You may have noticed that the issue you received last month looked a little different than what you’re used to seeing from the ONCOLOGY journal! I wanted to formally introduce you to the new look and feel of ONCOLOGY, and let you know what you can come to expect with this redesign.

ONCOLOGY is known as a publication dedicated to presenting review articles and commentary on the most relevant and up-to-date cancer treatment information. We will continue to publish these reviews-at an increased rate of 5 per issue-each with an accompanying commentary and a summary that puts the information into context, both from noted experts. We hope this will help our readers to get the full picture on issues in cancer care that will affect their practice.

In addition, we have also produced an assortment of new and relevant features that will appear regularly in ONCOLOGY. These include Q&As with experts in the field; Practice Matters, which deals with issues and topics relevant to running an effective oncology practice; and Comorbidity Consult, which examines how clinicians treat comorbid conditions that exist or arise in their cancer patients. In addition, you will continue to see the features you’re familiar with, such as How an Expert Approaches It, Clinical Quandaries, and Point/Counterpoint (formerly Pro/Con).

With the launch of the redesigned print journal, we have also taken steps to strengthen the connection between our print journal and our online presence at CancerNetwork.com. The print journal now includes a table of contents featuring highlights from the Cancer Network’s recent online-only articles and features. There are also links within print articles to additional relevant content on the site. Finally, to make ONCOLOGY easier to find online, we have given it a new portal on the Cancer Network, with its own URL: www.TheOncologyJournal.com. At this portal you’ll find a new digital magazine version of the journal, which facilitates the saving and printing of articles that interest you.

Our goal is to provide you with a comprehensive assortment of articles that deliver information relevant to your practice and that help you better care for your patients, and I know we will continue to do so through the new-and-improved ONCOLOGY.

- Nora Ray, Editorial Director, ONCOLOGY 

Articles

You may have noticed that the issue you received last month looked a little different than what you’re used to seeing from the ONCOLOGY journal! 

Introducing the New-and-Improved ONCOLOGY Journal

 Can you talk about the CLEOPATRA trial that was published earlier this year? What was the goal of this study?

The CLEOPATRA trial is a randomized, double-blind, placebo-controlled, international phase III study for patients with HER2-positive metastatic breast cancer. In brief, patients were randomized to receive docetaxel and trastuzumab with either placebo or pertuzumab. The primary endpoint of the trial was progression-free survival (PFS), and over 800 patients were included. At a median follow-up of 50 months, patients who received pertuzumab-based therapy had a median PFS of 18.7 months, compared with 12.4 months for those patients who received placebo-based treatment. The hazard ratio (HR) was 0.68.

Why was the overall survival benefit observed in this trial so significant? 

One of the most amazing results from the CLEOPATRA study was the overall survival (OS) data. Patients who received pertuzumab, trastuzumab, and docetaxel had a median OS of 56.5 months, and those patients who received placebo in combination with trastuzumab and docetaxel had a median OS of 40.8 months (HR, 0.68). So, median OS increased by almost 16 months. This result was clearly unexpected, and the reasons for this significant difference are being studied.

 Were there any concerning toxicities observed in any of the patients in this trial?

One of the most interesting things regarding pertuzumab-based therapy is that these improvements in outcomes were not associated with a significant increase in toxicity. Diarrhea and febrile neutropenia were the most relevant grade 3/4 adverse events. The rate of grade 3 and 4 diarrhea increased from 5.1% to 9.3% when pertuzumab was administered, and febrile neutropenia from 7.6% to 13.7%. However, the incidence of cardiotoxicity did not change with the addition of pertuzumab. Moreover, the rate of grade 3 or higher left ventricular dysfunction was somewhat lower in the pertuzumab group (3.3% vs 1.5%).

 Do you consider these practice-changing results, specifically for HER2-positive metastatic breast cancer?

Absolutely. These unprecedented data are, in my opinion, the most significant in the history of metastatic breast cancer research, establishing this combination of pertuzumab, trastuzumab, and chemotherapy as the new standard of care in the first-line treatment setting for patients with HER2-positive metastatic breast cancer.

Are there any follow-up studies currently planned or in progress? 

There are several studies that will help us to define the role of pertuzumab and trastuzumab with different partners. In my opinion, of greatest interest will be the upcoming data of these two monoclonal antibodies in combination with endocrine therapy, and the results of the PHEREXA trial, a randomized study that will define the role of pertuzumab with trastuzumab and capecitabine in patients progressing on trastuzumab-based therapy. In addition, other chemotherapeutic agents are being explored with this dual blockade.

Dr. CortÃ©s receives a consulting fee from Roche and Celgene; and receives an honoraria from Roche, Celgene, Novartis, and Eisai

In this interview we discuss the results of the CLEOPATRA trial, which studied the effect of adding pertuzumab to docetaxel and trastuzumab on HER2-positive metastatic breast cancer.

Javier Cortés, MD, on the CLEOPATRA Trial

Anthracyclines and human epidermal growth factor receptor 2 (HER2)-targeted agents play a key role in improving disease-free survival in breast cancer, sarcomas, and some hematologic malignancies. However, the cardiotoxicity of these agents can be clinically challenging and may adversely affect prognosis. We will discuss these commonly used chemotherapeutic agents and their deleterious cardiovascular effects in a case-based format, as well as specific approaches to prevention and treatment of associated cardiotoxicity.

A 29-year-old man with no known cardiac history was diagnosed with mesenchymal chondrosarcoma in the spine and underwent surgical resection, anthracycline-based chemotherapy, and adjuvant radiation. Over the next 10 years, he had three recurrences of chondrosarcoma, two in the lung and one in the abdomen, which were treated with surgical resection with or without anthracycline-based chemotherapy. Surveillance echocardiograms done before, during, and after anthracycline therapy showed normal left ventricular ejection fraction (LVEF). At age 41, he was cancer-free and asymptomatic. Since he had received a cumulative dose of 520 mg/m

 of doxorubicin, an echocardiogram was obtained, which showed an LVEF of 42%. A stress test was negative for ischemia. He was diagnosed with late anthracycline-induced cardiomyopathy and was optimized on medical therapy, including beta blockers and angiotensin-converting enzyme (ACE) inhibitors. At 5-month follow-up, his LVEF had improved to 52%; he remains asymptomatic.

Who is at risk for anthracycline cardiotoxicity?

Cardiotoxicity is a dose-limiting side effect of the anthracyclines doxorubicin, daunorubicin, epirubicin, and mitoxantrone. Acute cardiotoxicity is uncommon, usually occurring within 1 week after treatment completion, and can present with cardiomyopathy, arrhythmias, myocardial infarction, and myopericarditis/pericarditis syndromes.[1] With early treatment and discontinuation of the anthracycline, it is generally reversible. In some cases, acute cardiotoxicity may, in fact, be a form of stress-induced cardiomyopathy.

Anthracycline-induced cardiomyopathy manifesting as subacute and chronic cardiotoxicity is more common.[2] Congestive heart failure as a result of systolic and/or diastolic dysfunction is dose-dependent. Although historically the emphasis has been on systolic dysfunction, heart failure due to diastolic dysfunction is now being increasingly identified. A recent study showed a high incidence of diastolic dysfunction in patients after treatment with an anthracycline with or without trastuzumab.[3] Age and body mass index were independent predictors of diastolic dysfunction in this study.[3] The most important risk factor for cardiomyopathy is the cumulative dose of anthracyclines. Although the risk is low below 300 mg/m

, it exponentially increases with dose and is estimated at 26% for 550 mg/m

.[4] Susceptibility to cardiomyopathy is increased by various other host and treatment factors (Table).[5,6]

Topoisomerase (Top)2-alpha (overexpressed in tumors) is the cellular target for the drug’s anticancer effect. DNA damage via Top2-beta (expressed in adult cardiomyocytes) leading to cardiomyocyte death has recently been implicated as a major mechanism of anthracycline-related cardiomyopathy.[7]

Pretreatment assessment and subsequent monitoring help with early detection of cardiac dysfunction. Two-dimensional (2D) echocardiography is the approach most frequently used to monitor LVEF, due to its availability, cost-effectiveness, and lack of radiation. Limitations include inadequate acoustic windows and variability. Three-dimensional (3D) echocardiography and cardiac magnetic resonance (CMR) imaging have superior accuracy, especially relevant to screening for borderline left ventricular (LV) dysfunction.[8] Abnormalities in global longitudinal strain are a sign of subclinical myocardial dysfunction caused by anthracycline therapy, occur prior to change in 2D LVEF, and are more reproducible measurements than 2D LVEF. Importantly, these abnormalities predict the development of subsequent cardiotoxicity.[9]

Cardiac biomarkers, including troponin I and brain natriuretic peptide, are markers of early cardiac damage. In some studies, troponin I levels have been shown to predict future risk of cardiomyopathy; however, further validation is needed.[10]

There is a lack of evidence-based guidelines for monitoring patients during and after anthracycline therapy. However, expert opinion/consensus documents can serve as valuable resources.

Our clinical approach is similar to that recommended in the recently published expert consensus report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. We perform baseline evaluation of LVEF with 2D echocardiography (or 3D echocardiography, when available) prior to anthracycline-based chemotherapy. When feasible, global longitudinal strain can be additionally obtained. The cost-benefit of pre-therapy LV function assessment has been questioned, however. We recommend follow-up at completion of therapy and 6 months later for doses less than 240 mg/m

. Once this dose is exceeded, repeat assessment is recommended before each additional 50 mg/m

.[11] If any of the LV function parameters are abnormal or show a significant change from baseline, cardiology consultation should be obtained for consideration of medical therapy, risk-benefit discussion, and closer monitoring. For high-risk patients (eg, the elderly or patients with preexisting cardiac disease), we often employ a closer clinical and imaging surveillance schedule.[12]

Treating and preventing anthracycline cardiotoxicity

Historically, subacute and chronic forms of anthracycline-induced cardiomyopathy have been considered irreversible, and as such, labeled type I chemotherapy-related cardiac dysfunction (CRCD). However, recent studies have shown that with careful surveillance and early treatment, anthracycline-induced cardiomyopathy can be successfully treated.[13,14] Although there is no specific treatment for anthracycline-induced cardiotoxicity, the experience is that patients respond well to guideline-concordant medical therapy. Beta blockers and ACE inhibitors are the cornerstone of medical management. Appropriate patients should also be referred for advanced heart failure and device therapies when indicated.

Strategies to limit or prevent anthracycline-induced cardiomyopathy include limiting anthracycline dosage, use of doxorubicin derivatives, longer infusion durations, and concomitant use of the cardioprotective agent dexrazoxane.[15] Animal studies have suggested that pretreatment with statins may be preventive.[16] The benefit of preventive beta blockers and ACE inhibitors has recently been investigated, with promising results[17]; however, larger confirmatory studies are needed prior to using these agents prophylactically.

A 48-year-old woman with no cardiac history was diagnosed with breast cancer (estrogen receptor– and HER2-positive) metastatic to the brain. She was treated with left mastectomy as well as stereotactic radiosurgery of brain metastases, continuing on a trastuzumab-based regimen. Clinical cardiovascular status and surveillance parameters remained normal until 2 years into therapy, at which time she was admitted with acute systolic heart failure and an echocardiographic 2D LVEF of 33%. She was diuresed and optimized on heart failure medications, including beta blockers and ACE inhibitors. Evaluation showed no evidence of ischemic heart disease, and she was diagnosed with trastuzumab-induced cardiomyopathy. Trastuzumab was discontinued and LVEF slowly recovered to normal levels over the next 4 weeks. She was retreated with trastuzumab while continuing her heart failure therapies and tolerated it well without recurrence of LV systolic dysfunction or clinical heart failure.

Who is at risk for trastuzumab cardiotoxicity?

HERs are transmembrane tyrosine kinase receptors that normally regulate vital cellular responses.[18] Approximately 20% to 30% of patients with breast cancer have the subtype characterized by HER2/

 gene amplification, which is associated with more aggressive disease.[19] Trastuzumab is a monoclonal antibody that targets the extracellular domain of the HER2/

 tyrosine kinase[20]; it substantially reduces the risk of recurrence and early death in women with HER2-positive breast cancer.[21,22]

Cardiotoxicity is an important side effect of trastuzumab. The mechanism of trastuzumab-related cardiotoxicity is thought to be blocking of the HER2 pathway and its downstream signaling in cardiomyocytes, which disrupts the protective role of HER2 signaling in cardiomyocyte growth, repair, and survival.[18,23,24] Animal studies have shown that disruption in signaling through HER2 in cardiomyocytes causes dilated cardiomyopathy[25,26] and mitochondrial dysfunction in cardiomyocytes.[27]

The incidence of cardiotoxicity (manifested as abnormal LVEF and congestive heart failure) ranges from 3% to 7% with trastuzumab monotherapy, is 13% with paclitaxel and trastuzumab, and is 27% with concomitant anthracycline and trastuzumab.[28] Up to 16% of patients in the pivotal trials receiving combined anthracycline and trastuzumab have New York Heart Association class III or IV heart failure,[28] and thus concomitant administration should be avoided. Preexisting cardiac disease, older age, diabetes mellitus, and prior cardiotoxic therapy lead to an increased incidence of cardiotoxicity.[29] The cardiotoxicity caused by trastuzumab appears to be different from that caused by anthracyclines in that it occurs as a result of myocyte dysfunction rather than myocyte death, is often reversible, and historically has been labeled type II CRCD. However, it is important to understand that reversibility can be variable depending on the time of detection and treatment, and significant overlap occurs between type I and type II CRCD.

Pertuzumab is an antibody against HER2 dimerization. Meta-analysis of LV dysfunction in clinical trials using mono vs dual HER2 blockade (pertuzumab and trastuzumab vs lapatinib and trastuzumab vs trastuzumab alone) showed similar cardiotoxicity between all three groups.[30]

Monitoring and treating trastuzumab cardiotoxicity

Our practice for surveillance of cardiotoxicity due to trastuzumab is to obtain a 2D LVEF (or 3D LVEF, where available) at baseline. Global longitudinal strain should be obtained if feasible. After starting therapy, these assessments should be repeated every 3 months until completion of therapy.[11] If baseline or monitoring parameters are abnormal and/or show a significant change from baseline, cardiology consultation should be obtained. Trastuzumab is usually held for at least 4 weeks if there is a ≥ 16% absolute drop in LVEF, or if LVEF falls below normal with a ≥ 10% absolute decrease from baseline. CMR imaging is helpful for LVEF confirmation if echocardiographic image quality is inadequate when therapy interruption is being considered. Trastuzumab-related cardiotoxicity is usually reversible and not dose-related.[31] It usually responds well to standard heart failure management, and treatment rechallenge with the drug should be attempted in select cases.

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

 Bristow MR, Thompson PD, Martin RP, et al. Early anthracycline cardiotoxicity. Am J Med. 1978;65:823-32.

 Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998;339:900-5.

 Serrano JM, GonzÃ¡lez I, Del Castillo S, et al. Diastolic dysfunction following anthracycline-based chemotherapy in breast cancer patients: incidence and predictors. Oncologist. 2015;20:864-72.

 Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97:2869-79.

 Gupta D, Yadav N, Evans F, Steingart R. Chemotherapy-induced cardiomyopathy in the elderly. Curr Cardiovasc Risk Rep. 2014;8:1-8.

 Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91:710-7.

 Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012;18:1639-42.

 Armstrong GT, Plana JC, Zhang N, et al. Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol. 2012;30:
2876-84.

Thavendiranathan P, Poulin F, Lim KD, et al. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol. 2014;63:2751-68.

 Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109:2749-54.

 Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27:911-39.

 Gupta D, Verma S, Pun SC, Steingart RM. The changes in cardiac physiology with aging and the implications for the treating oncologist. J Geriatr Oncol. 2015;6:178-84.

 Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131:1981-8.

 Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010;55:213-20.

 Conway A, McCarthy AL, Lawrence P, Clark RA. The prevention, detection and management of cancer treatment-induced cardiotoxicity: a meta-review. BMC Cancer. 2015;15:366.

 Riad A, Bien S, Westermann D, et al. Pretreatment with statin attenuates the cardiotoxicity of doxorubicin in mice. Cancer Res. 2009;69:695-9.

 Bosch X, Rovira M, Sitges M, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol. 2013;61:2355-62.

Fuller SJ, Sivarajah K, Sugden PH. ErbB receptors, their ligands, and the consequences of their activation and inhibition in the myocardium. J Mol Cell Cardiol. 2008;44:831-54.

 Hudziak RM, Schlessinger J, Ullrich A. Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci USA. 1987;84:7159-63.

 Albanell J, Bellmunt J, Molina R, et al. Node-negative breast cancers with p53(-)/HER2-neu(-) status may identify women with very good prognosis. Anticancer Res. 1996;16:1027-32.

 Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-92.

 Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-72.

 Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7:332-44.

 Lemmens K, Doggen K, De Keulenaer GW. Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation. 2007;116:954-60.

 Ozcelik C, Erdmann B, Pilz B, et al. Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci USA. 2002;99:8880-5.

 Crone SA, Zhao YY, Fan L, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med. 2002;8:459-65.

 Grazette LP, Boecker W, Matsui T, et al. Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol. 2004;44:2231-8.

 Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20:1215-21.

 Serrano C, Cortes J, De Mattos-Arruda L, et al. Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. Ann Oncol. 2012;23:897-902.

 Valachis A, Nearchou A, Polyzos NP, Lind P. Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. Int J Cancer. 2013;133:2245-52.

Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol. 2005;23:7820-6.

We will discuss the deleterious cardiovascular effects of anthracyclines and HER2-targeted agents in a case-based format, as well as specific approaches to prevention and treatment of associated cardiotoxicity.

Chemotherapy-Induced Cardiomyopathy: Clinical Scenarios and Challenges

The review by Weathers and de Groot in this issue of ONCOLOGY[1] provides a comprehensive overview of the development of antiangiogenic strategies targeting the vascular endothelial growth factor (VEGF) receptor and pathway in patients with glioblastoma, an almost uniformly fatal disease and a malignancy recognized to be among the most highly angiogenic solid tumors. The authors describe the reported clinical experience with VEGF blockade using bevacizumab, a recombinant humanized monoclonal antibody, and a subsequent generation of promiscuous small-molecule tyrosine kinase inhibitors that typically target multiple cellular pathways in addition to the VEGF-mediated angiogenic cascade. These include cediranib[2] and cilengitide,[3] which were the subject of negative phase III trials in patients with recurrent and newly diagnosed glioblastoma, respectively. Despite early optimism, targeting VEGF and angiogenesis in glioblastoma has not yielded the revolutionary outcomes expected when dramatic imaging improvement was observed following bevacizumab treatment in initial cohorts of patients with recurrent glioblastoma. However, the development of bevacizumab in patients with malignant brain tumors provides an opportunity to review some of the defining principles of drug development, particularly in this challenging group of tumors characterized by limited drug accessibility, variable imaging appearance, and changing clinical symptomatology based on the status of the blood-brain barrier.

The first lesson to be learned from the past decade of clinical trials with bevacizumab in glioblastoma is that empiric evidence is just that, and requires careful clinical trial validation with mechanistic correlatives to understand the reasons why a specific anticancer agent does or does not produce responses in defined subsets of patients. Dr. Stark-Vance’s[4] seminal observation that the active combination of bevacizumab and irinotecan (emerging as an effective therapy for her patients with colorectal cancer) could produce dramatic and immediate symptom and imaging improvement in refractory glioblastoma patients initiated a cascade of clinical trials evaluating this combination in larger groups of patients with recurrent glioblastoma. Unfortunately, ample evidence at the time suggested that irinotecan and its active metabolites had limited blood-brain barrier penetration and minimal, if any, single-agent activity, and were also responsible for the frequent and often moderately severe gastrointestinal toxicity seen in treated patients.[5,6] Despite these data, and largely because of the accelerated approval of bevacizumab based on the results of a phase II study in which one non-comparative arm combined irinotecan and bevacizumab,[7] irinotecan remains a recommended option in the National Comprehensive Cancer Network guidelines and is still frequently used in first-line combination with bevacizumab, likely yielding excessive toxicity and no additional benefit in already symptomatic patients with recurrent glioblastoma. Although countless patients have been significantly, and at least transiently, helped by having access to bevacizumab following its expedited approval and availability, the absence of a well-designed phase III trial and the statistically forbidden yet commonplace comparison of efficacy between arms of a non-comparative phase II study has slowed our recognition of the true benefits and limitations of bevacizumab in this patient population.

A second reality in the development of novel agents in oncology-and perhaps in life in general-is that if a result seems too good to be true, it often is. The dramatic clinical improvement over hours to days seen in selected patients treated with bevacizumab, eerily reminiscent of the outcomes typically seen following initiation of glucocorticoid therapy in symptomatic glioblastoma patients with intracranial edema and mass effect, could not have represented an immediate antitumor response similar to those seen in highly aggressive malignancies like small-cell lung cancer and Burkitt lymphoma. Not until the elegant correlative imaging and biomarker work of Batchelor and colleagues in their phase II study of cediranib (in which they clearly described the rapid vascular normalization effects of VEGF receptor pathway blockade) did we truly understand the mechanism of the early beneficial effects of bevacizumab and get hints about the potentially limited antitumor activity of this agent.[8] Again, this steroid-like improvement of the disrupted blood-brain barrier and reduction in peritumoral edema and mass effect is a clinically important effect of bevacizumab, justifying its availability for selected highly symptomatic patients and/or those with large, contrast-enhancing tumors. It is critical, however, to distinguish these effects from true cytotoxic or cytostatic effects on tumor cells themselves as we seek to optimize single-agent and combinatorial strategies with bevacizumab.

Finally, in the absence of randomized clinical trial data, the effectiveness of a novel therapy in a specific subset of patients with cancer, such as recurrent glioblastoma, does not imply that those results can be generalized to the entire population of patients with that disease regardless of where they are in their disease trajectory. The rapid and vociferous declaration that the activity of bevacizumab in the recurrent setting justified, and even mandated, its widespread use in newly diagnosed patients in the absence of convincing clinical trial data resulted in wasted resources and potentially exposed patients to toxicity without providing benefit. Not until the publication of the rigorously conducted, prospective randomized Radiation Therapy Oncology Group (RTOG) 0825[9] and AVAglio[10] trials of bevacizumab in newly diagnosed patients with glioblastoma did we appropriately understand that bevacizumab has clear but modest effects on progression-free survival in these patients, a result largely expected based on the drug’s transient vascular normalization resulting in imaging and symptom improvement. In addition, it had no effect on overall survival and controversial effects on quality of life and neurocognitive functioning.

Despite its limited effectiveness, evaluation of bevacizumab in neuro-oncology has resulted in dramatic improvements in imaging interpretation and left us with many new and important questions to address. The difficulty in interpreting the status of tumor in the face of the imaging changes induced by active VEGF agents has directly led to the development of the Response Assessment in Neuro-Oncology (RANO) criteria,[11] an important standardization of our imaging analysis in clinical practice and in clinical trials of patients with malignant brain tumors. The observation of potential synergistic effects of bevacizumab on immunosuppression when combined with immune-based therapies is exciting and provides a rationale for investigation of combinatorial opportunities with the new immune modulators and checkpoint inhibitors entering the clinic. Of concern is the controversial data that suggest certain glioblastomas develop a more invasive phenotype following bevacizumab therapy, as well as the implications this could have on outcomes, treatment options, and symptomatology. Finally, the absence of any effective combinatorial therapy in patients progressing on bevacizumab and evidence supporting both continuation and discontinuation of bevacizumab in this setting remain important areas for additional clinical trial evaluation in order to better guide our therapeutic decision making in the clinic.

The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

 Weathers S-P, de Groot J. VEGF manipulation in glioblastoma. Oncology (Williston Park). 2015;29:720-7.

 Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013;31:3212-8.

 Stupp R, Hegi ME, Gorlia T, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1100-8.

 Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neuro Oncol. 2005;7:369. Abstr 342.

 Blaney SM, Takimoto C, Murry DJ, et al. Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. Cancer Chemother Pharmacol. 1998;41:464-8.

 Batchelor TT, Gilbert MR, Supko JG, et al. Phase 2 study of weekly irinotecan in adults with recurrent malignant glioma: final report of NABTT 97-11. Neuro Oncol. 2004;6:21-7.

Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733-40.

 Batchelor TT, Duda DG, di Tomaso E, et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010;28:2817-23.

 Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699-708.

 Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709-22.

 Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28:1963-72.

The absence of any effective combinatorial therapy in patients progressing on bevacizumab and evidence supporting both continuation and discontinuation of bevacizumab in this setting remain important areas for additional clinical trial evaluation in order to better guide our therapeutic decision making in the clinic.

Bevacizumab and Glioblastoma: The Ecstasy and the Agony

The approach to management of breast cancer patients has evolved from one of primary surgical treatment, in which traditional TNM staging dictated the need for adjuvant therapy, to a multidisciplinary one, with sequencing of surgical and systemic therapy determined by the biologic subtype of each tumor. Two decades ago, chemotherapy was administered preoperatively (neoadjuvant chemotherapy) to patients with locally advanced breast cancer, both to initiate early treatment of systemic disease and to convert inoperable disease to an operable status. Early trials demonstrated that neoadjuvant chemotherapy could be administered safely to patients with locally advanced disease without losing the surgical window of opportunity[1]; trials also showed that some patients had significant reduction in tumor burden with neoadjuvant chemotherapy, thereby allowing for breast-conserving surgery.[2]

Patients who achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy have more favorable outcomes, and nodal status after chemotherapy is a strong prognostic indicator of survival.[3,4] As systemic treatment regimens have evolved from a one-size-fits-all approach to a more targeted one based on underlying tumor biology, response rates in the primary tumor and regional nodal basins have increased, as has the likelihood of achieving pCR.[5] While breast-conserving surgery after neoadjuvant chemotherapy has become more accepted over time, methods of management of the axillary lymph nodes have remained matters of controversy.

In this issue of ONCOLOGY, Manguso et al review the published literature on the use of sentinel lymph node biopsy (SLNB) in patients receiving neoadjuvant chemotherapy; they conclude that while some patients may be able to avoid axillary lymph node dissection (ALND), those who are node-positive prior to chemotherapy should still undergo ALND after chemotherapy.[6] While on the surface, this may seem like a reasonable assumption, a deeper dive into the available data may lead to a different conclusion.

The majority of the literature on the use of SLNB after neoadjuvant chemotherapy comes from single-institution reports of retrospective data. Although this type of data can be hypothesis-generating, it is unlikely to provide robust support that can be used to change clinical practice. Several meta-analyses have attempted to combine single-institution data with the limited multi-institution data that are available, and the majority have concluded that SLNB is accurate after chemotherapy.[7-10] These analyses included studies that did not clearly define nodal status prior to chemotherapy, and some included both clinically node-negative and clinically node-positive patients. Very few studies evaluated response in the nodal basin prior to surgery, and many different surgical approaches were employed (eg, blue dye alone, isotope alone, combination blue dye and isotope). Studies of SLNB in both the upfront surgery and the post–neoadjuvant chemotherapy settings have reported higher identification rates and lower false-negative rates with SLNB performed with a combination of blue dye and isotope, and the number of sentinel lymph nodes removed has been shown to have significant impact on the false-negative rate.[11] Research at MD Anderson Cancer Center has shown that in patients with initially clinically node-negative disease, SLNB after neoadjuvant chemotherapy is just as accurate as in the upfront surgery setting.[12] In addition, in patients with initially clinically node-negative disease, SLNB after neoadjuvant chemotherapy eradicates occult nodal disease in a proportion of patients, eliminating the need for ALND in some patients and providing important prognostic information based on the presence or absence of nodal disease following chemotherapy.

While it has been standard at MD Anderson to use ultrasound prior to chemotherapy to evaluate regional nodal basins, computed tomography and positron emission tomography scans, which are suggested by Manguso et al, were not routinely performed. In a recent study of patients who received neoadjuvant chemotherapy compared with those who underwent surgery first, patients who underwent upfront surgery had an increased likelihood of positive sentinel lymph nodes with increasing T stage.[12] Similar to results in other institutional reports, a reduced incidence of node-positive disease (by T stage, in comparison with patients undergoing upfront surgery) was also seen in patients undergoing neoadjuvant chemotherapy. Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and B-27 randomized trials and the European Organisation for Research and Treatment of Cancer (EORTC) 10902 trial have also demonstrated this nodal downstaging.[13-15]

Until recently, data on the use of SLNB after chemotherapy in patients with initially node-positive disease also came largely from retrospective, single-institution studies. Manguso et al discuss several multicenter trials that have now reported outcomes in this patient population.[11,16,17] Interestingly, all reported higher identification rates and lower false-negative rates than the single-institution reports, but with false-negative rates as high as 14%,[11,16,17] the applicability of SLNB in this setting has come into question. Several important points should be considered, however, when examining these trial results. One is that not all of the studies required biopsy confirmation of nodal status prior to chemotherapy. We now know, though, that relying on physical examination to define nodal status is likely to lead to inaccurate staging in a substantial proportion of patients. Second, response to chemotherapy was not used to select patients for SLNB after chemotherapy. This means that patients with significant residual disease in the axilla were included and may have contributed to higher false-negative rates. Finally, there was no attempt to mark and remove the axillary node that was biopsied at presentation in order to confirm removal of the index node at the time of surgery. In the American College of Surgeons Oncology Group (ACOSOG) Z1071 trial,[11] it was reported that when a clip was placed at the time of initial node biopsy and the clipped node was confirmed to be removed with SLNB, the false-negative rate was substantially lower. If the clipped node is not one of the sentinel lymph nodes, as is reported in approximately 25% of cases, then it is more likely that a false-negative result will be obtained with SLNB.

At first blush, the results of the ACOSOG Z1071 and SENTINA (Sentinel-Lymph-Node Biopsy in Patients With Breast Cancer Before and After Neoadjuvant Chemotherapy) trials[11,16] may seem to herald the end of SLNB after chemotherapy in patients with initially node-positive disease. However, before committing all of these patients to ALND after chemotherapy, one should consider an alternative approach. First, a clip should be placed in the index node at the time of diagnosis, and the number of abnormal nodes should be assessed; this is a surrogate for disease burden in that nodal basin. Second, response to chemotherapy should be assessed prior to surgical intervention, since those having obvious residual nodal disease are the most likely to benefit from ALND. Underlying tumor biology is also a factor, since patients with triple-negative disease and human epidermal growth factor receptor 2 (HER2)-positive breast cancer are more likely to experience pCR. Third, the clipped node should be targeted for removal at the time of SLNB, since a significant proportion of clipped nodes will not be sentinel lymph nodes. This may be due to fibrosis of lymphatic channels or to residual cancer burden blocking lymphatics.

The plan to target the clipped node for resection at the time of SLNB has been described as targeted axillary dissection by Caudle and colleagues.[18] This approach embraces the concept of individualized and multidisciplinary management of the breast cancer patient. The goal is to deliver the right treatment to all patients and spare them from unnecessary toxicities and long-term effects related to surgical management.

Dr. Hunt serves on the Advisory Board for Armada Health.

 Swain SM, Sorace RA, Bagley CS, et al. Neoadjuvant chemotherapy in the combined modality approach of locally advanced nonmetastatic breast cancer. Cancer Res. 1987;47:3889-94.

 Hunt KK, Ames FC, Singletary SE, et al. Locally advanced noninflammatory breast cancer. Surg Clin North Am. 1996;76:393-410.

 Hennessy BT, Hortobagyi GN, Rouzier R, et al. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol. 2005;23:9304-11.

 Kuerer HM, Sahin AA, Hunt KK, et al. Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg. 1999;230:72-8.

 Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32.

 Manguso N, Gangi A, Giuliano AE. Neoadjuvant chemotherapy and surgical management of the axilla in breast cancer: a review of current data. Oncology (Williston Park). 2015;29:733-8;782.

 Xing Y, Foy M, Cox DD, et al. Meta-analysis of sentinel lymph node biopsy after preoperative chemotherapy in patients with breast cancer. Br J Surg. 2006;93:539-46.

 Kelly AM, Dwamena B, Cronin P, Carlos RC. Breast cancer sentinel node identification and classification after neoadjuvant chemotherapy-systematic review and meta analysis. Acad Radiol. 2009;16:551-63.

 van Deurzen CH, Vriens BE, Tjan-Heijnen VC, et al. Accuracy of sentinel node biopsy after neoadjuvant chemotherapy in breast cancer patients: a systematic review. Eur J Cancer. 2009;45:3124-30.

 Fu JF, Chen HL, Yang J, et al. Feasibility and accuracy of sentinel lymph node biopsy in clinically node-positive breast cancer after neoadjuvant chemotherapy: a meta-analysis. PLoS One. 2014;9:e105316.

 Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013;310:1455-61.

 Hunt KK, Yi M, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Ann Surg. 2009;250:558-66.

 Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Nat Cancer Inst Monogr. 2001:96-102.

 Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26:778-85.

 van Nes JG, Putter H, Julien JP, et al. Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat. 2009;115:101-13.

 Kuehn T. Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospectcive, multicentre cohort study. Lancet Oncol. 2013;14:609-18.

 Boileau FJ, Poirier B, Basik M, et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN FNAC study. J Clin Oncol. 2015;33:258-64.

 Caudle AS, Yang WT, Mittendorf EA, et al. Selective surgical localization of axillary lymph nodes containing metastases in patients with breast cancer: a prospective feasibility trial. JAMA Surg. 2015;150:137-43.

While breast-conserving surgery after neoadjuvant chemotherapy has become more accepted over time, methods of management of the axillary lymph nodes have remained matters of controversy.

Axillary Surgery After Chemotherapy: Challenges and Opportunities

Radiation therapy (RT) was once thought to be ineffective for cutaneous melanoma. Research has demonstrated the value of RT across the disease spectrum, from definitive treatment of melanoma in situ, to adjuvant treatment of resected high-risk disease, to palliative treatment of metastases.[1] In the current issue of ONCOLOGY, Drs. Mahadevan, Patel, and Dagoglu discuss preclinical and clinical data that guide the use of RT to treat melanoma.[2] The authors undertook a challenging task, given the many roles that RT can play in the treatment of melanoma of different origins (skin, uvea, and mucosa) and different stages. Nevertheless, given the advances in melanoma therapy over the last few years, a contemporary review highlighting ongoing clinical trials (Table) is timely.

Early in vitro studies of melanoma radiosensitivity in clonogenic assays suggested that successful treatment required high-dose-per-fraction RT. At least two randomized clinical trials[3,4] have failed to support this hypothesis, demonstrating similar rates of response with low to medium dose fractions (2.5 to 5 Gy) and larger dose fractions (8 to 9 Gy). Moreover, the clinical trial demonstrating an improvement in regional disease control with RT was conducted using low dose fractions (2.4 Gy/fraction), further dispelling the myth that RT is only effective for melanoma if given with high doses per fraction.[5] Although Mahadevan et al suggest that fractionation in melanoma is controversial, evidence suggests that clinicians should be comfortable using low-dose-per-fraction RT in appropriate settings.

A better understanding of the cellular and immunologic pathogenesis of melanoma has led to advances in treatment. Some of the findings from research into pathogenesis have had relevance for the use of RT. For example, an analysis of 37 melanoma cell lines corroborated prior observations that melanoma exhibits a wide range of radiosensitivity in vitro. Mutations in recurrently altered genes in melanoma (

) were not associated with radiosensitivity. However, a clinically available RAF inhibitor (vemurafenib) was able to increase radiosensitivity of 

-mutant cell lines.[6] A recent clinical analysis demonstrated the radiosensitizing effect of vemurafenib in patients with melanoma receiving RT.[7] Immunobiologic studies of a murine melanoma model demonstrated that immunodeficiency, depletion of CD8+ lymphocytes, and lymphotoxic chemotherapy abrogate the antitumor effect of RT.[8] With future preclinical studies related to melanoma, we are likely to gain a better understanding of the optimal use of RT.

Mahadevan et al discuss the notion that RT at the site of the primary tumor may improve disease control; additional data and ongoing trials support this contention. A recent systematic review of 537 patients treated with RT found a high rate (95%) of local control in patients with lentigo maligna (melanoma in situ).[9] This prompted development of a randomized trial comparing two nonsurgical therapies (RT and topical immunotherapy) for lentigo maligna (ClinicalTrials.gov identifier: NCT02394132). Moreover, for patients with desmoplastic melanoma, two recent analyses have suggested improvements in local tumor control with adjuvant RT to the site of the resected tumor.[10,11] An ongoing international randomized trial will evaluate RT in this setting in a prospective fashion (NCT00975520).

The authors discuss the controversial use of adjuvant RT in patients with resected stage III melanoma. Investigators recently updated results of the randomized trial of observation vs regional lymph node basin RT for patients with high-risk stage III melanoma after lymphadenectomy.[5] The investigators report a significant reduction in the likelihood of regional recurrence after RT (21%) as compared with observation (36%). Grade 2, 3, and 4 late RT-related adverse effects were observed in 74%, 20%, and 2% of patients, respectively. The National Comprehensive Cancer Network categorizes adjuvant RT as a level 2B recommendation, and many melanoma specialists do not recommend it because of side effects and lack of survival benefit. However, these data provide a basis for future studies evaluating novel approaches to adjuvant RT that employ improved patient selection or better delivery techniques; for example, patients might be selected who are at high risk for regional recurrence but at low risk for distant recurrence.[12] Our preliminary investigations suggest that fewer side effects may be possible using contemporary RT modalities, such as intensity-modulated RT (IMRT), which have not yet been employed in melanoma clinical trials (Mattes M et al, submitted).

Finally, Mahadevan et al discuss the use of RT for patients with metastatic melanoma. RT has a well-established role in the palliation of patients with symptomatic metastases. For patients with unresectable metastases, ablative RT may provide durable control. Brain metastases are frequently treated with stereotactic radiosurgery (SRS) for this reason. However, for patients with many (4 to 10) brain metastases, the role of SRS vs whole-brain RT (WBRT) is unclear; this is being investigated in a randomized trial (NCT01644591). In a related study, the value of WBRT to prevent recurrence in the brain after SRS is being studied (NCT01503827).

A novel concept is the use of RT as an immunotherapeutic “adjuvant.”[13] Radiation itself has several immunomodulatory properties, and many preclinical studies have demonstrated the interaction of immunotherapy and RT in models of melanoma (Samstein et al, submitted). This has been reported in clinical case reports,[14,15] series,[16-18] and early clinical trials of RT and immunotherapy.[19,20] A significant number of clinical trials are underway to further explore the hypothesis that RT may improve the outcomes of systemic therapy for patients with metastatic melanoma, but data from randomized trials clarifying the question of whether RT improves the response to immunotherapy are not available.

It is incumbent on melanoma and radiation oncology researchers alike to further our understanding of when and how RT can help patients. Considering that the last melanoma trial completed by the Radiation Therapy Oncology Group (83-05) was conceived over 30 years ago, it is clear that cooperative, international efforts are required to yield the advances that are needed to positively change clinical practice. In addition, as more effective therapies for melanoma become available, the importance of investigating rational therapeutic combinations will also grow. The rich history of research in melanoma has led to advances in treatment, as well as to a number of active investigations of RT. Results of these studies and future directions for the field are eagerly awaited.

 Barker CA, Lee NY. Radiation therapy for cutaneous melanoma. Dermatol Clin. 2012;30:525-33.

 Mahadevan A, Patel VL, Dagoglu N. Radiation therapy in the management of malignant melanoma. Oncology (Williston Park). 2015;29:743-51.

 Overgaard J, von der Maase H, Overgaard M. A randomized study comparing two high-dose per fraction radiation schedules in recurrent or metastatic malignant melanoma. Int J Radiat Oncol Biol Phys. 1985;11:1837-9.

 Sause WT, Cooper JS, Rush S, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys. 1991;20:429-32.

 Henderson MA, Burmeister BH, Ainslie J, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015;16:1046-60.

 Sambade MJ, Peters EC, Thomas NE, et al. Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. Radiother Oncol. 2011;98:394-9.

 Hecht M, Zimmer L, Loquai C, et al. Radiosensitization by BRAF inhibitor therapy-mechanism and frequency of toxicity in melanoma patients. Ann Oncol. 2015;26:1238-44.

 Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114:589-95.

 Fogarty GB, Hong A, Scolyer RA, et al. Radiotherapy for lentigo maligna: a literature review and recommendations for treatment. Br J Dermatol. 2014;170:52-8.

 Guadagnolo BA, Prieto V, Weber R, et al. The role of adjuvant radiotherapy in the local management of desmoplastic melanoma. Cancer. 2014;120:1361-8.

 Strom T, Caudell JJ, Han D, et al. Radiotherapy influences local control in patients with desmoplastic melanoma. Cancer. 2014;120:1369-78.

 Barbour AP, Tang YH, Armour N, et al. BRAF mutation status is an independent prognostic factor for resected stage IIIB and IIIC melanoma: implications for melanoma staging and adjuvant therapy. Eur J Cancer. 2014;50:2668-76.

 Barker CA, Postow MA. Combinations of radiation therapy and immunotherapy for melanoma: a review of clinical outcomes. Int J Radiat Oncol Biol Phys. 2014;88:986-97.

 Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925-31.

 Hiniker SM, Chen DS, Knox SJ. Abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:2035; author reply 35-6.

 Barker CA, Postow MA, Khan SA, et al. Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. Cancer Immunol Res. 2013;1:92-8.

 Gerber NK, Young RJ, Barker CA, et al. Ipilimumab and whole brain radiation therapy for melanoma brain metastases. J Neurooncol. 2015;121:159-65.

 Kiess AP, Wolchok JD, Barker CA, et al. Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys. 2015;92:368-75.

 Seung SK, Curti BD, Crittenden M, et al. Phase 1 study of stereotactic body radiotherapy and interleukin-2-tumor and immunological responses. Sci Transl Med. 2012;4:137ra74.

 Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373-7.

It is incumbent on melanoma and radiation oncology researchers alike to further our understanding of when and how RT can help patients.

Radiation Therapy for Cutaneous Melanoma: Clonogenic Assays to Clinical Trials

The treatment of patients with follicular lymphoma is undergoing a substantial shift due to rapid development of highly effective agents targeting lymphoma-specific biologic processes and the tumor microenvironment. This is particularly good news for patients and clinicians alike, since these drugs typically have favorable toxicity profiles relative to conventional cytotoxic chemotherapy, and in many instances have demonstrated substantial anti-lymphoma activity in heavily pretreated patients. The resulting US Food and Drug Administration (FDA) approvals of many of these drugs as single agents in specific indications have provided excellent therapeutic options for patients with relapsed or refractory follicular lymphoma.

In this issue of ONCOLOGY, Dr. Ujjani provides a comprehensive overview of the various agents in clinical development for treatment of B-cell lymphomas.[1] These agents include new monoclonal antibodies, antibody-drug conjugates, immunomodulatory drugs, agents targeting the B-cell receptor pathway, BH3 mimetics, checkpoint inhibitors, and chimeric antigen receptor (CAR)-modified T cells. Within each of these classes are several candidate therapeutic agents. Thus, with this ever-expanding repertoire it is becoming clear that many of the ingredients for the 21st century version of “CHOP” (cyclophosphamide, doxorubicin, vincristine, and prednisone) probably already exist, but the formulation of these into rationally designed biologic combinations is the key issue facing investigators. Since the approval of rituximab, monoclonal antibodies have been successfully combined with a variety of chemotherapies[2,3] and biologic agents,[4,5] as Dr. Ujjani describes in her article. In addition, Dr. Ujjani discusses experience with the next-generation monoclonal antibodies directed against B-cell surface antigens CD20, CD19, CD22, and CD79b. Importantly, however, while Sehn et al recently demonstrated that single-agent treatment with the next-generation anti-CD20 antibody obinutuzumab trended towards a higher objective response rate (ORR) than rituximab among patients with relapsed or refractory follicular lymphoma,[6] progression-free survival (PFS) was not significantly different between the two arms-a reminder that newer is not necessarily better.

Results of the phase III GALLIUM study of chemotherapy with either obinutuzumab or rituximab induction, followed by the same antibody as maintenance in treatment-naive indolent non-Hodgkin lymphoma are anticipated, although the different dosing schedules between the two monoclonal antibodies leaves the question of their relative equimolar potency open for debate. Nonetheless, a substantial PFS advantage in favor of obinutuzumab could result in this agent replacing rituximab as the monoclonal antibody of choice to be given with chemotherapy in front-line treatment of follicular lymphoma. Small-molecule inhibitors of key components of the B-cell receptor pathway-such as idelalisib, which inhibits the p110Î´ catalytic unit of phosphatidylinositol 3-kinase (PI3K),[7] and ibrutinib, which irreversibly binds to Bruton tyrosine kinase (BTK) to block downstream signaling[8]-have recently resulted in their FDA approval for specific disease indications. Although their toxicity profiles are more favorable than those of conventional cytotoxic agents, these agents are not entirely without risk: Idelalisib can cause transaminitis, colitis, and pulmonary toxicity,[9] while ibrutinib can provoke atrial fibrillation[10] and increase the risk of bleeding.[11] Unique toxicities may be dramatically and unpredictably potentiated when such agents are combined,[12] highlighting the need for caution in the design and conduct of these studies.

We are becoming increasingly aware that follicular lymphoma, like most cancers, is a heterogeneous disease. Casulo et al recently reported that patients who experience disease progression within 2 years of R-CHOP (rituximab with CHOP) therapy have a markedly increased risk of death.[13] It seems likely that many such patients bear mutations of genes responsible for DNA repair, such as 

, or of epigenetic modifiers, which govern a range of cellular processes including proliferation, response to DNA damage, and apoptosis.[14] Pastore et al recently studied recurrent somatic mutations in a large number of patients with follicular lymphoma and found that genes such as 

 were associated with shorter failure-free survival times, while mutations in 

 were associated with longer treatment failure–free survival.[15] Although our understanding of the clinical implications of these data is rapidly expanding, the increasing availability of technologies such as next-generation sequencing is likely to facilitate the design and conduct of studies specifically targeting deregulated pathways in specific patients-so-called “precision medicine.”[16] Furthermore, the vast number of potential drug combinations makes rational selection of agents critical. Although there are many ways to approach this problem, methods such as in vitro drug screening often do not take into account the importance of the tumor microenvironment. This is particularly relevant in follicular lymphoma, since tumor cells appear to depend heavily on the microenvironment for survival and proliferation.[17] It may prove successful to select combinations of agents that target different steps of the cancer immunity cycle (eg, use of checkpoint inhibitors that enhance T-cell killing of lymphoma cells, paired with drugs that enhance cancer antigen release or presentation, are associated with priming and activation of T cells, or promote T-cell infiltration into tumors).[18] There are many ways to make a cake, as the saying goes; the task for us now is to develop “recipes” with the right “ingredients,” as nicely summarized by Dr. Ujjani. With time and new understanding, we hope our efforts will bring patients with follicular lymphoma closer to a cure.

Dr. Fowler receives research funding from Celgene, Gilead, Janssen, and Roche, and he serves on the scientific advisory boards of Celgene, Janssen, and Roche. Dr. Cheah has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article

 Ujjani C. Targeted approaches in the management of follicular lymphoma. Oncology (Williston Park). 2015;29:760-8.

 Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203-10.

 Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123:2944-52.

 Fowler NH, Davis RE, Rawal S, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014;15:1311-8.

 Leonard JP, Jung S-H, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015 Aug 24. [Epub ahead of print]

 Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015 Aug 17. [Epub ahead of print]

 Gopal AK, Kahl BS, de Vos S, et al. PI3KÎ´ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-18.

 Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-16.

 CoutrÃ© SE, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015 May 19:1-8. [Epub ahead of print]

 McMullen JR, Boey EJ, Ooi JY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124:3829-30.

 Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29:783-7.

 Cheah CY, Nastoupil LJ, Neelapu SS, et al. Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma. Blood. 2015;125:3357-9.

 Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol. 2015;33:2516-22.

 Loeffler M, Kreuz M, Haake A, et al. Genomic and epigenomic co-evolution in follicular lymphomas. Leukemia. 2015;29:456-63.

 Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol. 2015 Aug 6. [Epub ahead of print]

 Intlekofer AM, Younes A. Precision therapy for lymphoma--current state and future directions. Nat Rev Clin Oncol. 2014;11:585-96.

 Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14:517-34.

 Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10.

The treatment of patients with follicular lymphoma is undergoing a substantial shift due to rapid development of highly effective agents targeting lymphoma-specific biologic processes and the tumor microenvironment.

Chemotherapy-Free Treatment of Follicular Lymphoma: We Have the Ingredients, Now for Some Recipes     

Salivary gland malignancies represent one of the most diverse groups of human tumors. The current World Health Organization (WHO) classification[1] lists more than 20 different histologic types of malignancies that can arise from the salivary glands, each with its own biology and underlying molecular pathogenesis. This diversity and complexity, combined with the rarity of these cancers, lead to definite and distinct challenges in their study, and consequently in advancing treatment options for affected patients. This is evident when comparing the current review by Goyal et al[2] with one published almost a decade ago[3]; despite a few additional trials (mostly in adenoid cystic carcinoma [ACC]), no clearly meaningful advances in treatment have been made.

The major factor accounting for this lack of significant advances is of course the rarity of these tumors. Salivary gland cancers account for no more than 5% of all head and neck cancers. Of these, the majority are low-grade, are cured with surgical resection, and thankfully never require systemic therapies. Some, however-such as ACC, high-grade mucoepidermoid carcinoma (MEC), salivary duct carcinoma, and high-grade adenocarcinoma-have a tendency to recur and metastasize. Of these, MEC, salivary duct carcinoma, and high-grade adenocarcinoma are particularly uncommon; it is possible that oncologists practicing outside a major academic institution might see one such patient in their entire career. ACC is a little easier to study because it is often indolent, leading to a prevalence higher than its incidence.

The rarity of salivary gland tumors often leads, in clinical trials, to the grouping of patients into those with ACC and those with non-ACC histologies. While more recently there have been clinical trials specifically for ACC, even these often involve considerable heterogeneity, particularly with respect to the number of prior therapies. To conduct even a single-arm phase II clinical trial limited to one of the other subtypes would require a large number of sites and a great deal of time. All of this adds to cost, and finding the financial support to conduct a trial in such a niche population is challenging. Furthermore, trials in such small subgroups run the risk of never coming to completion, as was the case, for example, with the trial of trastuzumab in human epidermal growth factor 2 (HER2)-overexpressing salivary gland cancers (most commonly, salivary duct carcinomas), which had to close because only 14 patients were enrolled, due to a low incidence of HER2 positivity and slow accrual.[4]

The complexity of the pathology of salivary gland cancers raises questions about the interpretation of older clinical trials, and also has a direct impact on patient care. It is important to ensure that patients have an accurate histologic diagnosis; consideration should be given to having the pathology reviewed by an experienced specialized head and neck pathologist. It is possible that in older trials, tumors may have been misclassified, using older versions of the WHO system. This may make the results of these trials an unreliable basis for predicting the efficacy of a regimen in some of the rare subtypes. Older publications are often retrospective series, rather than prospective clinical trials, reporting on heterogeneous groups of patients treated with regimens that varied in dose and schedule. Case reports of patients responding to a therapy are inherently biased towards positive outcomes, overestimating the true efficacy of regimens. Thus the quality of available evidence for the optimal chemotherapeutic regimen in salivary gland cancers is poor.

How do we move forward? Patients with salivary gland cancers should be enrolled in clinical trials whenever possible. Recent cooperative group studies have shown that, at least for ACC, clinical trials can be accomplished in a timely manner. Trials in salivary gland cancers should have at the very least separate ACC cohorts, and if others are lumped together in a non-ACC cohort, results for each histologic subtype should be presented separately. Multicenter, international cooperation is required to advance the science. Under the auspices of the International Rare Cancers Initiative (www.irci.info), the European Organisation for Research and Treatment of Cancer (EORTC) has recently launched a randomized phase II trial comparing platinum-based chemotherapy with total androgen blockade in androgen receptor–expressing salivary gland cancers. International databases and registries of outcomes with various treatments used outside of a clinical trial would be a big step forward in increasing the amount of data available for determining the true efficacy of commonly used regimens. Finally, in conjunction with a concerted effort to determine the underlying molecular phenotypes of the different salivary gland cancer subtypes, “window-of-opportunity” trials of potential targeted agents in early-stage resectable disease would be very informative.

Patients with rare cancers don’t suffer any less than those with more common tumors, and the lack of research into their illness can lead to its own kind of frustration for many of them. Those with salivary gland cancers deserve equal attention.

 Barnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization classification of tumors. Pathology and genetics of head and neck tumours. Lyon, France: IARC Press; 2005.

 Goyal G, Mehdi SA, Ganti AP. Salivary gland cancers: biology and systemic therapy. Oncology (Williston Park). 2015;29:773-80.

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The diversity and complexity, combined with the rarity of salivary gland malignancies, lead to definite and distinct challenges in their study, and consequently in advancing treatment options for affected patients. 

Oncology Vol 29 No 10