Chairman and Director Chief of Lymphoma Director, Clinical and Translational Cancer Research

		John Theurer Cancer Center at Hackensack University Medical Center

 takes a particularly important meaning this year, as Jan 1, 2014, is now a landmark date in the history of US healthcare with the implementation of the Affordable Care Act (ACA), also referred to as 

, which was passed into law in March 2010.

Almost 50 years have passed since the last big change in US healthcare came with the establishment of Medicare in 1965. However, the complexity and scope of the ACA is truly unprecedented given both the number of players (patients, physicians, hospitals, pharmacies, pharmaceutical industry, diagnostic companies, employers, and insurance providers) and the extensive medical progress since the implementation of Medicare, which has translated into much more complex and costly medical care.

The ACA was enacted with the goals of increasing the quality and affordability of health insurance. The law requires coverage through either an employer, Medicare, expansion of Medicaid (younger adults), or through personal mandate (or else financial penalty). It also requires minimum standards for health insurance policies and increases coverage: no coverage denial for preexisting conditions, no lifetime cap, no/lower copay for screening and preventive medicine, and children up to age 26 can be included under their parents’ coverage. The ACA will mostly be financed by increased taxes and decreased Medicare reimbursement to hospitals.

Despite more than 3 years of preparation since the law passed (with numerous attempts to repeal it) and putting politics aside, the reality of implementation of the ACA is and will be—as expected&mdash;facing numerous serious challenges. Appropriate concerns have emerged over the last few months, including difficulties for individuals trying to sign up (horrendous ACA website stories), challenges in the insurance exchanges from increased premiums, the inability to keep one’s previous plan, and forced loss of access to individuals’ existing healthcare providers. Meanwhile, the controversy about the reluctance of some states to even support Medicaid expansion adds to the growing anxiety.

Although to this day only a minority of Americans—much fewer than predicted&mdash;have signed on for new health plan coverage, it remains totally unclear in this transition phase how things will unfold practically. A number of justified concerns persist on how this is going to translate into doctors’ offices, from confusion about coverage, increased premiums and/or deductibles, to increased medical spending, and eventually poorer coverage and worsening of quality of care.

That being said, no one would (or could) deny that the current course of spending for healthcare in the United States is not sustainable. The Medicare Sustainable Growth Rate (SGR) is currently used by the Centers for Medicare and Medicaid Services to frame federal healthcare spending. Generally, this method aims to ensure that the yearly increase in the expense per Medicare beneficiary does not exceed the growth in gross domestic product. Though it is necessary to control healthcare costs, adjustments of SGR (hence, of reimbursement to physicians) occurred for many years solely through temporary remedies, keeping physicians and patients in a constant state of uncertainty, and this is also not sustainable.

At the end of 2013, the government issued a new temporary relief with a 3-month, 0.5% payment increase (the first since 2010) in lieu of the 24% cut in Medicare reimbursement initially scheduled for January 2014. A reliable payment system will be essential to support the enforcement of all these changes at a time when physicians are already facing pressure related to the electronic health record mandate and the upcoming new ICD- 10 coding implementation, on top of the uncertainties related to the ACA itself.

Amid all these controversies and growing concerns, public support for the law has dropped to a record low and is the subject of intense politics. I believe, however, that it is important that we do not lose track of the main goal, which is improving the health of all Americans.

Given the stakes, one should view this as an opportunity for greater and more commendable changes by focusing more on quality, outcome, and accountability, instead of just the possibility of rationed care though an increasingly complex and cumbersome regulatory and bureaucratic environment.

Being an oncologist, it appears rather obvious to me that cancer provides a perfect platform to develop a new and requisite model that could be an example of a move toward transformative care in medicine. A number of converging forces are undeniably reshaping oncology: costly medicine (with the bulk of expenses still spent in the palliative setting), an aging population (increasing cancer incidence), and better outcomes due to better therapies. Further, the molecular diversity of cancer will affect drug development and clinical trial design (targeting patient populations based on molecular rationale), which in turn could reduce the cost of drug development and hopefully the eventual cost of the drugs. Together with the availability of high-throughput diagnostic technologies (sequencing and other genomics approaches), a natural shift toward personalized or precision medicine in oncology is palpable and has already started.

More than ever, it will be particularly important in oncology to all work together to bring innovation and novel therapies to patients. The ACA needs to address the issues related to clinical trial support and access for patients while easing the burden of investigators subjected to an increasingly cumbersome regulatory environment. The enormously complex ACA has already been amended multiple times and is likely “not final”; let’s hope appropriate changes can and will be made to support innovation and continued progress, as knowledge remains the best medicine.

Meanwhile, proactively involving physicians in responsible initiatives to control cost and improve outcomes appears more constructive and promising. Moving toward bundled care with relevant patients’ stratification and innovation is the future. The answer is to view this as an opportunity to be transformative in oncology and medicine at large: Would anyone not want rationale care versus coercively rationed care?

Change of this scale is never easy, but with the well-being of our society at stake, as well as the future of medicine and innovation leadership in our country, the ACA needs to address, support, and embrace all the exciting changes happening in cancer care and medicine as a whole.

Articles

The classic saying Have a Happy and Healthy New Year takes a particularly important meaning this year, as Jan 1, 2014, is now a landmark date in the history of US healthcare with the implementation of the Affordable Care Act (ACA), also referred to as Obamacare

Can We Hope for the Best From the Affordable Care Act?

At first blush, the articles in this issue of 

 may appear to be unrelated; however, upon closer inspection, we see how they illustrate the challenging but fascinating changes that are currently taking place in oncology. This issue of 

 covers a diverse landscape: the implementation of sentinel node mapping in endometrial cancer; emerging questions on how we should combine very promising small molecules (ie, together / sequentially / alternating) in renal cancer or multiple myeloma; and an exploration of how these clinical decisions fit into the ongoing economic forces in how we manage patients with cancer.

Individually, each of these articles highlights the best benefit for a subpopulation of patients at a given stage of their disease (eg, in the relapse setting as part of a phase II trial). The common thread throughout these articles is how emerging, novel therapies fit into existing treatment paradigms. For example, will combinations of novel therapies affect the use or timing of high-dose therapy and stem cell transplantation in multiple myeloma? Collectively, the real question these articles pose is how will we best use our continually evolving armamentarium of treatments to deliver the best outcomes while optimizing the cost of care for our patients.

Given the unsustainable cost progression in oncology, and medicine as a whole, the adjustments required to meet these challenges provide a great opportunity to develop “smarter” algorithms that take into consideration all of our available therapies, as well as our growing awareness of the diversity of cancer patients. This implies that we need to do a better job of molecularly stratifying patients (ie, integration of molecular diagnostics) and of defining biomarker-driven pathways for both conventional therapies (ex vivo cytotoxics) and novel therapies—thus basing fewer treatment decisions solely on empiric choices.

Providing a better rationale for our decisions would not only help reduce costs in the routine practice of oncology, but this additional level of transparency may also have the added benefit of improving clinical trials enrollment, which remains a weak link in our current approach.

The real question is how will we best use our continually evolving armamentarium of treatments to deliver the best outcomes while optimizing the cost of care for our patients.

Novel Agents in Practice: Outcomes at What Cost?

 includes a focus on 2 challenging situations: management of metastatic triple negative breast cancer (TNBC) and of advanced stage non—small–cell lung cancer (NSCLC).

	Christiansen and colleagues report on actual first-line treatment patterns for the management of metastatic TNBC in community practice settings in the United States. TNBC is characterized by aggressive tumors with cells that lack estrogen receptors (ERs) and progesterone receptors (PRs), and do not overexpress HER2. The study looked at patients with stage IV metastatic TNBC in 2 databases (Georgia Cancer Specialists Database and International Oncology Network’s Treatment and Outcomes Database). Though the number of patients evaluated was relatively small, the patterns seen confirmed previous observations.That is, the analysis found that there was no general consensus in current treatment for stage IV TNBC. The basis of therapy remains the use of conventional cytotoxics from single agent chemotherapy (capecitabine, taxanes) or combinations regimens (cyclophosphamide, doxorubicin with and without bevacizumab), with corresponding significant differences in costs.

	Although the metastatic potential in TNBC is similar to that of other breast cancer subtypes, these tumors are associated with a shorter median time to relapse, a greater chance of visceral- and organ-based metastatic disease, and overall worse outcomes and survival. Unfortunately, there are no reliable prognostic factors in TNBC, and molecular studies have shown this is a very heterogeneous disease.

	Although TNBC is often referred to as surrogate for basal-like breast cancer, there is clearly a need for further subclassification. One of the main issues, as seen in these results, is the lack of clear guidelines in TNBC. Ongoing studies (more than 60 currently) looking at new combinations—including new targeted therapies focusing on EGFR, CHK-1, PARP-1, PI3K/mTOR inhibitor, and TKI (dasatinib), among others&mdash;may shed some light on the management of this disease. Recent work (Lehmann, BD et al. 

. 2011;121:2750-2767.) identified 6 molecular subtypes of TNBC. Using representative TNBC cell lines of the 6 distinct subtypes, investigators showed that the various subtypes had different sensitivities to targeted therapies currently under laboratory and clinical investigation, providing a rationale for future studies.

	Meanwhile, the treatment of NSCLC has seen a paradigm shift over the last decade, with the integration of novel therapies based on a better understanding of some of the driving mutations. In this issue, the article by Steven A. Sandler, MD, reviews these advances.

	NSCLC, which accounts for approximately 85% of all lung cancers, is divided further into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma histologies. Lung cancer is the leading cause of cancer-related mortality in men and women, both in the United States and worldwide. In 2006, lung cancer resulted in 158,000 deaths in the United States alone—more than colorectal, breast, and prostate cancer combined.

	Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis. Only a third of patients with NSCLC present at diagnosis with disease that is sufficiently localized to attempt curative surgical resection (stages IA and IB, IIA and IIB, and IIIA). Radiation is a reasonable option for lung cancer treatment for those who are not candidates for surgery. However, approximately half of patients who undergo an attempt at curative local therapy experience local or systemic relapse. As a result, about 80% of all patients with NSCLC receive chemotherapy at some point during the course of their disease. NSCLC is only moderately sensitive to chemotherapy, with single-agent response rates in the range of 15% or better. Newer agents (eg, gemcitabine, pemetrexed, docetaxel, vinorelbine) have shown promising single-agent activity, with response rates from 20% to 25% (although there has been no clear benefit demonstrated with triple agents combinations).

	The most impressive changes seen in NSCLC relate to the benefit of targeted therapies. These changes have been so dramatic that screening for “driver mutations” in NSCLC is now part of routine management and National Comprehensive Cancer Network guidelines. One driver mutation—overexpression of epidermal growth factor receptor (EGFR), which is common in NSCLC&mdash;correlates with increased resistance to therapy, metastatic potential, and poorer outcome. Gefitinib and erlotinib, both EGFR tyrosine kinase inhibitors (TKIs), have shown dramatic benefit in NSCLC, particularly in subsets of patients carrying a mutation for EGFR. (In one study, patients with mutated EGFR had significantly longer PFS in the gefitinib group, for example, compared with carboplatin-paclitaxel). These favorable mutations for EGFR were more common in women, non-smokers, and patients of Asian origin. On the other hand, patients with EGFR expression and absence of KRAS mutations (similar to what has been seen in colon cancer) may be considered for the addition of cetuximab to first-line chemotherapy.

	Another remarkable example of the benefit of targeted therapies is crizotinib (Xalkori), which was approved by the FDA in August 2011, for the treatment of locally advanced or metastatic NSCLC that is anaplastic lymphoma kinase, ALK-positive as detected by the Vysis ALK Break Apart FISH Probe test. Other directed therapies, such as the anti- VEGF monoclonal antibody (bevacizumab), have already been approved for clinical use, while a number of others are in clinical testing (eg, targeting MET, VEGFR, HER2, PIK3CA, and IGF-1). Finally, ongoing efforts to identify additional targetable driver mutations will help dissect further the heterogeneity of NSCLC to the benefit of our patients.

	The paradigm shift in lung cancer offers great hope for future endeavors, including in TNBC, but also represent a true illustration of the ongoing shift toward personalized medicine across the board in oncology.

This issue of Contemporary Oncology includes a focus on 2 challenging situations: management of metastatic TNBC and of advanced stage NSCLC.

Personalized Medicine: A Promising Future in Oncology Practice

		Chief, Lymphoma Division, Professor and Chairman

	This article offers highlights from some of the advances we’ve seen in hematological and solid tumors over the past 2 decades. The first report by Janssens and colleagues focuses on the changes in chronic lymphocytic leukemia (CLL) outcomes and the benefits of chemoimmunotherapy, namely rituximab, using a meta-analysis to compare regimens used in the United States and Europe. The second paper by Popek and Tsikitis reviews the broad changes that have occurred in the treatment and management of metastatic colon cancer.

	CLL is the most common form of leukemia and the second most common blood cancer after lymphomas. CLL has long been regarded as an incurable disease of the elderly, treated mainly by symptom palliation. While some patients can have a very indolent course (ie, never require treatment and have the same life expectancy as normal control groups), others can have a much more rapid course. In some cases, the disease can even transform into large cell lymphoma (eg, Richter syndrome). Prior generations of chemotherapy resulted in improved response rates but did not change the natural history of the disease. However, prolonged remissions and improvements in survival are now possible, owing to therapeutic advances in the use of purine analogs as frontline treatment and the emergence of monoclonal antibody-containing chemoimmunotherapy combinations.

	As is the case with indolent non-Hodgkin lymphoma (NHL), clinical criteria have been developed to help determine when to initiate therapy in patients with CLL. However, the criteria are somewhat subjective and tend to lead to heterogeneous treatment, which might affect comparisons from one trial to another. Moreover, as in indolent NHL, using overall survival (OS) as an endpoint can be a challenge due to the long natural history of the disease. Therefore, surrogate markers of outcome, such as overall response rate (ORR), complete response rate (CRR), and progression-free survival (PFS), have often been used. Over the past 3 decades, trials have looked at a number of regimens—from chlorambucil single agent to purine analogs (fludarabine and to a lesser degree pentostatin) to combinations with fludarabine and cyclophosphamide (FC)&mdash;based on significant synergistic cytotoxicity in preclinical models. Combination FC was shown to be superior to fludarabine alone, and fludarabine/cyclophosphamide/rituximab (FCR), which was developed at MD Anderson Cancer Center, has been shown to be superior by all parameters (ie, ORR, CRR, duration of response [DOR], and PFS).

	Rituximab, a chimeric anti-CD20 monoclonal antibody that targets the cell-surface antigen CD20 expressed on more than 90% of mature B-cell malignancies, has proven to be a game changer in B-cell NHL. However, rituximab has limited single-agent activity in CLL (ORR 12% at 375 mg/m2) which may be attributed in part to the reduced tumor expression of CD20 and the presence of soluble CD20 serving as a decoy receptor in CLL.

	The addition of rituximab to FC (ie, FCR) doubles the proportion of patients entering complete remission, and significantly prolongs remission duration and OS. The quality of the responses has led to the emergence of minimal residual disease (MRD), and patients with no MRD had the best outcome. Strategies of consolidation and maintenance therapies have been developed for patients to reach negative MRD. This includes more rituximab or better alemtuzumab, an anti-CD52 antibody. Unfortunately, FCR is not always a treatment option (eg, in elderly, “nonfit” patients), and patients with poor risk factors, especially those with p53 abnormalities (mutation/deletion), still have a poor outcome. Ongoing studies are looking at FCR plus alemtuzumab in these patients, but issues related to toxicity, myelosuppression, and immunosuppression (especially infection, pneumocystis pneumonia, and cytomegalovirus reactivation) are an obvious concern with this combination regimen.

	In the relapse setting, an increasing number of patients are fludarabine-resistant and represent a clear challenge to the clinician. A growing list of new salvage options has been developed, again showing a benefit from the combination with rituximab. Not surprisingly, some of these new options are being implemented in the frontline setting as well. Bendamustine, approved in relapsed CLL, is now being tested in the frontline setting in the CLL10 trial (bendamustine/rituximub vs FCR). Results of this trial are still pending. In addition, a number of new monoclonal antibodies have been developed or are currently in development for the treatment of CLL. For example, ofatumumab, which targets another epitope of CD20 and induces greater complement-dependent cytotoxicity, has shown activity in CLL double failures (fludarabine and alemtuzumab).

	Also, based on its promising activity in the relapsed setting, the immunomodulator lenalidomide is now being tested as maintenance and consolidation postinduction therapy or as new backbone for a nonchemotherapy option in elderly patients in the frontline setting. Finally, small molecules targeting the BCR pathway (ie, phosphoinositide-3 kinase inhibitor and Bruton’s tyrosine kinase inhibitor) have recently shown impressive activity in phase I and early phase II studies, even in patients with poor molecular risk subtypes. Remarkably, CAL1010 and PCI3275 showed a very favorable toxicity profile, offering a great opportunity to build upon the success of chemoimmunotherapy in CLL in a variety of combinations.

	The article by Popek and Tsikitis reviews new strategies for the diagnosis and treatment of colon cancer. Although significant advancements have been made, colorectal cancer (CRC) is still a common and lethal disease. Approximately 142,570 new cases of large-bowel cancer are diagnosed each year in the United States—about two-thirds are colon cancers and one-third are rectal cancers. Although mortality has been progressively declining since the early 1990s, CRC remains the second most common cause of cancer deaths.

	The majority of CRCs are sporadic and have modifiable risk factors that can be managed through diet, weight loss, and elimination of tobacco use. A small number of CRCs are familial cases that shed great light on the multistep oncogenic pathways of colon cancer, while chronic inflammatory bowel disease is considered the third player in CRC pathogenesis.

	Most CRCs are adenocarcinomas and are typically diagnosed by colonoscopy. A variety of serum markers have been associated with CRC, particularly carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA-19.9), but they both have a low diagnostic ability to detect primary CRC due to a significant overlap with benign disease and a low sensitivity for early-stage disease. Despite the large number of correlative studies exploring the prognostic significance of various histologic, molecular, and clinical features, the pathologic stage at diagnosis remains the best indicator of long-term outcome in CRC, especially the presence of distant metastases, local tumor extent, number of involved lymph nodes, and residual disease postsurgery. A number of prognostic tests, including routine use of p53, thymidine synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, IL-8, VGEF, CXCR2, microsatellite instability, 18q loss of heterozygosity, or testing for DNA mismatch repair genes, have been developed to stratify CRC patients, but none of these tools have translated into changes in the management of CRC patients.

	Surgery plays a critical role in the staging and treatment of CRC. In fact, we now have enough data to support when it is feasible to use laparoscopic approaches that produce no difference in relapse rate or outcome compared to standard surgery. The role of adjuvant therapy is well-established, at least for stage III/IV disease, and has truly impacted both PFS and OS. On the other hand, the majority of patients with metastatic colorectal cancer (mCRC) cannot be cured. Although a subset of patients with liver and/or lung-isolated disease are potentially curable with surgery, most patients receive palliative treatment and systemic chemotherapy.

	For decades, 5-fluorouracil (5-FU) was the sole active agent, but this has changed markedly since the mid-1990s with the approval of 3 new cytotoxic drugs and 3 new humanized monoclonal antibodies. The 3 new cytotoxic agents are capecitabine (an oral fluoropyrimidine), irinotecan (a topoisomerase I inhibitor that blocks DNA repair), and oxaliplatin (an inhibitor of DNA replication and possibly a down-regulator of the expression of thymidylate synthase). The 3 new humanized monoclonal antibodies target either VEGF (bevacizumab) or EGFR (cetuximab and panitumumab). Benefit from monoclonal antibodies targeting the EGFR is restricted to patients whose tumors do not contain mutated KRAS (ie, KRAS wild-type).

	A number of combinations and schedules of these available agents have been studied, and although the best combination, sequence, or duration of treatment are not firmly established, systemic adjuvant chemotherapy can produce meaningful improvements in median survival and PFS. These benefits are most pronounced with regimens containing irinotecan or oxaliplatin in combination with 5-FU; this led to median survival ranges >2 years versus 5 to 6 months for best supportive care alone. In addition, combination chemotherapy in the neoadjuvant setting can be helpful for patients whose metastases (especially to the liver) might then become potentially resectable after initial chemotherapy response. The use of bevacizumab is still debated, especially regarding the continuation of its use or after disease progression using a regimen containing bevacizumab. Given the lack of data from randomized trials, cost of the drug, and potential toxicity issues, the addition of bevacizumab after progression (ie, second- or third-line) cannot be considered a standard approach outside of a clinical trial, but could be considered in select patients, specifically in those with KRAS-mutated tumors where anti-EGFR therapies are not indicated.

	Finally, screening plays a major role in the early diagnosis of colon cancer. There are several screening methods, including occult fecal blood detection, computed tomographic colonography (CTC), sigmoidoscopy, or colonoscopy. However, given the lack of randomized trials to demonstrate that a reduction in mortality from CRC is associated with the performance of colonoscopy or CTC, there is still an ongoing debate on the actual benefits of screening. The results of large ongoing trials in both Europe and the United States might help develop better recommendations, but strategies that include risk stratification for colorectal cancer screening are still needed.

	Although the outcomes of advanced CRC or mCRC have improved over the past decade, the results are continue to be disappointing. Unfortunately, there is still frequent chemoresistance, and no perfect model exists to integrate conventional and targeted agents. To further complicate matters, these new targeted agents have their own issues of toxicity and have dramatically increased the cost of care.

	Despite the advances in treatment for both CLL and CRC, more work needs to be done to develop novel therapies and a rationale for new drug combinations using reliable clinical tests. These efforts will help guide us towards individualizing therapy and will ultimately help us improve outcomes for our patients.

A look at the benefits of the chemoimmunotherapy rituximab for CLL and a look at the treatments and advances made in treating metastatic CRC.

Progress Made, but More Work Lies Ahead in CLL and CRC Treatment

The oncology landscape is accelerating quickly. New agents, combination therapies, new technologies and targeted therapies are resulting in improved treatment and maintenance options for our patients. Our overall approach to medicine is rapidly evolving and oncology is leading the way in the reality of personalized medicine.

New Frontiers in the Management of Solid and Liquid Tumors

. My colleague, leukemia chief Stuart Goldberg, MD, and I are the Program Chairs and can promise you this will be an exciting professional education opportunity that will provide relevant, important new information, stimulating discussions, and an opportunity to personally meet your colleagues from across the globe.

The complimentary CME program will be hosted November 3-4 at the John Theurer Cancer Center and feature world-class physicians who are leading cutting-edge research into the state-of the-art treatment modalities for hematological and solid tumors. We’ll be addressing the following important topics:

		Emerging best practices and studies in hematological malignancies and solid tumors

		Impact of novel therapies in the care of hematology-oncology and solid tumor patients

		New modalities in imaging and its best use in cancer patients

		Biomarkers and new prognostic markers in lymphomas and leukemias

		Impact of emerging molecular markers in solid tumors

		Shifting paradigms in the treatment of multiple myeloma

To view the complete agenda and register online, visit 

. I hope you can join us for this important event and I look forward to seeing you there.

Chairman, Director and Chief, Division of Lymphoma

John Theurer Cancer Center at Hackensack University Medical Center

A Letter from Andre Goy, MD, MS, about the New Frontiers in the Management of Solid and Liquid Tumors in November.

New Frontiers in the Management of Solid and Liquid Tumors Letter from Andre Goy, MD, MS

	The current issue of Contemporary Oncology takes us through dramatic changes in the landscape of multiple myeloma (MM) that have occurred over the past decade and explores new developments in the context of stem cell transplantation in non-Hodgkin lymphoma (NHL), especially in the post-rituximab era.

	In MM the most striking feature is the use of novel therapies such as proteasome inhibitors (bortezomib) and immunomodulatory drugs (IMiDs) (thalidomide, lenalidomide), that, together with autologous stem cell transplantation (ASCT), have transformed the management of MM and extended overall survival (OS). The impact of novel therapies has been most prominent in both the relapse and frontline settings. especially in combination of biologics or with chemotherapy regimens, as well as in the context of ASCT and as part of consolidation and maintenance strategies. The combination of so-called biologics with steroids has led to unprecedented complete response rates in MM patients, leading to practice-changing results and raising discussion on the role of ASCT consolidation.

	Traditionally, ASCT in first response in MM was to reduce further residual tumor load after induction therapy while stem cells were often still “contaminated” with clonal plasma cells. With the current quality and depth of response seen in MM using novel biological triplets as induction, one could argue that ASCT consolidation might lead to an even greater benefit from high-dose therapy (HDT) and ASCT. On the other hand, some argue that ASCT as first consolidation became unnecessary and should be reserved for first relapse (ie, after the collection of stem cells postinduction at minimal disease burden). This important question of the role and timing of ASCT in MM remains unresolved pending ongoing clinical trials. However, elderly patients in whom HDT-ASCT is not appropriate might benefit more from these new biologic combinations, which offer very good cytoreduction with less toxicity.

	New weekly schedules, as well as subcutaneous use of bortezomib, offer not only better convenience but also a better toxicity profile (eg, less neuropathy). In addition, the use of biologics as consolidation or maintenance therapy in both younger and older patients is becoming an asset in the management of MM. Meanwhile, in the relapse setting, many new therapies are making their way from second-generation proteasome inhibitors (carfilzomib) to new IMiDs (pomalidomide), targeted therapies (inhibitors of NF-κB, MAPK, and AKT), epigenetic agents (histone deacetylase inhibitors, vorinostat and panobinostat), and humanized monoclonal antibodies (elotuzumab and siltuximab). Interestingly, some of these new therapeutics appear to be able to overcome chemoresistance and conventional poor-risk features in MM. As the awareness of molecular heterogeneity of MM continues to grow (including its progression over time in a given patient), the next challenge will be to try to stratify patients in the clinic for conventional and biologic approaches.

	When shifting to NHL, we can also see changes in the landscape of diffuse large B-cell lymphoma (DLBCL) over the past 2 decades. The introduction of rituximab with chemotherapy (ie, R-CHOP) was the first improvement in over 3 decades in the outcome of DLBCL. Shown initially in patients aged >60 years, the remarkable benefit of R-chemo has been confirmed across the board in all patients with DLBCL with an improvement in progression-free survival and OS confirmed with long-term follow-up and in all International Prognostic Index subgroups.

	In the frontline setting, studies looking at intensification (ie, beyond R-CHOP) in poor-risk patients tend to show that in the era of rituximab there is no benefit of dose-dense CHOP-14, and that rituximab is likely to decrease potential differences between conventional and high-dose regimens. This was confirmed with several studies just presented at ASCO in June.

	The use of rituximab has also altered the landscape in the relapse setting. In patients who fail prior R-chemo, the results of conventional strategy with salvage chemotherapy (ie, R-ICE) followed by HDT and ASCT have worsened, especially in patients who failed initial therapy within 1 year. The same is true in patients considered primary refractory to R-CHOP with very poor outcome, illustrating a need for improvement in the field of stem cell transplantation in DLBCL.

	Several of these new approaches are reviewed by Scott D. Rowley, MD, in this issue (see page 9). In his commentary, Dr Rowley discusses the use of PET scans (trying to reach a PET-negative response to salvage therapy prior to HDT-ASCT), new agents (radioimmunotherapy consolidation prior to ASCT), new combinations (lenalidomide or other small molecules/monoclonal antibodies with R-ICE [rituximab, ifosfamide, carboplatin, etoposide]), and consolidation or maintenance strategies post-ASCT. Of note, a recent update of the CORAL trial at ASCO did not show a significant benefit with the use of rituximab maintenance post-ASCT, suggesting that other strategies are needed. Interventional immunotherapy post-ASCT is still early in its development, but extensive preclinical work, as well as known prognostic factors related to the immune system status and immune reconstitution post-ASCT (eg, impact of absolute lymphocyte count/absolute monocyte count ratio at day 15 post-ASCT) in DLBCL, provide a rationale for exploratory ongoing studies. Preliminary results looking at the use of MAb targeting PD-1 (CT-011) post-ASCT, as well as maintenance post-ASCT using the immunomodulator lenalidomide are encouraging.

	The ultimate immunotherapy would be allogeneic stem cell transplant, which has strong limitations related to toxicity and/or graft versus host disease (GVHD), and the frequent need to use an unrelated donor (ie, due to the lack of a sibling donor); these factors are very relevant given the profile of the population of DLBCL patients. The development of nonmyeloablative approaches has certainly led to intriguing results—unfortunately, mostly in indolent diseases (follicular lymphoma and chronic lymphocytic leukemia) and, to a lesser degree, in mantle cell lymphoma. While data of allogeneic stem cell bone marrow transplant in DLBCL is limited, encouraging results are emerging with immunodepletion (using EPOCH with fludarabine and rituximab to deplete host CD4  cells before transplantation), as well as TH2 amplification of donor T cells. The goal is to skew the immunological repertoire in favor of graft-versus-solid-tumor as opposed to graft-versus-lymphoma effect, as shown in preclinical models. We at John Theurer Cancer Center have partnered with the National Cancer Institute to explore this strategy with very promising and potentially game-changing results, including in some patients with refractory/relapsed DLBCL. As in MM, a growing awareness of the molecular heterogeneity of DLBCL will hopefully lead to a better stratification of patients, both in the frontline and relapse settings where a variety of new agents are also being developed.

	Finally, patients’ outcomes also rely on best supportive care, and there are new developments in that setting as well. Bisphosphonates introduced the concept of disease-modifying therapy by effectively reducing bone pain and skeletal-related events; they are now commonly used in patients with bone metastatic cancer or MM. In the past decade, the growing knowledge of bone biology and our understanding of the molecular mechanisms involved between cancer cells and the bone matrix led to the identification of new therapeutic targets for innovative “smart drugs.” The most investigated is the receptor activator of nuclear factor-Κb/(RANK)/RANK ligand/osteoprotegerin (RANK/RANKL/OPG) pathway, and denosumab is the first RANKL inhibitor approved by the FDA to reduce bone events (eg, pain control, fewer fractures, better functional outcome). Several other targeted agents in the field are being evaluated, illustrating the complexity of future therapies from targeting the tumor cells themselves to the microenvironment, including angiogenesis regulation, control of the dialogue between bone and tumor cells, and tumor cells with the immune system.

	As I always tell residents on the floor, oncology is becoming more fascinating by the day and the dramatic changes seen over the past 2 decades will just continue exponentially, enabling us to move toward more rational therapeutics—a first step toward personalized medicine to further improve our patients’ outcomes.

A look at dramatic changes in the landscape of multiple myeloma that have occurred over the past decade and new developments in the context of stem cell transplantation in non-Hodgkin lymphoma.

Accelerating Changes in Oncology

	It is my sincere pleasure to be joining 

as the Editor-in-Chief. In this role, I hope to help the journal achieve its mission in bringing readers high-quality, peer-reviewed research, provocative commentaries, and personal patient stories.

	As the Chairman and Chief of the Lymphoma Division of the John Theurer Cancer Center at Hackensack University Medical Center and an avid oncology educator and researcher for more than 25 years, I am keenly aware of the importance of obtaining relevant and current clinical cancer information. The partnership between John Theurer Cancer Center and Intellisphere’s Oncology Specialty Group will help ensure that we are delivering timely information that you can apply in your practice.

	The breadth and depth of new technology, targeted therapies, and new diagnostics heralds a truly exciting age for our specialty. Understanding the latest research— from novel therapies to translational and personalized medicine&mdash;allows us to deliver the best cancer care to our patients. 

 will provide reviews of standards of care in oncology that focus on the practical application of these emerging new treatment modalities.

	The John Theurer Cancer Center has been fortunate to have played a critical role in some of the recent progress in cancer care. Our Blood and Marrow Stem Cell Transplantation team performed more than 350 transplants last year—half of which were allogenic. We initially were the lead enroller in the pivotal trial of trastuzumab (Herceptin) in breast cancer. Since then we have continued to be among the premier centers for the development of several new compounds from tyrosine kinase inhibitors and proteasome inhibitors to immunomodulatory derivatives of thalidomide, as well as new monoclonal antibodies. My own research focuses on developing both novel targeted therapies and biomarkers for lymphoma. I reported first the activity of bortezomib in mantle cell lymphoma (MCL) and became the co-principal investigator on the PINNACLE trial&mdash;the largest study to date for patients with MCL&mdash; which led to the FDA’s approval of Velcade (bortezomib) for patients with relapsed/refractory MCL.

	We recently opened a brand-new $130 million outpatient facility that will foster multidisciplinary care across our 14 specialized divisions with a full research platform onsite, including a clinical research team, a phase I unit, and state-of-the-art tumor banking capability. With more than 120 clinical trials currently open for enrollment, we are doing our best to help expand the scientific knowledge of the cancer field.

	In addition, we are collaborating with a number of other institutions such as the MD Anderson Cancer Center, Dana- Farber Cancer Institute, Mayo Clinic, and the National Cancer Institute to further our research. We hope to share our collective experience and perspectives with our readers as part of this partnership and help you continue to improve the outcomes for your patients.

	I look forward to working with the community of 

readers and welcome your feedback to help make this publication more relevant and useful to you in your daily practice. We also invite readers to submit research, as this is a tremendous way to highlight achievements and to disseminate knowledge.

	The promise of improved cancer care is what drives us all and access to quality information is paramount to ensuring that this progress continues. I am excited about this opportunity and I offer a warm welcome to all of you as we work together to translate innovations in oncology to the community setting.

In this role, I hope to help the journal achieve its mission in bringing readers high-quality, peer-reviewed research, provocative commentaries, and personal patient stories. 

Andre Goy, MD, MS