phase II trial of 76 patients randomized to MDX-010 injections once a month for 4 months, alone or with dacarbazine.

 In the group treated only with MDX-010, PR was observed in 2 patients compared with 5 patients in the combination arm. These early results suggest that the MDX-010 antibody has activity in melanoma as a single agent and possibly improved efficacy combined with other therapies, such as vaccines, cytokines, or growth factors.

	A recent phase I/II study administered MDX-010 with concomitant high-dose IL-2 therapy to 36 heavily pre-treated patients with stage IV melanoma.

 Objective tumor response was observed in 8 (22%) patients, comprising 3 CR and 5 PR. Although there was no evidence of a synergistic effect between the antibody and IL-2, investigators observed a correlation between tumor regression and the development of autoimmune phenomenon, such as vitiligo, a finding supported by previous studies.

	Weber and colleagues have also shown MDX-010 monotherapy to be effective in a trial of 88 patients with stage IV melanoma.

 They investigated 3 dosing regimens: multiple doses of 5 mg/kg, multiple doses of 10 mg/kg, or single doses of 20 mg/kg. Across all arms, ORR was 4.6%, with 1 CR and 3 PR, and 14 SD, 9 of which lasted ≥24 weeks. The more rigorous 10 mg/kg schedule was associated with an increase in severe adverse effects, most commonly colitis with diarrhea. In the 10 mg/kg arm, 2 patients with SD regressed to PR by the end of the study and 2 patients improved from SD to CR by week 48; another patient had a sustained CR lasting >57 weeks. The disease control rate (CR PR SD) was 19% for the study overall, with the greatest rate of disease control observed in the 10 mg/kg dosing group, at 39%, compared with 14.4% for the 5 mg/kg arm and 13.3% for the 20 mg/kg arm. OS at 18 months was 39%, and at 2 years, it dropped to 30%. (

	In a phase I proof-of-concept study, 55 previously treated patients with advanced melanoma received PLX4032, a small molecule oral inhibitor of BRAF.

 Approximately 60% of patients with melanoma have the BRAF mutation, believed to drive cell division in melanoma. PLX4032 induces cell cycle arrest and apoptosis exclusively in cells positive for the V600E BRAF mutation and does not affect healthy cells, minimizing adverse effects. Patients without the BRAF mutation did not respond to PLX4032.

	After establishing a maximum tolerated dose (MTD) of 960 mg twice daily, researchers proceeded with a phase I extension study, in which 31 patients—all with the BRAF mutation&mdash;received the MTD until progression. Data for 27 evaluable patients showed a 70% ORR, including 1 CR after 3 cycles.

 Another 18 patients had PR, with 15 demonstrating >50% response. One patient with PR achieved CR after the data cutoff date. Minor response (10%-30%) was observed in 6 patients. Sites of tumor regression included subcutaneous tissue, liver, lung, bladder, gastrointestinal tract, and bone, and several patients had resolution of most symptoms. Although the study was not designed to measure PFS, investigators estimated PFS at ~8.5 months, noting that the median was not reached. Grade 3 dose-limiting toxicities included fatigue (7%), arthralgias (3%), photosensitivity (3%), and rash (3%).

 Squamous cell skin cancer developed in 23% of patients, and one-quarter of patients required treatment interruption or dose reductions. Although initial response rates are high, this may be partly attributable to the fact that all patients were prescreened and only those with the BRAF mutation were enrolled. Responses were transient, with the authors reporting that many patients with initial response subsequently relapsed and became resistant to PLX4032.

	Two multinational studies of PLX4032 are now underway, including the phase II BRIM2 trial, which began recruiting in September 2009, and the phase III randomized, controlled BRIM3 study, initiated in January 2010. BRIM2 is giving the MTD of PLX4032 to 100 patients with previously treated advanced melanoma. BRIM3 plans to recruit 700 previously untreated melanoma patients, who will receive PLX4032 or dacarbazine, with OS as the primary endpoint. Patients will be selected for both studies using an investigational diagnostic test developed to detect the BRAF mutation.

	The overall prognosis for patients with advanced melanoma (stage III or IV) is poor.

 Most patients who experience a locoregional recurrence subsequently undergo a complete lymphadenectomy, with a 5-year OS rate of ~25%; any distant recurrence carries a much poorer prognosis, with a 5-year OS of 5% to 10%.

Surgical options for patients with metastatic melanoma generally fall into three categories: curative, palliative, and immunotherapeutic.

	The risks of attempting curative surgery should be weighed carefully against potential benefits. Recent data on the surgical management of metastatic melanoma indicate that certain factors are associated with improved OS, such as the ability to achieve a complete resection with negative margins, location of the initial site of metastasis, extent of metastatic disease, disease-free interval after excision of the primary melanoma, and stage of disease at initial diagnosis.

 Favorable sites of resection include the skin, subcutaneous tissue, lymph nodes, lung, and gastrointestinal tract; unfavorable sites of metastases are the brain, kidneys, and liver.

 Wong and associates found that skin and subcutaneous sites have the best long-term outcomes, with 5-year OS of 20% to 30% and median OS of 48 months. They had no 5-year survivors among patients with metastases to unfavorable sites, and the median OS was only 18.2 months. OS and possible long-term outcomes for most patients with stage IV disease seem ultimately to depend on the intrinsic biologic activity and nature of the melanoma (aggressive vs non-aggressive).

	The primary goal of palliative surgery is to relieve identifiable symptoms, such as chronic pain resulting from the progressive growth of metastatic tumor deposits. For instance, patients often present with bulky, recurrent lymphadenopathy of the axilla or groin, which can cause severe pain and partial sensory and motor limitations of the involved extremity. Other sites for successful surgical palliation include the gastrointestinal tract, where single metastatic deposits can cause bleeding or a high-grade obstruction. Single metastatic deposits within the brain can be resected for palliative intent; waiting may lead to surrounding brain edema, which can be fatal if left untreated. However, the outcome for such patients has been uniformly dismal, with a median survival of <1 year.

 Careful consideration should be given to palliative surgical intervention, with the benefits of alleviating the symptoms weighed against the likely morbidity and the complexity of the procedure.

	The last type of surgical intervention for stage IV melanoma is best described as 

oncologic surgical cytoreductive immunotherapy:

removal of the bulk of metastatic disease to leave what is often referred to as 

, in hopes of improving the overall function and dynamic nature of the host anti-tumor immune response.

 It is thought that complete resection of the tumor burden (or “tumor cell factory,” as Morton and associates describe it) may allow the host immune system to overcome tumor-induced immunosuppression and stimulate a more robust host immune response.

Articles

Various immunotherapeutic strategies to treat advanced melanoma have been under investigation for more than a decade

Treatment Options for Patients with Stage III & IV Melanoma: Part II: Experimental treatments for stage III/IV or refractory/recurrent melanoma

	In our last issue, we published a review of treatment options for acute and delayed chemotherapy-induced nausea and vomiting. Since then, a few things have happened on this front. In March, the National Comprehensive Cancer Network (NCCN) updated its “Antiemesis Guidelines,” releasing Version 2.2010. In addition to updating the “Discussion” section, the NCCN changed the structure for preventing emesis in patients receiving chemotherapy with a moderate emetic risk, separating day 1 from days 2 and 3. A more substantive edit of the guidelines occurred in January 2010 (v. 1.2010). At that time, NCCN added romidepsin to the list of intravenous drugs with low emetic risk. Estramustine was added as an oral agent for which antiemetic prophylaxis is now recommended, and the newly approved drug pazopanib (Votrient) was added to the list of oral agents for which antiemetic agents should be administered as needed. The panel also added a statement on breakthrough treatment, noting that “some patients may require several agents utilizing different mechanisms of action.”

	The new NCCN guidelines are available at the Website, at 

 The Multinational Association of Supportive Care in Cancer held a workshop on updating its antiemetic guidelines at its latest annual meeting in June 2009. The group expects to put the new guidelines on its Website,

next month. The FDA approved generic orally disintegrating ondansetron tablets to prevent CINV. The drug is not approved for delayed emesis. Another manufacturer received FDA approval to market a generic injectable form of ondansetron. An Indian company was granted FDA approval to sell different doses of injectable granisetron, another 5-HT

antagonist. NCCN guidelines include ondansetron and granisetron in the list of drug options for preventing acute emesis, but the panel states that these agents are less effective at preventing delayed emesis.

	The guidelines note that “intravenous palonosetron (Aloxi) is superior to other 5-HT

antagonists for preventing delayed nausea”; this is likely because it has a binding affinity for 5-HT

that is 100 times greater than the other 5-HT

antagonists and has a significantly longer half life (approximately 40 hours). Palonosetron is the only FDA-approved 5-HT

antagonist approved to treat delayed-onset CINV.

	A.P. Pharma had applied to the FDA for approval of its novel injectable drug APF530, a long-acting form of granisetron, to treat acute and delayed chemotherapy-induced emesis, but the FDA rejected the application last month, citing multiple issues. The agency asked for reanalysis of the trial data submitted with the application, expressed concerns about certain aspects of the dosing system, and questioned whether the complicated two-syringe delivery system could result in improper administration. The FDA also identified deficiencies at the company’s manufacturing facility. The company plans to meet with the FDA on how to resolve the issues but stated the drug would definitely not come to market in 2010.

	Palonosetron, which has long been approved in the United States to treat acute and delayed CINV, recently launched in Japan, following regulatory approval in January 2010. Japan is the 63

In our last issue, we published a review of treatment options for acute and delayed chemotherapy-induced nausea and vomiting. Since then, a few things have happened on this front.

Updates in CINV Including NCCN Guideline Revisions

	The National Comprehensive Cancer Network (NCCN) 15th Annual Meeting in March opened with a roundtable discussion on "Cancer Care at the End of Life: When is Enough Enough?" The discussion panel featured individuals from all sides of the cancer experience, including David S. Ettinger, MD, with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Scott Hamilton, who won an Olympic gold medal for men’s figure skating and is a survivor of testicular cancer for more than a decade; Kayce Freed Jennings, wife of Peter Jennings, who died of lung cancer; Sloan Beth Karver, MD, who runs a palliative care program at H. Lee Moffitt Cancer Center; Deborah Morosini, MD, with Lung Cancer Alliance and AstraZeneca, whose sister Dana Reeve succumbed to lung cancer; Lee N. Newcomer, MD, of UnitedHealthcare; and Jai Pausch, an advocate and the wife of Randy Pausch, who died of pancreatic cancer in 2008.

	Former news anchor Sam Donaldson, a survivor of melanoma, chaired the roundtable. He opened the discussion by detailing some of the questions the panel would address: “How do you tell a patient, a patient’s family, that you think it’s the end? How do they react to it? How do you pay for it?”

	Before deciding how to tell a patient the end is near, the clinician has to decide when to tell the patient. A general consensus emerged that it was important for the physician to take cues from the patient. “It depends on when the patient comes to you,” Ettinger said. “I will tell you that 90% of patients want to know the truth about what they can anticipate.” Ettinger stressed that supplying statistics is not always helpful because “patients are not statistics” and can do better or worse than the statistics predict.

	Hamilton agreed. “So much about this cancer subject is personal. The statistics—hundreds of thousands or millions of people are diagnosed with cancer, but each patient feels like they’re the only one.” Hamilton said in his case, he wanted to know everything.

	Morosini suggested that, like other aspects of care for patients with cancer, when and how to have an end of life discussion should be personalized. “It’s really going to differ for all families,” she said. Morosini believes the best approach is to initiate the conversation with the patient at the outset, asking, “How much do you want to know?”

	“We owe it to patients to answer two questions: What will happen to me and how can you help me?” said Newcomer. He said physicians do not need to mention death more than once “unless the patient wants to hear that…but we should at least give that to them one time.”

	Everyone agreed that physicians must listen to patients, discuss prognosis with them honestly, and help them understand when a treatment is likely to help or when it is more likely to degrade quality of life while providing no real clinical benefit. Jennings said her experience with her husband taught her the discussion “is an art, not a science.” In her view, physicians should be honest but they should also take care not to rob the patient of hope. “What Peter’s doctors never did was take away hope,” she said. “Not stupid hope, I mean, we got it. But we knew there were exceptions to the numbers.” Jennings also said she recognized that she and her husband were fortunate that they did not have the financial pressures many people experience when a loved one develops cancer.

	Karver also believes in the need to be truthful with patients and their families. “I really do feel that patients appreciate the honesty with which I speak with them. I listen to them and try to help them move towards a goal that will produce a better quality of life,” she said. She described one patient who was in constant pain and continuing with a relentless series of therapies that were clearly wearing him down. She suggested the patient “take a break” to get his symptoms under control, for his wife’s benefit as well as his own.

	Pausch made an important point about the conversations clinicians have with patients on end of life care: many patients and caregivers struggle with the terminology. She said when the physician brought up palliative care after her husband’s pancreatic cancer metastasized to his lungs and brain, “I had to Google what palliative care meant…it took me time to process the words and for my mind to re-engage and then to emotionally accept what this meant.”

	Newcomer expressed concern that the roundtable, and the nation at large, seemed to be avoiding the cost issue associated with end of life care. He said he was very concerned that healthcare spending was not sustainable at its current rate and something needed to change in how we answer these questions. “Medicare is going broke, nobody can deny that,” he said. “We as a country need to decide how much is too much…we’re going to have to wrestle with it someday, when the money is gone.” Newcomer noted that other countries, like the United Kingdom, have already set limits on how much a year of life should cost (<£30,000 pounds).

	Pausch said there were other areas where costs could be cut, and she described how it took several months before physicians discovered that her husband lacked an enzyme to tolerate 5FU. “It would have been nice to know that before he’d been on that drug for four months,” she said. Pausch recommended taking an “intelligent approach” to cancer care and said we should consider whether more testing is needed before administering treatment.

	The panel concurred that there are no easy answers to these questions. Donaldson asked Newcomer how you say no to a patient who wants an experimental bone marrow transplant, for example. Newcomer said that is what the NCCN guidelines and guidelines from other professional oncology societies are for—giving physicians and insurers the tools to explain to patients why a treatment is not advised and why a recommended treatment is better. “Sometimes patients need permission to know that it’s okay not to do everything that you could do,” he said.

	While the discussion never answered “When is enough, enough?” regarding end of life care for cancer patients, it did shed light on why this question remains unanswered. Patients are individuals, not just part of a collective of patients with cancer, and most want to take an active role in their care. Perhaps the best clinicians can do is have the conversation—talk to patients and their families honestly and openly and let them know that having fewer minutes, to borrow a phrase from Hamilton, does not mean having to settle for worse ones.

The National Comprehensive Cancer Network (NCCN) 15th Annual Meeting in March opened with a roundtable discussion on "Cancer Care at the End of Life: When is Enough Enough?"

Sam Donaldson Hosts Roundtable on End-of-Life Care for Cancer Patients

	Erythropoiesis-stimulating agents (ESAs) are genetically engineered forms of erythropoietin that stimulate erythropoiesis through direct or indirect action on the erythropoietin receptor producing an increase in reticulocyte count, hemoglobin (Hb), and hematocrit levels.

The first recombinant human erythropoietin was introduced in the United States in 1989.

Currently, there are 3 available ESAs—epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). The use of ESAs has been associated with a reduced need for blood transfusion, reduction in the frequency and severity of anemia-associated morbidity, and improvement in quality of life.

	ESAs were a biotechnology medical innovation, initially marketed for the treatment of anemia in end-stage renal disease.

 Today, labeled indications for the use of these agents include the treatment of anemia associated with chronic renal failure in dialysis and nondialysis patients and the treatment of anemia in metastatic cancer patients (nonmyeloid malignancies) due to concurrent chemotherapy. These agents are not indicated for use in cancer patients who are receiving lone hormonal therapy, therapeutic biologic therapy, or radiation therapy, and patients receiving myelosuppressive therapy when the expected outcome is cure. Additional US Food and Drug Administration (FDA)-approved indications for epoetin alfa include the treatment of anemia (1) associated with HIV therapy and (2) in those undergoing selective, noncardiac, and nonvascular surgeries, to reduce the need for allogeneic blood transfusions.

 However, these indications lack extensive study and will not be covered in detail in this review.

 ESAs for the Treatment of Anemia Associated with Chronic Kidney Disease

	The 2006 National Kidney Founda&shy;tion’s Kidney Disease Out&shy;come Quality Initiative (KDOQI)guidelines define anemia of chronic kidney disease as an Hb level <13.5 g/dLin men or <12.0 g/dLin women.8Two clinical trials, the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) study and the Correction of Hb and Out&shy;comes in Renal Insufficiency (CHOIR) study, revealed findings that led to changes for target Hb levels with ESA therapy.

In September 2007, the 2006 KDOQI clinical practice guidelines on anemia and chronic kidney disease were updated to reflect the new evidence that supports a target Hb level in the range of 11.0 to 12.0 g/dLin dialysis and nondialysis patients receiving ESA therapy. This target range was selected to maintain flexibility in medical decision making and supports a patient-centered treatment approach. The guidelines were also updated to reflect the importance of not targeting Hb levels >13 g/dL due to an increased risk of serious cardiovascular events and death associated with ESAadministration.

	Full prescribing information outlines a weight-based calculation for dosing ESAs. In chronic renal failure patients, the recommended starting dose for epoetin alfa is 50 to 100 units/kg administered either subcutaneouslyor intravenously 3 times per week. The approved starting dose for darbepoetin alfa is 0.45 mcg/kg once weekly or an alternate dosing of 0.75 mcg/kg every 2 weeks for nondialysis patients, administered either by the subcutaneous or intravenous route. The intravenous dosing route is the preferred method of administration for hemodialysis patients. Maintenance therapy should be individualized to maintain target hemoglobin levels. Increases in dosages should be limited to once every 4 weeks to allow sufficient time for changes in Hb levels. Doses should be titrated by 25%, and if a rapid rise in Hb (>1 g/dL per 2-week time period) occurs, therapy should be discontinued until the Hb level decreases. Therapy should be resumed at a dose that is 25% less than the previous dose.

 When adjusting doses, clinical judgment plays an important role because therapy is individualized. Retrospective cohort studies focusing on dosing regimens of epoetin alfa show similar results in achieving Hb levels to those reported in clinical trials.

 In practice, extending dosing of darbepoetin alfa from once every 2 weeks to once monthly while maintaining Hb levels may be possible in hemodialysis or nondialysis patients. An advantage to the use of darbepoetin alfa compared with epoetin alfa is its longer serum half-life, which allows for dosing of the medication once weekly or every 2 weeks. Estimated dosing conversion from one agent to the other is outlined in the 

 ESAs for the Treatment of Chemotherapy-Related Anemia

	The American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) updated their guidelines in 2007 to address the thromboem&shy;bolic risks associated with ESAs and the use of darbepoetin alfa, which was not included in the original ASCO/ASH guidelines published in 2002. Initiation of ESA therapy is recommended in patients with an Hb level that is approaching or falling below 10 g/dL.

	The FDA-approved starting dose of epoetin alfa is 150 units/kg 3 times per week or 40,000 units weekly via subcutaneous administration. Subcutaneous administration of darbepoetin alfa is recommended at an initial dose of 2.25 mcg/kg once weekly or an alternative dosing of 500 mcg once every 3 weeks. Adjustment of doses should be aimed at maintaining the lowest Hb level to avoid red blood cell transfusion. Dose escalation of epoetin alfa 3 times per week by an increase of 300 units/kg 3 times per week is suggested if there is no reduction in transfusion requirements or no increase in Hb levels after 8 weeks of therapy. The recommended weekly dose of epoetin alfa should be increased to 60,000 units if Hb levels do not increase by 1 g/dL or more after 4 weeks of therapy. If after 6 weeks of therapy with weekly dosing of darbepoetin alfa there is a greater than 1-g/dL rise in Hb level, then it is recommended to increase the dose to 4.5 mcg/kg. The epoetin alfa dose should be reduced by 25% when the Hb level approaches 12 g/dL or increases >1 g/dL in 2 weeks. The darbepoetin alfa dose should be reduced by 40% when the Hb level exceeds 11 g/dLor rises >1 g/dL in 2 weeks. Doses of ESAs should be withheld when the Hb level exceeds12 g/dL.5-7,

 Two randomized controlled trials comparing ESA use in cancer patients with anemia dueto chemotherapy were inconclusive with respect to superiority of one agent over another.

	In recent clinical studies, the use of ESAs has been associated with an increased risk of serious cardiovascular events, thromboembolic events, tumor progression, and death.4These risks were associated with a rapid rise in Hb (>1 g/dL over 2 weeks) and maintenance of higher Hb levels. Disease-related concerns associated with ESAs for cancer patients and chronic renal failure patients have led the FDA to mandate a black box warning on ESA product labeling. It is advised to individualize dosing in patients with renal failure so the Hb level is achieved and maintained within target range. Higher Hb levels were associated with increased risk of death and serious cardiovascular events.5-7 These data are further supported by recent findings in the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), which linked a target Hb level of approximately 13g/dL in patients given darbepoetin alfa with an increased incidence of stroke.

The FDA has warned that ESA use in patients with breast, non—small-cell lung, head and neck, lymphoid, and cervical cancers can shorten overall survival and/or increase the risk of tumor progression. Additionally, ESAs are not indicated for cancer patients when the anticipated outcome is cure. Discontinuation of ESA therapy is recommended when chemotherapy is complete. In all patient populations, the appropriate use of ESAs is defined as Hb levels not surpassing the target range of 10 to 12g/dL and not exceeding an increase in Hb levels >1 g/dL per 2-week period during therapy.

	Since the arrival of the first ESA, the financial impact on institutions and payers has been significant. ESAs account for the single largest expenditure for Medicare ($1.8 billion).

 In 2007, the Centers for Medicare & Medicaid Services (CMS) issued a statement regarding reimbursement, which closely followed the black box warning from the FDA, suggesting that reimbursement is becoming more closely tied to drug safety. CMS further issued changes to the Medicare claims-processing policy for ESAs administered to patients receiving dialysis, capping the maximum cumulative dose per billing cycle at 400,000 units for epoetin alfa and 1200 mcg for darbepoetin alfa. Furthermore, as of January 2008, CMS requires a 50% dose reduction in patients whose Hb level persists at >13 g/dLfor 3 consecutive months.16While CMS stops short of denying claims in this circumstance, the claim will be paid at a reduced rate. In addition, Medicare will only reimburse costs for ESAs in chronic kidney disease and cancer-induced anemia when ESAs are initiated at an Hb level of >10 g/dL. Implementation of bundled payments by Medicare promotes an additional incentive to reduce the expense of these medications by removing financial incentives and encouraging providers to operate in a more cost-conscious manner.

Much of the literature to date has focused on claims data and cost-minimization strategies with few studies examining cost-effective utilization. Studies have been criticized for using average wholesale price or wholesale acquisition cost to conduct the cost comparisons, which tends to favor epoetin alfa over darbepoetin alfa. Manufacturer rebates and discount programs have led to poor price transparency in the US market, making it difficult for direct comparisons of these 2 products. Some studies in Canada and Europe suggest that using either of these agents may be cost-effective, but this has not been demonstrated in the United States.

 In addition, most studies fail to account for baseline Hb levels, which can bias the results.18 In a few randomized trials and observational studies that controlled for cost, the advantage typically favored epoetin alfa.

	The setting in which a patient receives ESA therapy can play an important role in determining the choice of agent. When choosing between agents, both the direct and indirect acquisition costs should be weighed along with clinical efficacy and reimbursement. According to marketing information from the manufacturer, darbepoetin alfa offers the advantage of extended interval dosing relative to epoetin alfa. Evidence, however, suggests that extended interval dosing with epoetin alfa can be successful in some patients. Research has also shown that patients receiving epoetin alfa achieved goal more rapidly than patients administered darbepoetin alfa, with lower overall indirect costs despite more frequent administration. These results, however, may not translate for all patient populations or disease states associated with the use of ESAs.

	In the inpatient setting, a strategy of cost minimization should be used when diagnosis-related groups are used for reimbursement. With the flexible dosing schedule of epoetin alfa, patients could be treated in a cost-effective manner by using divided dosing via a hospital-approved protocol. This has the potential to reduce the number of units that are administered in the inpatient setting, thus minimizing cost. Establishing patient-specific doses is another methodology that can reduce waste and should be a standard, as it is consistent with the Joint Commission Medication Management Standards as well as cost-effective. The 340b program can also be used to maximize savings to an organization that qualifies as a disproportionate share under the Medicare Cost Report. Financial savings from this program could drive the use of one agent versus another in the outpatient setting, especially if the patient is seen in a health system clinic. Because the subcutaneous route of administration requires approximately 30% of the intravenous dose to maintain comparable Hb levels, the route of administration should also be further examined.

	After more than 20 years in the market, a review of literature shows a rapidly changing landscape with ESAs, with the need for additional research being the most repetitive theme. It is no wonder that ESAs continue to be a high-profile topic given the evolving information and complex array of factors that play a role in the cost-effective use of these molecules. Key factors that will influence stakeholders include patients’ quality of life, efficacy, safety, cost of ESAs, and outcomes. Certainly, when ESAs first appeared on the market, they were hailed as wonder drugs due to their ability to reduce the number of blood transfusions, while benefiting patients by reducing fatigue. While these agents are effective in raising Hb levels, recent studies have raised concerns that ESAs may increase the risk of complications such as thromboembolic events, stroke, and lead to rapid tumor progression in some types of cancer. Entry of “biosimilar” agents into the market will likely further complicate and compound these issues, but may lead to price reductions due to competition. As healthcare reform takes shape in the United States, cost-effective medication management will continue to be an integral part of a cost-avoidance strategy. The large expenditure of healthcare dollars on ESAs will likely continue to receive scrutiny, especially in the presence of an ever-increasing diabetic population and the aging baby boom generation that will see an increased prevalence of cancer.

Erythropoiesis-stimulating agents (ESAs) are genetically engineered forms of erythropoietin that stimulate erythropoiesis through direct or indirect action on the erythropoietin receptor producing an increase

Clinical and Economic Considerations for the Use of Erythropoiesis-Stimulating Agents

	Practicing clinicians and healthcare administrators face many challenges in treating cancer patients, including management of chemotherapy-induced anemia. Information on how to best treat these patients comes from a variety of sources: clinical guidelines provide direction based on evidence-based literature, the US Food and Drug Administration (FDA) provides guidance on safe administration and use of erythropoiesis-stimulating agents (ESAs), and insurance providers drive treatment based on evidence and policy. With all of the directives on how to treat chemotherapy-induced anemia, integration of concepts and current data must be completed to determine the appropriate use of ESAs in cancer. The landscape surrounding erythropoietin agents is shifting as questions surround the safety and appropriate use of these agents in cancer patients. The clinical decision between blood transfusions and use of ESAs has become more difficult, as there are safety warnings concerning ESAs and questions regarding the safety of blood transfusions.

	The American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO) has called for a meta-analysis of data to determine factors contributing to (1) the risks surrounding transfusions or adverse event of ESAs, or both; (2) faster tumor progression or shorter survival in some ESA-treated patients; and (3) a better understanding of effectiveness of ESAs for anemia not related to chemotherapy (anemia of cancer) and eventually help guide the design of new clinical trials. The Erythropoiesis Stimulating Agents in Cancer Patients: Individual Patient Data Meta-Analysis Collaborative Group presented a meta-analysis at the December 2008 ASH meeting. Their timely efforts analyzed data for 13,933 patients from 53 studies. ESAs increased on-study mortality by 17% (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.06-1.30; 

= .002) and worsened overall survival by 6% (HR, 1.06; 95% CI, 1.00-1.12; 

= .005). Chemotherapy patients also had worse outcomes, with on-study mortality increasing by 10% (HR, 1.10; 95% CI, 0.98-1.24; 

= .12) while overall survival decreased by 4% (HR, 1.04; 95% CI, 0.97-1.11; 

= .26). Since the CI crossed 1 in the chemotherapy subset, it appears from this meta-analysis that ESAs decrease survival in chemotherapy patients, but caution should be used in all patients using ESAs.

	From the meta-analysis, Bohlius et al2 determined the number needed to harm (NNH) for cancer patients with various prognoses. For low-risk patients who have a 5% chance of mortality within the next 4 months, the NNH was 121 (95% CI, 69-343). For medium-risk patients who have a 20% risk of mortality within months, the NNH was 34 (95% CI, 19-94). Finally, for high-risk patients with a 70% risk of mortality within 4 months, the NNH was 24 (95% CI, 14-67).

	These data confirmed the FDA warnings issued in March 2007 and proposed a framework for the ASH/ASCO 2007 guidelines. The guidelines included warnings derived from prior published or presented data that were then solidified as black box warnings in ESA labeling which: (1) shortened the time to tumor progression in patients with advanced head and neck cancers receiving radiation therapy when administered to target a hemoglobin level >12 g/dL (Ezetimibe and Simva&shy;statin in Hypercholesterolemia Enhances Atherosclerosis Regres&shy;sion [ENHANCE] and Danish Head and Neck Cancer Study [DAHANCA] Group, 10 trials); (2) shortened overall survival and increased mortality attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a hemoglobin level >12 g/dL (Breast Cancer Erythropoietin Trial [BEST]); and (3) increased the risk of death when administered to target a hemoglobin level of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy (Randomized Trial of Epoetin Alfa in Patients With Advanced Non-Small Cell Carcinoma of the Lung [EPO-CAN-20] and Amgen 20010103 trials). The FDA warning established that treating patients to a hemoglobin level >12 g/dL can lead to negative consequences.

	The Oncology Drug Advisory Committee (ODAC) of the FDA met after the letter in March 2007 to further analyze the safety data and clarify safety directives. It restated that patients with advanced breast, head and neck, lymphoid, and non—small-cell lung cancers (when hemoglobin levels are targeted at 

12 g/dL), survival can be shortened and tumor progression more likely. Further warnings of changes in survival and tumor progression were made for ESAs at any targeted hemoglobin level (specifically <12 g/dL). Dosing should be targeted at the lowest dose to avoid blood transfusions. Anemia as a result of chronic disease is addressed as a nonindication. In March 2008, this information was added to the product labeling.

	In August 2008, a medication guide was drafted for epoetin alfa and darbepoetin alfa. The accompanying letter also stated that patients should not be started on ESAs unless their hemoglobin level is <10 g/dL. A warning was also added about not using ESAs when the expected outcome of chemotherapy is cure, as well as instructions on how to report an adverse event. The FDA plans to create a new Risk Minimization Action Plan or Risk Evaluation and Mitigation Strategy program for ESAs to better assess the true risks using these agents in anemia caused by chemotherapy. The overall risks and benefits of red blood cell transfusions (

) should be outlined in addition to those outlined in the medication guides for the ESA products.

	When treating patients for anemia related to chemotherapy, the possibility that ESAs may help improve hemoglobin levels and avoid the need for transfusion must be taken into consideration. Witzig et al

demonstrated that weekly epoetin alfa significantly increased hemoglobin levels (10.9 g/dL for placebo, which was a change of 0.9 g/dL and 12.6 g/dL for epoetin alfa, a change of 2.8 g/dL by week 4 of the study; 

<.001). Significant reductions in the percentage of patients undergoing transfusions was also described in a subset (110/329) of patients (27% transfused in the epoetin alfa arm, 40% in the placebo arm; 

= .012). Patients were transfused at a median hemoglobin level of 8 g/dL, but transfusion triggers may differ in individual institutions and clinical situations, so the true benefit of the reduction in transfusions is difficult to determine.

	Although the efficacy of ESAs is well established, because safety issues have been raised, adjunctive therapy could be more crucial to treatment of chemotherapy-related anemia. Auerbach et al18 conducted a trial evaluating the addition of intravenous and oral iron to ESAs. The study did not enroll enough patients to achieve the required statistical power, but the results provided compelling evidence for the use of intravenous iron. Of the patients who received intravenous iron, 68% responded (defined as an increase in hemoglobin 

12 g/dL). In the no iron and oral iron therapy groups, 25% (

<.01) responded, respectively. This evidence shows that iron could potentially provide overall improvement in hemoglobin levels and possibly lessen the need for blood transfusions. The ASH/ASCO guidelines have not completely addressed intravenous iron therapy, but the data discussed appear to support concomitant use with ESAs.

 The Mayo Clinic Cancer Research Consortium is completing a larger trial that should provide insight as to the use of oral iron and intravenous iron gluconate.

	Current clinical guidelines by ASH and ASCO were published after the safety warning by the FDA in March 2007, the ODAC meeting in May 2007, and the Centers for Medicare & Medicaid Services (CMS) National Coverage Decision (NCD) in July 2007.1,

 The hemoglobin level clinicians need to be aware of is 10 g/dL for Medicare patients, according to the new NCD, but the ASH/ASCO guidelines leave the limit for treating chemotherapy-induced anemia at 12 g/dL. Some private insurers follow the ASH/ASCO guidelines as opposed to the CMS decision. Clinicians have shown their frustration over the new limit of 10 g/dL set by the CMS NCD. In May 2007, a total of 2600 patients, physicians, and other parties responded to the new NCD. Some concessions were made, but the limits to chemotherapy-related anemia and a restriction of treatment for patients with a hemoglobin level of <10 g/dL endured the suggestions.

 The ASH/ASCO guidelines support the dosing for epoetin alfa at 150 U/kg subcutaneously 3 times weekly and 40,000 units subcutaneously weekly. For darbepoetin alfa, they recommend 2.25 mcg/kg subcutaneously weekly or 500 mcg subcutaneously every 3 weeks. Alternative dosing can be utilized following the guidelines, which our clinic uses but continues to evaluate because of specific wording on dosing. New long-term studies are needed to evaluate whether giving ESAs on the same day of chemotherapy has a tumor progression benefit or adverse effect.

	As to when to increase or decrease doses of ESAs, dosing should be reduced once the hemoglobin level approaches 11 g/dL and stopped once it is >12 g/dL to hopefully prevent any thrombo&shy;embolic events. Increases in doses can be made at week 4 for epoetin and week 6 for darbepoetin, and clinicians must take this into account prior to stopping therapy. Physicians should also consider erythropoietin levels to determine which patients will respond, as this may help to make better decisions as to who should receive therapy.

	The other unanswered question is the use of the data concerning quality of life (QOL). This is a “soft” end point and difficult to measure. The objective end point of transfusion avoidance is much easier to assess. Future studies should focus on QOL outcomes so clinicians have better information to share with patients on the actual benefits of treatment. The QOL data do help in practice, but the actual impact is difficult to quantify. To further help clinicians answer questions about QOL benefits, this concept should continue to be a secondary end point in trials.

	Guidelines from the National Comprehensive Cancer Network have addressed the risks and benefits of ESAs and transfusion medicine. The critical question for evaluating patients and creating institution policies surrounds the intent of the chemotherapy goals. If it is for curative intent, then ESAs are not indicated/appropriate. If the patient requires immediate resolution of symptoms from anemia (fatigue, chest pain, dsypnea, lightheadedness, syncope, and/or tachycardia), then a transfusion should be considered. If they are not symptomatic or do not require immediate attention, then iron studies should be completed and ESAs should be considered. Dosing and titration are similar to previous versions of the guidelines and to the ASH and ASCO guidelines. The risks and benefits of both ESAs and transfusions should be considered as outlined in 

	After stepping back and taking in the impact of the last 2 years of new data analyses, guidelines, and safety updates, it appears that treating patients for chemotherapy-induced anemia can be difficult. Reducing the number of transfusions with a limited blood supply is the current primary goal of therapy. Patients provide feedback as to what they hope to receive from supportive care therapy, but with current guidelines and safety data, clinicians must continually re-evaluate the literature and treat with the patient’s best interests in mind. Patients in our clinic have read the warnings from the FDA concerning the discontinuation of ESA therapy 8 weeks following the last course of chemotherapy. For a variety of rationales, they cite that they “feel better” and wish to “avoid transfusions.” Future studies must take this into account (particularly the avoidance of transfusions) postchemotherapy. To quantify the impact of ESA therapy on transfusion avoidance, postchemotherapy trials need to continually consider the risks and benefits of supportive care therapy. Another question to take into account is the length of therapy beyond chemotherapy that would be safe and appropriate. With the mass of data in nonchemotherapy-related anemia, we must make heads or tails of the clinical conundrum in which we are now practicing. Administrators should work closely with clinicians to determine the appropriate course of action to help ensure that patients receive the best possible care as new data and guideline updates emerge.

Practicing clinicians and healthcare administrators face many challenges in treating cancer patients, including management of chemotherapy-induced anemia.

Challenges in Treating Chemotherapy-Induced Anemia

	Recent statistics show lymphoid malignancies to be the fifth most common cause of cancer-related death in the United States. In 2009, nearly 65,980 new cases of non-Hodgkin lymphoma (NHL) were diagnosed and 19,500 patients died despite currently available treatments.

Diffuse large B-cell lymphoma (DLBCL), the most common type of NHL in the Western Hemisphere, accounts for 30% to 40% of all NHL cases diagnosed annually in the United States.

	DLBCL typically afflicts patients in their sixth decade of life; primary mediastinal DLBCL variant, however, primarily afflicts women in their late 20s or early 30s. The incidence of DLBCL has increased in the past few decades, and this trend is independent of the human immunodeficiency virus (HIV) epidemic.

	Revisions in the pathological classification of lymphomas in the past 30 years or so have resulted in several variations in DLBCL nomenclature. It had been called 

	Recently, the Revised European and American Lymphoma classification defined DLBCL as a specific disease. Within this classification, however, it is still heterogeneous, manifesting a variety of morphological features (eg, anaplastic, Burkitt’s-like), protein and gene expression patterns, and clinical presentations (eg, primary mediastinal or central nervous system [CNS] lymphomas). Studies of gene expression profiling (GEP) contributed greatly to our understanding of DLBCL biology. GEP studies identified and validated 3 different subtypes of DLBCL—germinal center B-cell (GCB), activated B-cell (ABC), and primary mediastinal lymphoma (PML)&mdash;all with significant differences in terms of prognosis, progression-free survival (PFS), and overall survival (OS).

	GCB-DLBCL, apparently derived from germinal center B cells, is driven primarily by deregulation of apoptosis by BCL6 and responds well to rituximab-based immunochemotherapy. ABC-DLBCL is believed to be driven by high levels of nuclear factor kappa-B (NFκB) activity and is associated with worse outcomes despite immunochemotherapy. PML shares GEP signatures similar to those of patients with classical Hodgkin’s lymphomas and is associated with a better prognosis than other DLBCL subtypes. Treatment-related toxicities remain a concern, even without the use of involved-field radiation therapy (IF-XRT), and are being addressed in clinical trials.

PATHOLOGICAL AND CLINICAL CHARACTERISTICS OF DLBCL

	Morphologically, DLBCL is characterized by large B cells with a high proliferation index resembling that of germinal centroblasts. DLBCL usually develops de novo, but can emerge as a clonal transformation in patients with low-grade lymphomas or chronic lymphocytic leukemia (CLL). De novo DLBCL tends to respond better to standard therapy and has a better prognosis than transformed DLBCL. Several morphologic variants of DLBCL have been described: centroblastic, immunoblastic, plasmablastic, T-cell/histiocyte-rich, and anaplastic B-cell lymphoma (usually anaplastic lymphoma kinase—positive).

 While pathological evaluation can distinguish between these variants, their prognostic significance remains controversial.

	Immunophenotype studies demonstrate that DLBCL co-expresses pan B-cell markers, including CD19, CD20, CD79a, CD45RA, and the nuclear transcription factor PAX5. The expression of additional markers may have prognostic implications. The proliferation factor Ki67 is usually high, with a mean percentage of 65. High Ki67 levels (>80%) have been associated with shorter OS.

The germinal center—associated marker CD10 is expressed in 30% to 40% of cases, and BCL6 is expressed in 60% of cases. Retrospective studies have associated BCL6 expression with prolonged PFS and OS following rituximab-based immunochemotherapy.

 Only 10% of DLBCL cases express CD5, which has been associated with shorter survival. The expression of CD5 should raise suspicion of transformation from a more indolent form of NHL, such as small lymphocytic lymphoma (SLL) or CLL.

	Information obtained from genetic studies of DLBCL tumor specimens stresses the complexity of the disease’s biology. DLBCL expresses clonally rearranged IgH genes with somatic mutations in the variable region. Thus, it is thought that DLBCL cells are derived from antigen-exposed B cells. No single gene abnormality is pathognomonic of DLBCL. Recurrent translocations involving BCL6, BCL2, and MYC genes had been described in about 50% of cases. Chromosomal translocation leading to upregulation of BCL2 [t(14;18)] is present in 20% to 30% of DLBCL cases and specially observed GCB variants. Gene abnormalities in ABC-DLBCL are more complex and include trisomies, deletions, and chromosomal inactivation.

	GEP studies have established distinct molecular subtypes of DLBCL; ABC-DLBCL, which resembles activated peripheral blood cells; and GCB-DLBCL, which has a similar profile to germinal center cells. BCL6 translocations occur 3 times as often in the GCB subgroup than in ABC-DLBC patients. Activation of NFκB has been recognized as a key feature of ABC-DLBCL pathophysiology, and its downregulation effectively induces cell death in ABC-like tumor cells.

 Although GEP may be the best way to differentiate subtypes of DLBCL with prognostic variation, GEP studies need to be validated prospectively, and widespread use of GEP as a routine diagnostic tool is not practical nor recommended outside of a clinical trial. Recently, GEP results have been adapted to a more “user-friendly” approach that depends on immunohistochemistry (IHC). Note that differences in clinical behavior and therapeutic response in newly diagnosed patients with GCB versus those with non-GCB subtypes may not translate to the relapsed/refractory setting.

	Clinical staging of patients with DLBCL is fundamental to defining a treatment plan and stratifying risk according to the international prognostic index (IPI) system. Pretreatment evaluation should include obtaining a detailed history, performing a physical examination, complete evaluation of end-organ (cardiac, renal, liver, and hematologic) function, determining lactate dehydrogenase (LDH) levels, and HIV serology when indicated. As rituximab has become integral to the management of DLBCL, rare but serious adverse events such as hepatitis B reactivation have been documented. Fatal cases of fulminate hepatic failure due to reactivation or progression of hepatitis B or C have occurred in DLBCL patients receiving immunochemotherapy; therefore, pretreatment with hepatitis B and C serologies in patients with hepatitis B or C is recommended.

	Staging of DLBCL patients requires functional and nonfunctional imaging studies, pathological examination of the bone marrow, and, when indicated, CNS evaluation. Most practicing oncologists routinely conduct computed tomography scanning of the neck, chest, abdomen, and pelvis. Functional imaging with positron emission tomography (PET) has become an important prognostic tool in managing DLBCL, and whole-body PET scanning is used to complement pretreatment staging and post-treatment evaluation of patients. Retrospective studies have demonstrated that PET scanning during and after treatment provides strong prognostic information in terms of PFS and OS. The optimal timing of PET scanning to assess prognosis and response is controversial and currently under study, with recommendations varying among academic institutions.

	Risk stratification is important when managing patients with DLBCL and should take place prior to initiating therapy. The IPI score system

 calculates a sum based on 5 variables: age ≥65; performance status ≥2; elevated LDH level; Ann Arbor stage III or IV; and ≥2 extra-nodal sites of disease. The IPI score determines whether the patient is classified as low, low-intermediate, high-intermediate, or high risk. OS differs for each category, ranging from 23% for the low-risk group to 75% for the high-risk group. The IPI score was validated in multiple clinical trials before and after rituximab was incorporated into frontline therapy for DLBCL.

 It has also been validated in relapsed, aggressive NHL.

 Other IPI score variations have similar prognostic capabilities, such as the age-adjusted IPI score for patients aged <65 years and the rituximab-IPI score.

 While the clinical value of the IPI score is extremely high, it does not provide much insight into disease biology or mechanisms of resistance. This emphasizes the need to identify more biomarkers representative of disease response.

	Unless contraindicated by significant and preexisting comorbid conditions, treatment of DLBCL should include rituximab- and anthracycline-based multiagent chemotherapy and aim to produce durable complete remission (CR). At this point, treatment is tailored to stage or bulk of disease and therapy response. In general, the approach to frontline management of DLBCL depends on whether it is localized or advanced-stage disease.

Multidisciplinary Management of Early-Stage DLBCL

	About 5% of patients with DLBCL present with early-stage disease. Localized DLBCL is defined as Ann Arbor stage I or II (non-bulky) disease and is typically managed with an abbreviated course of combined systemic immunochemotherapy followed by IF-XRT (

	The Southwest Oncology Group (SWOG) study 8736 randomly assigned 401 patients with non-bulky stage I or II aggressive B-cell lymphoma to receive 3 cycles of cyclophosphamide, vincristine, doxorubicin, or prednisone (CHOP) followed by IF-XRT at 40 to 50 cGy or to 8 cycles of CHOP chemotherapy alone.

 Patients taking CHOP followed by IF-XRT versus CHOP alone had a better OS (77% vs 64%, respectively; 

= .03) and PFS (80% vs 72%, respectively; 

= .02). An updated analysis after 10 years of follow-up showed an increase in late recurrences, which explained the absence of plateau effect in the survival curve.

 A phase II study by the British Columbia Cancer Agency confirmed the SWOG results. In this study, 308 patients were treated with 3 cycles of chemotherapy followed by IF-XRT. At 5 years, the overall PFS and OS were 80% and 81%, respectively; and at 10 years, PFS and OS were 63% and 74%, respectively.

	Two studies by the Groupe d’Etude des Lymphomes de l’Adulte (GELA) have challenged the role of radiation therapy in the management of early-stage DLBCL. The first study randomized patients aged <60 years to 3 cycles of CHOP chemotherapy followed by IF-XRT or an intense regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) for 6 cycles.

 After a median follow-up period of 7.7 years, OS and PFS were significantly better in the ACVBP arm. In contrast to previous clinical trials, this study included patients with bulky disease. The ACVBP regimen was associated with increased chemotherapy-related toxicity and a more hospitalizations. Moreover, vindesine is not commercially available in the United States. In the second study, DLBCL patients older than 60 with localized disease and no other adverse IPI factors were randomized to 3 cycles of CHOP plus IF-XRT or 8 cycles of CHOP alone. After a median follow-up of 7 years, the median OS and PFS were not significantly different between the 2 treatment arms.

Recent statistics show lymphoid malignancies to be the fifth most common cause of cancer-related death in the United States.

Spring 2010 | Special Issues

Treatment Options for Patients with Stage III & IV Melanoma: Part II: Experimental treatments for stage III/IV or refractory/recurrent melanoma

Updates in CINV Including NCCN Guideline Revisions

Sam Donaldson Hosts Roundtable on End-of-Life Care for Cancer Patients

Clinical and Economic Considerations for the Use of Erythropoiesis-Stimulating Agents

Challenges in Treating Chemotherapy-Induced Anemia

Biology and Management of Diffuse Large B-cell Lymphoma

Moving Beyond Standard of Care: Novel Treatments in Gynecologic Cancer

Kareem Abdul-Jabbar Takes on a Tough Opponent:Chronic Myeloid Leukemia

Judge Rules Myriad Cannot Patent BRCA1 and BRCA2-Genes