	Radiation therapy is frequently recommended for patients who have undergone mastectomy for breast cancer. For appropriate patients, postmastectomy radiation therapy is associated with improved locoregional control (an absolute decrease in recurrence of 20% to 27%) and better survival (an absolute gain in overall survival of 8% to 9%).

	Although recent advances have greatly minimized many of its side effects, radiation therapy still can be associated with serious complications, with cardiac complications among the most common concerns. Thus, it is appropriate to review which patients are most likely to benefit from radiation therapy and which, if any, can avoid it. In a session at the 30th Annual Miami Breast Cancer Conference, Lawrence J. Solin, MD, chair of Radiation Oncology at Albert Einstein Medical Center in Philadelphia, discussed whether all patients with 1 to 3 positive lymph nodes who have undergone mastectomy need postoperative radiation therapy.	

	Guidelines from the American Society of Clinical Oncology,

 the National Comprehensive Cancer Network,

 all agree that post-mastectomy radiation therapy is indicated for patients with four or more positive lymph nodes. However, these patients account for only a minority of node-positive mastectomy patients, with most patients having small (T1-2) tumors and 1 to 3 positive nodes, Solin noted. Unfortunately, all three of the above guidelines report that insufficient evidence exists to make any evidence- based post-mastectomy recommendations for patients with 1 to 3 positive nodes.

 Two of the three guidelines do suggest, however, that physicians at least consider chest wall and regional nodal irradiation for these patients.

	The only randomized trial to attempt to address the issue of post-mastectomy radiation therapy in patients with 1 to 3 positive nodes, SWOG 9927, failed to meet its accrual target and was therefore unable to provide answers regarding this controversial issue. This leaves only subset data from other randomized trials and meta-analyses from which to draw conclusions about the usefulness of post-mastectomy radiation therapy in this patient population. Subset analyses from two large, randomized clinical trials that examined a total of 735 patients with 1 to 3 positive nodes both demonstrated an overall survival advantage for patients receiving post-mastectomy radiation therapy, producing a 7% to 9% absolute improvement in long-term survival (15-20 years).

		Individualized Treatment Recommendations

	Perhaps even more compelling are results from a meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) of women from 20 randomized trials designed to evaluate post-mastectomy radiation therapy.

 Again examining the subset of patients who had 1 to 3 positive nodes, the EBCTCG reported that radiation therapy was associated with an absolute reduction in locoregional recurrence of 16.1% at 5 years and an absolute improvement in breast cancer survival of 8.1% at 15 years. It was also of interest to note that investigators reported no evidence of a differential treatment effect among patients grouped by number of positive lymph nodes (ie, 1, 2, or 3). When EBCTCG investigators restricted the data to be more consistent with contemporary treatment regimens and surgical techniques, benefits in locoregional recurrence and breast cancer survival were maintained, albeit at more modest levels (10.1% at 5 years and 3.3% at 15 years, respectively). An ongoing EBCTCG meta-analysis may yield additional clinically relevant information.	

	In the absence of direct randomized clinical trial data examining post-mastectomy radiation therapy in patients with 1 to 3 positive lymph nodes, physicians are left to use their clinical judgment in deciding whether or not to recommend radiation therapy to such patients in their practices.

	Solin reported that this population of patients is a heterogeneous mix, with a wide range of prognostic characteristics. Thus, he individualizes his treatment recommendations for these patients, maintaining that tumor size and number of positive lymph nodes are probably the most important considerations, because the larger the tumor and the greater the number of positive lymph nodes, the more obvious the benefit of post-mastectomy radiation therapy. However, particularly in patients with more favorable disease characteristics (eg, smaller tumors and a single positive lymph node), he considers other patient and disease characteristics, including patient age, lymphovascular invasion, extracapsular extension, resection margins, and even the type of adjuvant chemotherapy received. His approach highlights the fact that informed treatment recommendations for this patient population require a multifactorial decision process.

				Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. 

				Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c Trial. 

				Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. 

				Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. 

				NCCN Clinical Practice Guidelines in Oncology: Breast Cancer V.3.2012. National Comprehensive Cancer Center Network website. 

www.nccn.org/professionals/physician_gls/pdf/breast.pdf

				Taylor ME, Haffty BG, Rabinovitch R, et al. ACR appropriateness criteria on postmastectomy radiotherapy expert panel on radiation oncology-breast. 

				Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials. 

				Ragaz J, Olivotto IA, Spinelli JJ, et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. 

				Darby S, on behalf of the Early Breast Cancer Trialists’ Collaborative Group. Overview of the randomised trials of radiotherapy in early breast cancer (Abstract). Presented at the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, TX.

Articles

For appropriate patients, postmastectomy radiation therapy is associated with improved locoregional control and better survival.

Deciding When Post-Mastectomy Radiation Therapy Is Warranted

	Arguments Against Delaying Sentinel Lymph Node Biopsy

In the last decade, sentinel lymph node biopsy has become established as an alternative to axillary lymph node dissection for nodal staging in patients with early-stage breast cancer, as a result of several randomized trials showing similar disease-free and overall survival of these two procedures,

 as well as less morbidity (such as reduced arm lymphedema and sensory deficits) and improved quality of life with sentinel lymph node surgery.

 With increasing use of neoadjuvant chemotherapy, however, controversy has erupted regarding the optimal timing of this procedure. Some argue that sentinel node biopsy prior to neoadjuvant chemotherapy provides the most accurate staging, whereas others argue that performing a sentinel node biopsy after neoadjuvant chemotherapy could allow patients with node-positive disease who achieve a pathologic complete response to avoid the morbidity of an axillary node dissection. Anees B. Chagpar, MD, MSc, MA, MPH, associate professor of Surgery at Yale University and director of The Breast Center—Smilow Cancer Hospital at Yale-New Haven, discussed this issue at the 30th Annual Miami Breast Cancer Conference.

The primary objection to delaying sentinel node surgery until after neoadjuvant chemotherapy is its false-negative rate. In 2006, a meta-analysis of nearly 1300 patients undergoing sentinel lymph node biopsy after neoadjuvant chemotherapy reported a false-negative rate of 12%,

 and a 2012 presentation of the ACOSOG Z1071 trial, which also examined the procedure after neoadjuvant chemotherapy, reported a false-negative rate of 12.6%.

 This is in contrast to the 5% to 9.5% false-negative rate reported when the sentinel node procedure is performed prior to any therapy.

It has been hypothesized that the elevated falsenegative rate with delayed sentinel node surgery may be caused by uneven sterilization of the lymph nodes by the chemotherapy; certainly, it raises concern about the impact of this residual disease on the locoregional recurrence rate. When performed after neoadjuvant chemotherapy, sentinel lymph node biopsy also has a poorer identification rate of the sentinel lymph node than when it is performed prior to chemotherapy (87% vs 97%-100%).

 This decreased identification rate is postulated to be caused by structural changes in lymphatic drainage, such as fibrosis within the axilla.

 Finally, pretreatment determination of the pathological status of the lymph nodes can impact decisions regarding postoperative radiation therapy, and this information would be unavailable to patients who delayed sentinel node biopsy until after receiving chemotherapy.

Arguments for Delaying Sentinel Lymph Node Biopsy Proponents of performing sentinel lymph node biopsy after chemotherapy acknowledge both the lower sentinel node identification rate and the higher false-negative rate of this approach, but propose that both are reasonable. “Risk, like beauty,” Chagpar said, “is in the eye of the beholder. For some, the false-negative rate of 12% is too high; for others, it is acceptable.” She argued that there is less worry about residual disease in recent years, with regard to both its impact on locoregional recurrence and survival. For instance, the randomized NSABP B-04 trial, which was designed to determine whether outcomes would be compromised when the extent of surgery was reduced (from radical mastectomy), demonstrated that locoregional recurrences in the arm with the least extensive surgery (having no targeted axillary treatment) produced no worsening of overall survival.

 This suggests that the surgical resection of additional lymph nodes may have little to no impact on survival. It is also true that the timing of axilla staging in patients with locally advanced disease has minimal influence on the type of chemotherapy they will receive, and while upfront sentinel node biopsy may influence the decision to provide post-mastectomy radiation therapy, many of these patients would qualify for radiation therapy on the basis of tumor size alone.

Those in favor of delaying sentinel node surgery suggest that the benefits of this approach overshadow the modest risks (ie, residual disease in the axilla) associated with it, because it not only provides information regarding patients’ sensitivity to chemotherapy, which may be useful when making future treatment decisions, but it also permits those who achieve a pathologic complete response to chemotherapy to avoid the morbidity and reduced quality of life associated with axillary lymph node dissection.

Regardless of when sentinel lymph node biopsy is performed, certain technical considerations are critical to optimal outcomes. For instance, Chagpar said it is now well accepted that nodal status is best determined by evaluating at least two sentinel nodes,

 and that a dual tracer—both a blue dye and a radioactive isotope&mdash;be used, if possible.

 A number of studies have tried to identify factors that can predict the status of nonsentinel nodes, but no robust variables have yet been found. However, research continues to search for ways to bolster sentinel lymph node findings. Despite the findings of the ACOSOG Z1071 and SENTINA trials, this remains an area of controversy, and physicians continue to search for the optimal means to stage their patients with locally advanced disease.

			Krag DN, Anderson SJ, Julian TB, et al. Technical outcomes of sentinel-lymph-node resection and conventional axillarylymph- node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. 

			Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. 

			Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. 

			Purushotham AD, Upponi S, Klevesath MB, et al. Morbidity after sentinel lymph node biopsy in primary breast cancer: results from a randomized controlled trial. 

			Xing Y, Foy M, Cox DD, Kuerer HM, Hunt KK, Cormier JN. Meta-analysis of sentinel lymph node biopsy after preoperative chemotherapy in patients with breast cancer. 

			Boughey JC, Suman VJ, Mittendorf EA, et al. The role of sentinel lymph node surgery in patients presenting with node positive breast cancer (T0-T4, N1-2) who receive neoadjuvant chemotherapy: results from the ACOSOG Z1071 trial. 35th Annual San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract S2-1.

			Iida S, Haga S, Yamashita K, et al. Evaluation of sentinel lymph node biopsy in clinically node-negative breast cancer.

			Krag DN, Ashikaga T, Harlow SP, et al. Surgeon training, protocol compliance, and technical outcomes from breast cancer sentinel lymph node randomized trial. 

			Papa MZ, Zippel D, Kaufman B, et al. Timing of sentinel lymph node biopsy in patients receiving neoadjuvant chemotherapy for breast cancer. 

			Cohen LF, Breslin TM, Kuerer HM, Ross MI, Hunt KK, Sahin AA. Identification and evaluation of axillary sentinel lymph nodes in patients with breast carcinoma treated with neoadjuvant chemotherapy. 

			Fisher B, Jeong JH, Anderson S, Bryant J, Fisher ER, Wolmark N. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. 

			Kennedy RJ, Kollias J, Gill PG, Bochner M, Coventry BJ, Farshid G. Removal of two sentinel nodes accurately stages the axilla in breast cancer. 

			Newman LA. Lymphatic mapping and sentinel lymph node biopsy in breast cancer patients: a comprehensive review of variations in performance and technique. 

With increasing use of neoadjuvant chemotherapy in early-stage breast cancer, controversy has erupted regarding the optimal timing of sentinel lymph node biopsy.

Should Sentinel Lymph Node Biopsy Be Postponed Until After Neoadjuvant Therapy?

Following publication in 1990 of the National Institutes of Health (NIH) consensus statement recommending breast-conservation surgery as the preferred surgical treatment for the majority of women with stage I and stage II breast cancer,

 several studies have confirmed similar long-term survival rates of breast-conservation therapy compared with mastectomy 18 to 20 years postoperatively, although these studies present conflicting results as to whether breast-conservation therapy is associated with increased local relapse rates.

The results of this collective research and the NIH Consensus Statement led to a steady decline in mastectomy rates in the United States for women with stage I or stage II disease receiving surgery

—from a 1988 pre-consensus statement rate of 77%, to a rate of 38% in 2004.

 National databases, such as Surveillance, Epidemiology, and End Results (SEER), can provide an overall picture of mastectomy procedures performed in the United States. The most recent publication of mastectomy rates from the SEER database presents data through 2008 for women with T1-2 N0-3 M0 tumors who had surgery (either breast-conservation surgery or mastectomy).

 Mastectomy rates steadily decreased from 2001 to 2005, from a high of 40.2% to a nadir of 35.6%. Following this, mastectomy rates began to rise from 2005 through 2008, back up to 38.4%, the highest rate since 2002.

A publication of mastectomy rates from the European Society of Breast Cancer Specialists suggests that this trend observed here is distinct from trends in mastectomy rates in Europe.

 In this study, mastectomy rates were analyzed from 2003 to 2010 from >15,000 women throughout Italy, Belgium, Germany, and Switzerland who underwent surgery for early-stage disease. Investigators reported that rates steadily declined from a high of 29.9% in 2005 to only 18.6% in 2010.

Is the Mastectomy Rate Among US Women Too High?

		The 30th Annual Miami Breast Cancer Conference ® (MBCC) featured clinical perspectives on this question from Patrick I. Borgen, MD, chair, Department of Surgery, and director, Maimonides Breast Cancer Center, at the Maimondes Medical Center, Brooklyn, New York, and J. Michael Dixon, MD, professor of Breast Surgery at the University of Edinburgh, Scotland, and consultant breast surgeon at Western General Hospital. Below are excerpts from their presentations and from video interviews with 

There are both desirable and undesirable explanations for an increasing mastectomy rate. Examples of positive reasons include improvements in the radiographic identification of occult lesions and an increase in the identification of genetic risk factors for aggressive disease (eg, BRCA mutations). Undesirable reasons for increasing mastectomy rates include an unsubstantiated worry about recurrence, an overestimation of the survival benefit of mastectomy, and a general lack of knowledge about the available surgical choices. Additional reasons include improved postmastectomy reconstructive outcomes and a desire to avoid the side effects of adjuvant radiation therapy.

Another crucial factor in judging the significance of an increasing mastectomy rate is the distinction between mastectomy performed therapeutically on the primary tumor and that performed on the contralateral breast as a prophylactic measure. An analysis of records from >150,000 women with stage I-III disease from the SEER database demonstrated that contralateral prophylactic mastectomy rates have increased from 4.2% in 1998 among women already receiving therapeutic mastectomy to 11.0% in 2003.

Most recently, a large, population-based study of women with early-stage breast cancer treated with lumpectomy and radiation found that women who chose the breast-conserving option had both better disease-specific and overall survival compared with their mastectomy counterparts.

Our goal should not be to raise the thermometer up to the highest possible level of breast conservation. The patients I see are highly educated, and we should work with our patients to make sure that with all of the data and the storm of facts that swirl around them in their lives, we wind up in a place where they are happy with their decision. I’ve heard some surgeons say that we shouldn’t mention mastectomy for their stage I breast cancer patients. I don’t really understand that. If 62% of surgeons treating breast cancer patients in an American College of Surgeons survey say, “I would choose mastectomy,” how do we not mention that to our patients? Our goal should be to match patient concerns, values, and priorities with their treatment choice. The best we can hope for is to establish a good enough relationship with our patients that we wind up getting it right as often as possible.

Mastectomy in the right patient is the right operation. The problem is, there is huge variation within and between countries in the number of women treated by mastectomy, and there are also huge variations in the mastectomy rate even in the same unit, depending on the surgeon you see. This has to be wrong. Recently published research has shown that survival may be better with breast-conserving surgery and radiation than with mastectomy alone.10 We also have a big problem with breast screening—we’re overdiagnosing cancer that previously wouldn’t even have appeared in a woman’s life, and therefore we have to be careful that we don’t overtreat. The primary reason for patients choosing mastectomy is fear of recurrence, but recurrence rates are falling, and the majority of patients may not be well enough informed to make an evidence-based choice. The outcomes from mastectomy and breast reconstruction are not as good as we think or as good as we tell our patients.

			Treatment of Early-Stage Breast Cancer. NIH Consens Statement Online 1990 Jun 18-21;8(6):1-19.

			Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. 

			Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. 

			Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial. 

			Lazovich D, Solomon CC, Thomas DB, et al. Breast conservation therapy in the United States following the 1990 National Institutes of Health Consensus Development Conference on the treatment of patients with early stage invasive breast carcinoma. 

			Freedman RA, He Y, Winer EP, et al. Trends in racial and age disparities in definitive local therapy of early-stage breast cancer. 

			Mahmood U, Hanlon AL, Koshy M, et al. Increasing national mastectomy rates for the treatment of early stage breast cancer [published online ahead of print November 2012]. 

			Garcia-Etienne CA, Tomatis M, Heil J, et al. Mastectomy trends for early-stage breast cancer: a report from the EUSOMA multi-institutional European database. 

			Tuttle TM, Habermann EB, Grund EH, et al. Increasing use of contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical treatment. 

			Hwang ES, Lichtenstein DY, Gomez, Fowble B, Clarke CA. Survival after lumpectomy and mastectomy for early stage invasive breast cancer: the effect of age and hormone receptor status. 

A review of several studies examining the long-term benefits of breast-conservation therapy compared with mastectomy for women with stage breast cancer.

Framing the Mastectomy Debate-The Trends

 Melanoma is one of the most frequent cancers; more than 2 million Americans are treated for skin cancer annually. However, in its earlier stages, it can be easily cured by removal of the skin lesion.

 “Melanoma is on the surface of the skin, and therefore easily visible to patients, doctors, and other health professionals without the use of x-rays or invasive procedures,” said Lynn M. Schuchter, MD, professor of Medicine, University of Pennsylvania School of Medicine, Philadelphia. “Therefore, early detection is highly feasible. Most melanomas are cured with surgery because the melanoma is detected at an early stage of disease before melanoma cells have the potential to metastasize.” Schuchter explained, “Once melanoma metastasizes to distant sites, it is highly resistant to therapy.” Melanoma caused an estimated 8700 deaths in 2010.1

	Chemotherapy for advanced disease has yielded poor 5-year survivals for patients with metastatic disease—16% of those with metastatic melanoma survive 5 years post-diagnosis.

 Dacarbazine has long been the only drug approved by the FDA for treating metastatic melanoma, and it is often ineffective.

 In other words, the prognosis for patients whose melanoma has spread is generally poor, and very few therapies existed before 2011 that could make more than a marginal difference. Only recently have investigational products emerged that, alone or in combination, seem to yield positive responses in some patients.

	Taking Advantage of the Body’s Immune Response

	Melanoma is one of the few cancers that triggers the body’s immune response naturally.

 The problem is that the response is easily overwhelmed by the malignancy. Ipilimumab, which was approved by the FDA in March 2011, works by spurring the body’s immune system to attack the tumor. The melanoma pipeline comprises several examples of investigational agents that seek to enhance the immune response, including therapeutic vaccines.

 The therapeutic vaccine that is perhaps furthest along the pipeline is OncoVEXGM-CSF, which is customized to the patient by using his/ her own tumor antigens. This viral vaccine invades both healthy cells and melanoma cells, but it does not harm the healthy cells, only replicating within the malignant cells, according to the manufacturer, BioVex, which was acquired by Amgen in March 2011.

 The virus produces granulocyte-macrophage colony-stimulating factor (GM-CSF), which gathers dendritic cells, causing the rupture of the tumor cell. This releases GM-CSF and tumor-cell peptides into the local area. The dendritic cells collect the tumor-cell peptides, allowing the immune system to recognize and attack them.

	In 2009, phase II testing of the vaccine in 50 patients with metastatic melanoma revealed overall survival at 2 years of 52%, and an objective response rate of 26% (stable disease rate of 20%).

 Phase III testing is currently under way, and this OPTiM trial is expected to be completed in June 2012 (ClinicalTrials.gov, NCT00769704). The OPTiM trial compares the vaccine with the use of GM-CSF administered subcutaneously in patients with stage III (b-c) and stage IV (M1a-c) disease.

 (vitespen). Not all autologous vaccinebased therapies entering phase III trials have met with success. This vaccine (formerly known as Oncophage), which is developed using gp96 and other peptides from the patient’s own tumor, was found to not improve survival in patients with stage IV melanoma compared with any other choice of therapy. In this phase III trial, only patients with better prognostic characteristics who were injected with vitespen seemed to improve.

 In the case of MVax, from Avax Technologies, the phase II clinical trial results were encouraging, yet the phase III study was halted in 2010, not for safety reasons or poor outcomes, but because of a lack of capital. It is unclear as to when or if this phase III trial may be continued, or if an interim analysis of the study results will take place as planned.

	Most melanomas are cured with surgery...[but] once melanoma metastasizes to distant sites, it is highly resistant to therapy. ”

	Similarly, in 2005, CancerVax Corp halted its phase III trial of the vaccine Canavaxinin for latestage melanoma, not because of safety reasons, but because it had not shown any benefit over placebo.

	Schuchter commented that, “Current approaches to vaccine development are still a major challenge. Unless there is a whole new approach to melanoma vaccines, I am not optimistic about the future of vaccines for patients with melanoma."

 A plasmid that contains the genetic sequences for HLA-B7 and β2-microglobulin, Allovectin-7 is a receptor that activates T cells to provoke an immune response.

 This immunomodulator can be injected directly into the tumor lesion, which may help T-cell recognition of the malignancy and trigger attacks on these specific tumor cells.9 In phase II studies, Allovectin-7 injection in patients with recurrent or refractory advanced melanoma produced a 12% response rate, with a median duration of response of 13.8 months.

 The phase III AIMM trial was begun in 2007 and compares Allovectin-7 with dacarbazine or temozolomide in patients who had not been previously treated with chemotherapy (Clinical- Trials.gov, NCT00395070). This trial is scheduled for completion in the third quarter of 2012.

 GSK2132231A is a recombinant fusion protein with potential immunostimulatory and antineoplastic properties that is derived from the melanoma antigen MAGE-3 and protein D from Hemophilus influenzae (it is also referred to as a MAGE-3 AS02B by the manufacturer). No clinical trial data using this agent have yet been made public, but a phase III trial called DERMA is ongoing to examine the use of GSK2132231A as adjuvant therapy for patients with resected melanoma (ClinicalTrials.gov, NCT00796445). Thirteen hundred patients will be enrolled, and the study is expected to be completed in December 2016.

 This product, a fully human IgG2 monoclonal antibody targeted to CTLA-4, like ipilimumab, may summarize the key learning of research on melanoma to date: The shotgun approach to drug development in metastatic melanoma works poorly. In a previous phase III trial, tremelimumab failed to demonstrate a significant improvement in overall survival compared with temozolomide or dacarbazine in a cohort of patients without prior systemic treatment for their metastatic melanoma.

 However, Pfizer came to an agreement with Switzerland’s Debiopharm to revive plans for a clinical trial of tremelimumab in patients with a biomarker indicating it would most likely be effective. Under this arrangement, Debiopharm would be responsible for funding and running the phase III trial (not yet under way).

 In October 2011, Pfizer granted global rights to the product to MedImmune, a subsidiary of AstraZeneca, for development of this product for other indications.

 Approved in March 2011 for use in nonresectable or metastatic (untreated) melanoma, its manufacturer, Bristol-Myers Squibb (BMS), is conducting additional trials to determine if ipilimumab is also effective in untreated metastatic disease when combined with dacarbazine (ClinicalTrials.gov, NCT00324155) and if it is effective as adjuvant therapy in patients with high-risk stage III disease (ClinicalTrials. gov, NCT00636168). Randomized phase II data have demonstrated 65% 1-year survival and 23% 3-year survival for the ipilimumab dacarbazine combination in patients with chemotherapynaïve advanced disease.

	Ipilimumab is a fully human monoclonal antibody targeted to CTLA-4, a molecule known to negatively regulate the immune system.

 By inhibiting CTLA-4, ipilimumab can enhance the immune system’s T-cell response to tumor cells. In its pivotal 3-arm trial, another BMS agent, gp100 peptide vaccine, which was dubbed MDX- 1379, was used as the active control, despite the fact that no standard of care exists for this patient population. Patients were randomized to receive ipilimumab and gp100, gp100 and placebo, or ipilimumab and placebo. Compared with the median overall survival (OS) of the gp100 arm (6.4 mo), both ipilimumab-containing arms produced significant improvements, with a median OS of 10.0 months in the combination therapy arm (

 <.001) and 10.1 months in the monotherapy arm (

 =.003). In addition to these promising data, ipilimumab is also in phase III testing as an addition to dacarbazine chemotherapy for patients with untreated advanced melanoma (ClinicalTrials.gov, NCT00324155). Clinical trials have identified potential toxic liver effects.

	There is no evidence that BMS is proceeding with the developmental program for MDX-1379.

	Much research in metastatic melanoma has involved testing of agents on specific melanoma cell targets or biomarkers. The targeted medication that has received the most attention, vemurafenib, was approved along with its companion diagnostic test in August 2011 to treat patients with metastatic (late-stage) or unresected (inoperable) melanoma in patients whose tumors express the BRAF gene’s V600E mutation, a driver of tumor growth. Other targets include c-kit, MEK, and Bcl-2 inhibitors. However, successful targeting is difficult, as demonstrated by Genta, which in May 2011 terminated its phase III trial and development program for the Bcl-2 inhibitor oblimersen (genasense) for the treatment of melanoma.

 On the other hand, GlaxoSmithKline’s GSK2118436, a BRAF inhibitor, has entered phase III testing (the first phase III study is scheduled to be completed in June 2012), which if successful in clinical trials won’t reach the market for some time (2014 at the earliest).

 Another targeted agent, GSK1120212, is an inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes, preventing Raf-dependent MEK phosphorylation, resulting in antitumor effects in early-stage trials.

 This GlaxoSmithKline product is the subject of multiple clinical trials for different oncology indications. For melanoma, it is being tested in an open-label, randomized Phase III study comparing GSK1120212 with chemotherapy (either dacarbazine or paclitaxel) in up to 297 patients with stage IIIc or stage IV malignant cutaneous melanoma (all having a 

 mutation—positive tumor). This trial is not scheduled for completion until September 2012 (ClinicalTrials.gov, NCT01245062).

 Developed by Plexxicon and Roche, this BRAF V600E inhibitor seems to be effective

— in some cases, dramatically effective&mdash;for patients with this mutation, although its effects seem to wane after a period of time.

	In previous studies, vemurafenib had induced response rates of 50% and more in patients with metastatic melanoma who have the 

 mutation. In the phase III BRIM3 study, this oral agent (960 mg bid) was compared with intravenous dacarbazine (1000 mg/m2 of body surface area) every 3 weeks as monotherapy in 675 previously untreated patients with stage IIIC or IV melanoma.

	After 6 months of treatment, vemurafenib demonstrated an OS of 84% compared with 64% in the dacarbazine group. In the interim analysis for OS and final analysis for progession-free survival (PFS), vemurafenib demonstrated a 63% relative reduction in risk of death from melanoma compared with dacarbazine. Response rates were 48% for vemurafenib and 5% for dacarbazine (

 <.001). In addition, the risk of the composite endpoint, death, or disease progression was 74% lower in the vemurafenib group (

	However, this agent is not without significant side effects. Thirty-eight percent of the study population taking vemurafenib required dose adjustments to alleviate side effects such as photosensitivity skin reactions, arthralgia, and fatigue.

	Although this study did not report long-term follow-up, there is anecdotal evidence that patients who benefit from vemurafenib may not experience a recurrence for 7 months to 2 years or more.

	With the recent progress in treating metastatic melanoma using targeted therapies like ipilimumab and vemurafenib, might combination approaches of these 2 agents be next in line for clinical trials? Samjiv S. Agarwala, MD, at St. Luke’s Cancer Center in Bethlehem, Pennsylvania, said, “Combination therapy would be an interesting research approach given the differences between ipilimumab (low response rate, prolonged duration) and vemurafenib (high response rate, possibly less durable).” Agarwala pointed out, however, that “Future trials with other agents in combination should address specific biomarkers.”

	A study to test this combination of vemurafenib and ipilimumab is listed on ClinicalTrials.gov but is not currently under way. Additionally, it is expected that the use of vemurafenib will be tested in coming years in a phase IIII study as adjunctive therapy in patients with metastatic melanoma.

	There are few positive data to report on conventional chemotherapeutic agents in the treatment of metastatic melanoma. One agent in development, tasisulam, has run into safety problems in phase III testing.

 Tasisulam is an acyl-sulfonamide compound that induces apoptosis through the mitochondrial-mediated cell death pathway. In phase II trials, 47% of patients taking tasisulam experienced some level of disease control, and a 2.6-month PFS (median) as second-line treatment of patients with unresectable or metastatic melanoma.

 This was not a controlled trial. In December 2010, the SUMMIT-1 phase III registration trial of tasisulam versus paclitaxel stopped recruiting patients with metastatic melanoma because of 12 patient deaths that were potentially associated with the medication.

	There is no further word from the manufacturer (Eli Lilly) whether dosing will be changed for continued enrollment or whether the trial has been discontinued permanently.

	Although the late-stage pipeline for melanoma seems bustling, most of the interest is occurring around ipilimumab and vemurafenib, which have been approved for their initial indications.

	The success of these 2 agents in treating metastatic melanoma may encourage more drug development activity for targeted therapy, according to Agarwala. “I believe it will spur more drug development, as we are still a long way off from curing patients and the encouraging results seen so far have at least opened the door to even more effective drugs in the future,” he remarked. “I believe the results with vemurafenib and ipilimumab are proof of principal trials that show these approaches are effective. Now let’s move that up a notch and find drugs or combinations with even greater efficacy.”

		Table. Drug Pipeline for Melanoma Products.

					Tyrosine kinase inhibitor/ c-kit inhibitor

					Metastatic melanoma in treatment-naïve patients

					In combination with low-dose interleukin-2 in patients with stage IV melanoma

					Raf kinase inhibitor/ vascular endothelial growth factor receptor inhibitor

					In combination with standard chemotherapies after receiving 1 prior therapy of dacarbazine or temozolomide in patients with stage III or IV melanoma

					In combination with GM-CSF in patients with metastatic melanoma

Melanoma is one of the most frequent cancers; more than 2 million Americans are treated for skin cancer annually.

Jennifer Klem, PhD

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