Can you explain how radiotherapy and immunotherapy work together to elicit responses in certain patients?

At the time of clinical diagnosis, most cancers have already established multiple mechanisms to escape control of the host’s immune system, which results in varied degrees of tolerance to their growth. Particularly at the tumor site, cancer cells are embedded in a prevalently immunosuppressive microenvironment, which is difficult to subvert; even with the help of current immunotherapy agents such as immune checkpoint blockade, only a minority of patients with solid tumors experience a response to treatment. Radiotherapy is widely used as an anticancer modality that is based on focusing the damaging effects of ionizing radiation to the tumor and its microenvironment. During the past decade, scientific evidence has emerged that shows that radiotherapy can induce: A) immunogenic cell death, a form of cancer cell death that is effectively signaling to the immune system; and B) a series of “danger” and pro-immunogenic signals that are sensed by the host’s immune system, and can be harnessed to reject the tumor. When radiotherapy is used alone, these effects are generally insufficient at subverting the tumor-specific immunosuppression that is present in cancer patients. However, when combined with immunotherapy, such as immune checkpoint blockade, localized radiotherapy can effectively immunize the patient against the irradiated tumor, converting the tumor into an individualized in situ vaccine. When successful, this acquired immune response enables both rejection of the irraidated tumor and of metastasis outside the radiation field, with mechanisms comparable to those acquired after vaccination that result in rejecting viral or bacterial infections. This out-of-the-field effect of local radiotherapy is called the abscopal effect, a phenomenon originally described by Mole et al[1] in 1953, which our group first connected to immune-mediated mechanisms.[2]

In what areas have you seen the greatest benefit from radiotherapy combined with immunotherapy?

We have demonstrated the advantages of immunotherapy/radiotherapy combinations preclinically in multiple tumor models, and clinically in metastatic solid tumors,[3] particularly breast cancer and non–small-cell lung cancer (NSCLC). In the latter setting, anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) therapy alone failed to demonstrate significant activity; however, we found preclinically,[4] and later clinically, that it is quite effective when combined with local radiotherapy. After we reported a successful case treated with ipilimumab (anti–CTLA-4) and radiation to a liver lesion,[5] we conducted a prospective study in 40 similarly chemotherapy-refractory patients with metastatic NSCLC. The objective response rate was 33% among the patients who completed 4 cycles of ipilimumab and a course of 3 to 5 fractions of radiation to one metastasis. These patients had a significantly better survival and many remain alive with controlled disease.[6]

“Personalized medicine” is usually thought of as a development that pertains mainly to medical oncology. In what ways are radiation oncologists increasingly able to offer a personalized medicine approach to their patients?

 In radiation oncology, the standard delivery of a dose of radiotherapy is very personalized, since it takes into account the specific size, shape, and anatomy of each recipient, as well as the unique position of cancer; each treatment is personalized from a geometric, geographic, and physical point of view. From a biological point of view, combining radiation with immunotherapy has further enhanced the personalized nature of radiotherapy. In fact, by eliciting an anti-tumor immune response that is specific to the individual cancer, radiotherapy combined with immune checkpoint blockade rises to the role of personalized medicine. In addition, we have strong preclinical and clinical evidence that irradiated patients responding to the combination tend to shift their T-cell receptor repertoire in circulating lymphocytes toward a more oligoclonal one; evidence that radiotherapy has induced new antigens or overexpressed existing ones to trigger a novel immune response against the tumor.

. What other recent developments in the field of radiation therapy for breast cancer do you think are particularly exciting?

 First is the administration of radiotherapy to women with breast cancer in a prone position, similar to the way they are imaged at MRI. This approach both eliminates motion during treatment and allows for the breast to be displaced away from the chest by gravity, and be targeted while avoiding heart and lung.[7] By sparing normal tissue we can drastically reduce their dose exposure and prevent late toxicities, including radiation-induced lung cancers and cardiovascular mortality from breast radiation. Another exciting development is the efficacy and safety of shorter radiation regimens, which reduces the course of radiation from 6 weeks to 1 to 3 weeks. We have contributed to this research by converging the prone setup with the use of fewer larger fractions of radiation, which has drastically reduced the risk to normal tissue while maintaining optimal efficacy in tumor control.[8,9]

Dr. Formenti has received grant/research support from Eli Lilly, Janssen Biotech, and Regeneron; she is on the speaker’s bureau of Varian; and she is on the advisory committee of AstraZeneca, Bristol-Myers Squibb, Eisai, and GlaxoSmithKline. 

Mole RH. Whole body irradiation: radiobiology or medicine? Br J Radiol. 1953;26:234-41.

 Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58:862-70.

Golden EB, Chhabra A, Chachoua A, et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol. 2015;16:795-803.

 Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11(2 Pt 1):728-34.

Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1:365-72.

 Golden EB, Chachoua A, Fenton-Kerimian MB, et al. Abscopal responses in metastatic non-small cell lung cancer (NSCLC) patients treated on a phase 2 study of combined radiation therapy and ipilimumab: evidence for the in situ vaccination hypothesis of radiation. Int J Radiat Oncol Biol Phys. 2015;93:S66-S67.

 Formenti SC, DeWyngaert JK, Jozsef G, Goldberg JD. Prone vs supine positioning for breast cancer radiotherapy. JAMA. 2012;308:861-3.

 Osa EO, DeWyngaert K, Roses D, et al. Prone breast intensity modulated radiation therapy: 5-year results. Int J Radiat Oncol Biol Phys. 2014;89:899-906.

Formenti SC, Hsu H, Fenton-Kerimian M, et al. Prone accelerated partial breast irradiation after breast-conserving surgery: five-year results of 100 patients. Int J Radiat Oncol Biol Phys. 2012;84:606-11.

Articles

During the past decade, scientific evidence has emerged that shows that radiotherapy can induce: A) immunogenic cell death, a form of cancer cell death that is effectively signaling to the immune system; and B) a series of “danger” and pro-immunogenic signals that are sensed by the host’s immune system, and can be harnessed to reject the tumor.

Silvia Formenti on the Promise of Combining Radiotherapy and Immunotherapy to Treat Cancer

Advances in basic science and clinical medicine in the past few decades have increasingly elevated the profile of personalized medicine, ie, the identification of individual tumor or biologic features that offer targets for therapy. In the case of classic genomics, driver mutations such as epidermal growth factor receptor (

) or human epidermal growth factor receptor 2 (

) can be reliably detected in a tumor, indicating a pathway that can be interrupted with a targeted drug. The identification of such clear predictive biomarkers placed personalized therapies within reach for some cancer patients, inspiring the hope that individualized treatment decisions lay around the corner for all areas of cancer treatment, including immunotherapies. While strides in this direction have undoubtedly been made, developing personalized regimens to overcome immune tolerance to tumors may prove more challenging than parallels with other targeted therapies might initially suggest.

The goal of immunotherapy is to sensitize (or resensitize) the host immune system to the presence of a tumor antigen. Several methods have been tested, including:

 A vaccine presents a specific tumor protein or proteins to the immune system, coupled with an adjuvant to activate and prime dendritic cells.[1] So far, vaccines have not been shown, at least in isolation, to routinely induce objective antitumor responses, although a survival benefit has been demonstrated for at least one such agent.[2]

 As Carneiro et al nicely discuss in their review,[3] checkpoint inhibitors downregulate a tumor’s ability to employ either intrinsic or extrinsic immune inhibitory pathways, reactivating T cells that have become exhausted. We are all familiar with the recent triumphs achieved with the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways, which have a proven survival benefit in several tumor types, including melanoma, renal cell carcinoma, and lung adenocarcinoma.[4]

 If immune checkpoint inhibition removes a braking mechanism, a third strategy presses the accelerator: immune agonist antibodies, such as Î±4-1BB, Î±OX40, and Î±CD40, activate either T cells (4-1BB, OX40) or dendritic cells (CD40) via cross-linking antibodies. While translational efforts are still in relatively early stages across the board, 4-1BB activation has shown some efficacy in melanoma, although it initially demonstrated liver toxicity as well. It is now being reintroduced more cautiously, in combination with PD-1 blockade.[5]

 Numerous combinations of immune therapies appear promising or have already led to improved outcomes, eg, combined CTLA-4/PD-1 inhibition in melanoma and renal cell carcinoma.[6-8]

Despite several recent US Food and Drug Administration approvals, only a minority of patients demonstrate durable responses to immune therapy, leading to unnecessary toxicities and costs for patients who receive these drugs without benefit. Predictive biomarkers could help to identify which patients are likely to respond, and might also point to future therapies. Carneiro et al outline some promising efforts to uncover tumor characteristics with therapeutic value, eg, microsatellite instability (MSI) for pembrolizumab, mutational burden in lung cancer, and PD-L1 expression on tumor cells or associated myeloid cells. Other areas of inquiry include vaccine targets such as overexpressed self-antigens, cancer-testis antigens like MAGE-A3, and mutation-associated neoantigens.[9] A methodology developed by the Ribas group[10] demonstrates yet another encouraging line of investigation: evidence in melanoma patients shows that the density of CD8+ T cells at the tumor margin, along with density of PD-1– and PD-L1–positive cells, can fairly reliably predict tumor response. In contrast to a binary assay for the presence of, for example, PD-L1, this is a complex discriminatory model that will require standardization and automation before it can be used widely. Further study will also be needed to show generalizability across other tumor types.

With the notable exceptions discussed above, other efforts to discover predictive immune biomarkers have generated exciting ideas and some progress, but fewer solid results. This may merely reflect the early stage of the field, or it may turn out that personalized cancer immunology is truly a slippery fish, one we may or may not wrap our hands around soon. Perhaps the best illustration of this complexity comes from animal studies: multiple groups, including our own, have shown that even genetically identical laboratory mice, implanted with genetically identical tumors and living in a single cage, show disparate responses to PD-1/PD-L1 blockade.[11,12] How to explain this variability when host and tumor genetic factors have been controlled for? One possibility involves the T- and B-cell repertoire of the host: even genetically identical animals have distinct repertoires because T- and B-cell receptors are generated through random recombination events in the thymus and bone marrow, respectively. A second possibility could be that epigenetic factors emerging after implantation could affect the host response to tumors. Finally, recent clinical and preclinical data show that variability in the host microbiome can profoundly influence the host response to immunotherapy.[13,14]

In addition to the implications of random events in the development of the host immune system, a predictive biomarker will be challenged by the dynamic nature of an immune response, in which PD-L1 and similar markers vary in time and space over the tumor parenchyma. Indeed, depending on the placement of a core needle, PD-L1 staining could conceivably vary from 100% to undetectable (Herbst RS, unpublished data), pointing to a potential requirement for multiple sampling, or perhaps eventually to more global image-based assessment approaches.[15]

In summary, the recent successes in cancer immunotherapy have launched widespread efforts to identify biomarkers to personalize treatments, while the complexity of the immune tumor response presents an exciting-but daunting-landscape for this research. Some of the most successful approaches to date have parallels with more classic tumor genomics: they identify a genetic feature that carries direct therapeutic implications. For example, MSI testing can be termed a genetic biomarker for immunotherapy, and offers an easily measured and portable assay. Other research has focused on more phenotypic features-of tumors, or of the quality and density of immune presence/response. Unlike the binary biomarkers in use in personalized targeted therapy, these phenotypic biomarkers occur on continuums, or involve multiple factors requiring statistical modeling, and overall present a far greater challenge. Given the plasticity and complexity of the immune response, we may find genetic biomarkers rare, and phenotypic biomarkers necessary. These approaches will probably require deep dives into basic and clinical immunity; but deep diving will likely be required to catch those slippery fish.

Dr. Drake has consulted for AZ MedImmune, Bristol-Myers Squibb, Compugen, F-star, NexImmune, Potenza Therapeutics, Roche/Genentech, Merck, Tizona Therapeutics, and ImmuneXcite; has done sponsored research for Aduro Biotech and Bristol-Myers Squibb; has had patents licensed for AZ MedImmune and Bristol-Myers Squibb; and owns stock options in Compugen, NexImmune, Potenza Therapeutics, and Tizona Therapeutics. Dr. Hunter has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this commentary. 

 Drake CG, Lipson EJ, Brahmer JR. Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat Rev Clin Oncol. 2014;11:24-37.

 Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22.

 Carneiro BA, Costa R, Taxter T, et al. Is personalized medicine here? Oncology (Williston Park). 2016;30:293-303, 307.

 Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450-61.

 Yonezawa A, Dutt S, Chester C, et al. Boosting cancer immunotherapy with anti-CD137 antibody therapy. Clin Cancer Res. 2015;21:3113-20.

 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.

 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-33.

 Hammers HJ, Plimack ER, Infante JR, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32(suppl 5s):abstr 4504.

 Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.

 Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568-71.

 Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917-27.

 Lesterhuis WJ, Rinaldi C, Jones A, et al. Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations. Sci Rep. 2015;5:12298.

 Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350:1084-9.

 Vetizou M, Pitt JM, Daillere R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079-84.

 Tavare R, McCracken MN, Zettlitz KA, et al. Engineered antibody fragments for immuno-PET imaging of endogenous CD8+ T cells in vivo. Proc Natl Acad Sci USA. 2014;111:1108-13.

Advances in basic science and clinical medicine in the past few decades have increasingly elevated the profile of personalized medicine, ie, the identification of individual tumor or biologic features that offer targets for therapy. 

Personalized Immune Therapy: A Slippery Fish?

Brain metastases develop in approximately 10% to 20% of cancer patients each year in the United States (~500,000 patients). With insufficient brain imaging to detect the number and location of the metastases, clinicians previously had no option other than empiric whole-brain radiation therapy (WBRT).[1,2] The development of better systemic targeted cancer therapies coupled with the recognition of the long-term deleterious effects of WBRT has spurred rapid expansion of the use of stereotactic radiosurgery (SRS).

Although current level I evidence supports the use of SRS in patients with up to four brain metastases, specialists are already treating patients with many more than four brain metastases. Outcomes after Gamma Knife surgery (GKS) for multiple brain metastases have been defined in a number of retrospective studies over the past 2 decades. Routinely, patients harboring as many as 20 or more metastases are successfully treated in a single, minimally invasive, outpatient procedure. In most retrospective series, a higher number of metastatic lesions has not been shown to change survival for patients with more than five brain metastases if all are treated. The total cumulative volume of brain metastases, Karnofsky performance score (KPS), older age, and control of systemic disease are much more important factors that affect survival.

In a retrospective study by Bhatnagar et al, median overall survival (OS) in patients with four or more brain metastases was 8 months after treatment with SRS, and higher intracranial burden (but not the number of brain metastases) predicted poorer outcomes.[3] Grandhi et al studied 61 patients with 10 or more brain metastases (a total of 806 tumors [mean, 13.2 lesions]) who underwent SRS.[4] The median survival for a patient with fewer than 14 brain metastases, nonmelanomatous primary tumor, and controlled systemic disease was 21 months. Sustained local tumor control was achieved in 81% of patients. Mohammadi et al retrospectively evaluated OS and factors predicting outcome in 170 patients with more than five brain metastases treated with GKS.[5] Median OS after GKS was 6.7 months. Lower KPS, patient age younger than 60 years, multiple extracranial metastases, and greater intracranial burden of disease (volume) were prognostic factors for poor outcome. These studies suggest that the number of brain metastases (1–4 vs > 5) do not affect the outcome, but rather it is the total tumor burden that may impact local tumor control and patient survival. The tumor burden depends upon the size, not the number, of brain metastases. For example, the total volume of a single spherical brain metastasis with a 3-cm diameter is approximately 14 mL, while total volume of 10 brain tumors each measuring 1 cm in maximum diameter has only 5 mL total volume.

In a study of 26 patients with 10 or more brain metastases each, Kim et al observed a median OS of 34 weeks after SRS.[6] The tumor control rate was 86.9% and 79.5% at 3 and 6 months, respectively, following treatment. On univariate analysis, synchronous time of discovering brain metastases, a higher KPS, and controlled primary disease were positive prognostic factors. The use of upfront WBRT, tumor volume, number of metastases, and tumor margin dose had no significant effect on survival. In a retrospective study, Serizawa et al compared the outcomes after GKS and WBRT for the treatment of up to 10 brain metastases from non–small-cell lung cancer in 96 patients.[7] The tumor control rate was 94.8% 1 year after therapy. Both the estimated OS and estimated intervals free from neurologic death were significantly higher in the GKS group (mean survival time, 377 days vs 199 days). Univariate analysis revealed that systemic control, treatment method, and pathologic composition were prognostic for survival, whereas multivariate analyses confirmed that systemic control and treatment method, as well as KPS, were positively prognostic. These studies again highlight the fact that although some physicians may consider the number of brain metastases as an indicator of their prognosis, this has not been substantiated in long-term studies; they also suggest that systemic disease burden, patients’ functional status, and the type of treatment offered may be more important for overall prognosis than the number of brain metastases.

Serizawa et al evaluated the results of patients with 1 to 10 brain metastases receiving GKS alone.[8] Seven hundred seventy-eight consecutive cases met inclusion criteria. On multivariate analysis, adverse prognostic factors for OS were active systemic disease, poor (< 70) initial KPS, and male gender. The mean survival for these patients was 7 months. Neurologic survival and qualitative survival rates at 1 year were 92.7% and 88.2%, respectively. New lesion–free survival at 6 months and 1 year were 69.8% and 43.8%, respectively. Yamamoto et al enrolled 1,194 patients with brain metastases in an observational multi-institutional study.[9] Median OS after SRS in all patients was 12 months, with no difference in median OS for patients with 2 to 4 tumors and 5 or more tumors. These data supported the hypothesis that the volume, and not the number, of metastases may be the driver in determining the outcomes of patients with brain metastases.

SRS achieves high rates of local progression-free survival for patients with treated lesions, and its efficacy may be less influenced by histology or radiosensitivity vs WBRT. Only a minority of patients experience adverse effects after SRS.

Collectively, the outcomes reported in retrospective and prospective studies, as well as the ability to salvage intracranial relapses with further application of SRS, have recently led to the use of SRS alone for patients with multiple brain metastases. During follow-up surveillance imaging (done every 3 months for the first year), newly recognized brain metastases can be effectively treated by repeat SRS. The current role of WBRT is reserved for patients who develop miliary brain disease or carcinomatous meningitis. This approach enhances neurocognitive outcomes[10] and virtually eliminates the development of brain leukodystrophy, which can occur in patients who undergo WBRT.[11,12]

The aggressive management of brain metastases with SRS has supplanted radiation therapy in an effort to maintain patient quality of life in an era of advancing systemic cancer options. Death from brain progression is now rare. SRS for patients with one or many brain metastases provides a high rate of tumor control, a low risk of adverse effects, and does not delay systemic cancer management. SRS is now the standard of care for patients with newly diagnosed brain metastases.

Dr. Niranjan has served as a consultant for the International Gamma Knife Research Consortium. Dr. Lunsford is a consultant and stockholder with AB Elekta; he is also a member of Insightec DSMB.

 Delattre JY, Krol G, Thaler HT, Posner JB. Distribution of brain metastases. Arch Neurol. 1988;45:741-4.

 Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer. 1996;78:1781-8.

 Bhatnagar AK, Flickinger JC, Kondziolka D, Lunsford LD. Stereotactic radiosurgery for four or more intracranial metastases. Int J Radiat Oncol Biol Phys. 2006;64:898-903.

 Grandhi R, Kondziolka D, Panczykowski D, et al. Stereotactic radiosurgery using the Leksell Gamma Knife Perfexion unit in the management of patients with 10 or more brain metastases. J Neurosurg. 2012;117:237-45.

 Mohammadi AM, Recinos PF, Barnett GH, et al. Role of Gamma Knife surgery in patients with 5 or more brain metastases. J Neurosurg. 2012;117(suppl):5-12.

 Kim SH, Weil RJ, Chao ST, et al. Stereotactic radiosurgical treatment of brain metastases in older patients. Cancer. 2008;113:834-40.

Serizawa T, Iuchi T, Ono J, et al. Gamma knife treatment for multiple metastatic brain tumors compared with whole-brain radiation therapy. J Neurosurg. 2000;93(suppl 3):32-6.

 Serizawa T, Hirai T, Nagano O, et al. Gamma knife surgery for 1-10 brain metastases without prophylactic whole-brain radiation therapy: analysis of cases meeting the Japanese prospective multi-institute study (JLGK0901) inclusion criteria. J Neurooncol. 2010;98:163-7.

 Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15:387-95.

 Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10:1037-44.

 Monaco EA 3rd, Faraji AH, Berkowitz O, et al. Leukoencephalopathy after whole-brain radiation therapy plus radiosurgery versus radiosurgery alone for metastatic lung cancer. Cancer. 2013;119:226-32.

 Stokes TB, Niranjan A, Kano H, et al. White matter changes in breast cancer brain metastases patients who undergo radiosurgery alone compared to whole brain radiation therapy plus radiosurgery. J Neurooncol. 2015;121:583-90.

The aggressive management of brain metastases with SRS has supplanted radiation therapy in an effort to maintain patient quality of life in an era of advancing systemic cancer options. 

Gamma Knife Radiosurgery for 5 to 10 Brain Metastases: A Good Option for Upfront Treatment 

Current management of patients with multiple (≥ 5) brain metastases (MBMs) is in flux and remains controversial, based on increasing emphasis on the use of stereotactic radiosurgery (SRS) for patients with three or fewer brain metastases,[1] and the desire to expand this indication further. Though there have been many retrospective studies showing feasibility and efficacy of SRS for MBMs, few practice-changing messages have emerged from them. Substantial selection biases in these studies exist; patients with poorer performance status and uncontrolled systemic disease are often more likely to receive whole-brain radiation therapy (WBRT), and subsequent interpretations of superior efficacy are therefore flawed. In light of these well-documented caveats, there are very few data to support SRS, especially SRS only, for MBMs at present (a situation that could change pending completion of appropriate randomized trials, some of which are ongoing), a primary reason for the National Comprehensive Cancer Network’s current recommendations for WBRT in patients with more than three brain metastases.[2]

One prospective study has offered the best available data to observationally evaluate overall survival (OS) for patients with 5 to 10 brain metastases treated with SRS only compared with patients with 1 or 2 to 4 brain metastases treated with SRS only.[3] This is clearly not a comparison of SRS with WBRT or SRS with SRS + WBRT; therefore, unbridled enthusiasm for over-interpretation of these data should be curtailed. Even in this trial, the OS for the single brain metastasis group was clearly the highest (13.9 months); there was no significant difference in OS for patients with 2 to 4 or 5 to 10 metastases (10.8 months each), indirectly underscoring the long-held observation that the addition of SRS to WBRT improves survival only in patients with more indolent biology, as represented by patients with a single metastasis, a high Graded Prognostic Assessment (GPA) score, etc. The fact that no survival discrimination in favor of SRS exists for patients with 2 to 10 lesions challenges SRS to become cost-effective, as well as quality-effective, if it is to replace WBRT.

SRS is clearly an effective focal therapy, but unlike WBRT, which categorically decreases failure elsewhere in the brain in patients with MBMs, SRS is simply unable to achieve this endpoint. It has often been promulgated that the consequences of failure elsewhere in the brain are trivial or irrelevant, but genuine, high-quality data supporting such claims are simply not available. In fact, at least two recent studies in the literature, one a re-analysis of a Japanese randomized trial,[4] and the second, a retrospective analysis,[5] suggest that SRS alone actually results in inferior survival. An apparent benefit of SRS is its ability to offer superior short-term neurocognition as compared with WBRT, although long-term data from randomized trials to support this benefit are not yet available in the peer-reviewed literature, and therefore some question and debate persists regarding this issue. Highly promising randomized clinical data using memantine[6] and hippocampal-sparing WBRT[7] could potentially lead to similar posttreatment cognitive outcomes, and ongoing randomized trials will answer these questions. A randomized study from the North American Gamma Knife Consortium for patients with MBMs is testing WBRT vs SRS for patients with up to 10 brain metastases (ClinicalTrials.gov identifier: NCT01731704), although it is unclear to what extent hippocampal-sparing and memantine will be utilized in this trial; in fact, it is likely that if only conventional WBRT is used, it could deliver results that almost instantaneously become less relevant.

Moreover, we posit that the questions and research directions of substantial clinical relevance are actually not nested in the “WBRT vs SRS for 

 number of brain metastases” concept, but rather in appropriate and selected use of both modalities, with a view toward integrating these with the rapid advances in multiple other therapeutic options. For example, rather than blithely accepting the almost 70% or higher likelihood of eventual failure in the brain following SRS alone, we should be considering judicious studies to identify patients at greatest risk of early and multiple lesion failure, and utilizing WBRT (with strategies to diminish neurocognitive sequelae, such as the use of memantine, hippocampal avoidance, the emerging field of striatal-enriched protein tyrosine phosphatase [STEP] inhibitors,[6-8] etc.) more extensively in these patients, while deferring it in others. This might require histology-specific molecular and clinical factor stratification. We should also consider incorporating blood–brain barrier (BBB)-penetrating therapies, specifically in target-enriched clinical scenarios in combination with SRS, to replace WBRT, and simultaneously eliminate the associated unacceptably high elsewhere-in-the-brain failure rates (eg, the SRS plus BBB-penetrating anti-HER2–directed systemic therapy approach based on the LANDSCAPE trial as an illustrative example[9]). Several other options, such as epidermal growth factor receptor–directed therapies for mutated non–small-cell lung cancer (NSCLC), second-generation anaplastic lymphoma kinase (ALK) inhibitors for NSCLC, and others, are now emerging. A third such opportunity would be either SRS or fractionated stereotactic radiotherapy approaches to one or a limited number of brain metastases in combination with immune checkpoint inhibitors to exploit the immunogenic potential of radiation; NRG Oncology is developing one such protocol for melanoma brain metastases. Lastly, it is important to test alternative therapeutic strategies, such as NovoTTF, in combination with SRS to achieve the microscopic disease control so readily attained by WBRT, a concept to be tested in the forthcoming METIS trial. Outside of the clinical trial context, individualized assessment of each patient is of primary importance to guide treatment decisions, such as whether expected patient survival is too short to warrant expensive technologies like SRS alone or MRI surveillance, or if the risk of intracranial relapse from SRS alone puts them at risk for loss of survival, as elegantly demonstrated by Aoyama et al[4] and others, therefore necessitating the incorporation of WBRT.

In summary, until prospective randomized clinical data accrue and mature, this controversial issue will continue to suffer from overinterpretation of inadequate supporting data. This absence of data will, at least for the time being, provide an insufficient evidence base for using SRS 

 in patients with MBMs, which remains a problem from the health economics and insurance payment perspective.[10] The importance of careful patient selection for the use of SRS, with WBRT as appropriate, in patients with MBMs cannot be overemphasized. Doing so can offer the best prospects of effective and cost-conscious cancer care in this patient population, aimed at sparing neurocognition, improving survival, and achieving the best possible tumor local control.

Dr. Mehta has served as a consultant for Abbott, Bristol-Myers Squibb, Cavion, Celldex, Elekta, Novartis, Novocure, and Roche; has research funding from Cellectar and Novocure; has served in a leadership capacity on the Pharmacyclics BOD (with stock options); and serves on the Data Monitoring and Safety Board of Monteris. Dr. Verma has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

 Mehta MP, Tsao MN, Whelan TJ, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys. 2005;63:37-46.

 National Comprehensive Cancer Network. NCCN Guidelines for CNS Cancer. 

www.nccn.org/professionals/physician_gls/f_guidelines.asp#cns

 Aoyama H, Tago M, Shirato H, et al. Stereotactic radiosurgery with or without whole-brain radiotherapy for brain metastases: secondary analysis of the JROSG 99-1 randomized clinical trial. JAMA Oncol. 2015;1:457-64.

 Wang TJ, Saad S, Qureshi YH, et al. Outcomes of gamma knife radiosurgery, bi-modality & tri-modality treatment regimens for patients with one or multiple brain metastases: the Columbia University Medical Center experience. J Neurooncol. 2015;122:399-408.

Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15:1429-37.

 Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014;32:3810-6.

 Goebel-Goody SM, Baum M, Paspalas CD, et al. Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders. Pharmacol Rev. 2012;64:65-87.

 Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14:64-71.

 Sullivan R, Peppercorn J, Sikora K, et al. Delivering affordable care in high-income countries. Lancet Oncol. 2011;12:933-80.

Until prospective randomized clinical data accrue and mature, this controversial issue will continue to suffer from overinterpretation of inadequate supporting data.

Gamma Knife Radiosurgery for 5 to 10 Brain Metastases: May Not Be Reasonable as Sole Upfront Treatment 

For both the patient and provider, managing nonmetastatic castration-resistant prostate cancer (CRPC) can be frustrating. Often, as Luo et al review in this issue of ONCOLOGY,[1] management of nonmetastatic CRPC involves either a waiting game or treatment with agents that have modest activity with acceptable tolerability (eg, first-generation antiandrogens). However, hope is on the horizon in the form of novel androgen receptor signaling inhibitors (ARSIs). Both abiraterone, a CYP17A1 inhibitor able to suppress intratumoral androgens, and enzalutamide, an antagonist of androgen receptor ligand binding, have been tested and approved in increasingly earlier prostate cancer disease states.[2-5] So it is no surprise that enzalutamide, as well as the next-generation antiandrogens ARN-509 and ODM-201, are currently in phase III testing in nonmetastatic CRPC (in the PROSPER, SPARTAN, and ARAMIS trials, respectively).[6-10] Although these trials of ARSIs seem likely to generate the level 1 evidence now sorely lacking, several key issues deserve discussion. Here we will address these issues and provide insights.

The primary endpoint in all three ongoing phase III studies in nonmetastatic CRPC is metastasis-free survival. This endpoint is typically a composite defined as time to first occurrence of bone metastasis (whether symptomatic or asymptomatic) or death from any cause. As detailed by Luo and colleagues, metastasis-free survival has previously been evaluated as a primary endpoint in nonmetastatic CRPC.[11] Several lessons can be learned from this earlier phase III, double-blind trial, in which 1,432 men with nonmetastatic CRPC at high risk for metastasis (prostate-specific antigen [PSA] level ≥ 8 ng/mL or PSA doubling time ≤ 10 months, or both) were randomly assigned 1:1 to either the osteoclast inhibitor denosumab or placebo. Denosumab modestly prolonged metastasis-free survival by 4.2 months (hazard ratio [HR], 0.85 [95% CI, 0.73–0.98]; 

 = .028) but not overall survival (HR, 1.01 [95% CI, 0.85–1.20]; 

 = .91). Importantly, there was a 5% rate of osteonecrosis of the jaw (ONJ) in the denosumab arm, compared with 0% in the placebo arm. The Oncologic Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted 12 to 1 that the risk-benefit ratio was insufficient to expand use of denosumab to include the indication of delaying spread to the bone in men with high-risk nonmetastatic CRPC, and the FDA did not grant approval.

Thus, it seems that ARSIs must do better than denosumab in terms of risk-benefit ratio. Specifically, in order to have a high likelihood of approval, we believe that novel ARSIs must demonstrate an overall survival advantage, ideally in addition to other patient-centered benefits (ie, increases in time to symptomatic progression, time to first skeletal-related event, and time to initiation of cytotoxic chemotherapy). Furthermore, in a perfect world, any survival difference would be large, because otherwise the question of early vs late use of ARSIs would arise. For example, docetaxel for 6 cycles demonstrated a 13.6-month improvement in overall survival when used in an earlier disease state, compared with a 2.9-month improvement with later use for 10 cycles, essentially resolving this potential debate before it started.[12,13] Finally, ARSIs must be tolerable and not cause clinically meaningful declines in quality of life.

Patient-Reported Outcomes and Quality of Life (Risks)

If ARSIs have clinically significant side effects (like ONJ with denosumab) or are chronically intolerable for the long durations during which they are likely to be used, this also may adversely tilt the risk-benefit ratio. In these men with a median life expectancy of 3 to 4 years, depending on the magnitude of benefits, negative effects on quality of life could prove pivotal to the early-vs-late-use calculus. Of course, the best evidence will come from the large randomized trials (1,200 to 1,560 patients) mentioned previously, but data from two earlier-phase trials is instructive.

The single-arm phase II IMAAGEN trial enrolled 131 patients with high-risk nonmetastatic CRPC and treated them with abiraterone/prednisone. Adverse events (AEs) of grade 3 or higher occurred in 54.9% of patients, and 38.2% had a serious AE, with 13% of patients having an AE resulting in discontinuation of the study drug, and with four patients experiencing AEs that resulted in death.[14] The best available evidence regarding tolerability is from the recently published double-blind, randomized phase II STRIVE trial of enzalutamide vs bicalutamide, which included 139 patients with high-risk nonmetastatic CRPC.[15] (It should be noted that AEs were not reported separately for the nonmetastatic CRPC group.) In the entire study cohort, AEs more commonly reported with enzalutamide than with bicalutamide included fatigue (38% vs 28%), hot flashes (16% vs 10%), falls (14% vs 8%), hypertension (12% vs 5%), dizziness (12% vs 7%), and decreased appetite (12% vs 7%). Interestingly, with a median time on treatment of 8.4 months for bicalutamide vs 14.7 months for enzalutamide, the median time to clinically significant decline of the FACT-P (Functional Assessment of Cancer Therapy-Prostate, a quality-of-life instrument) score appeared equivalent at 8.3 and 8.4 months, respectively. This suggests that while the decline in quality of life with bicalutamide may have been due to disease progression, the decline with enzalutamide was most likely related to treatment effect.

Measures of quality of life included as secondary endpoints in all three phase III studies will be critical. Because patients may report symptoms and health status better than clinicians, future studies of ARSIs should also include tools such as the PRO-CTCAE (Patient-Reported Outcomes version of the National Institutes of Health’s Common Terminology Criteria for Adverse Events).[16] Finally, it is well established that supervised exercise can mitigate a variety of treatment-related adverse effects resulting from conventional androgen deprivation therapy.[17] A study is underway examining whether exercise can mitigate adverse effects of higher-potency ARSIs.[18,19] If exercise can mitigate important side effects of ARSIs, this would likely tilt the risk-benefit balance toward use in a larger number of men.

We wholeheartedly agree with Luo and coauthors that at this time, men with high-risk nonmetastatic CRPC should if possible be enrolled in a clinical trial and that patients with low-risk disease can be safely observed. Phase III studies scheduled to report in about 4 years will shed light on the risk-benefit ratio of second-generation ARSIs. In the meantime, we caution against using these agents off-label for nonmetastatic CRPC due to their significant side effects and the resulting diminishment in quality of life, with uncertain significance of benefits. The Table speculates-pending data from phase III and other trials-how risk stratification for nonmetastatic CRPC treatment selection may look in the not-so-distant future.

Dr. Harrison has received research funding from Janssen and Medivation/Astellas. Dr. Ramalingam has no significant financial interest or other relationship with the manufacturer of any product or provider of any service mentioned in this commentary.

 Luo J, Beer TM, Graff JN. Treatment of nonmetastatic castration-resistant prostate cancer. Oncology (Williston Park). 2016;30:336-44.

 de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.

 Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-48.

 Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-97.

 Beer TM, Armstrong AJ, Sternberg CN, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): results of phase III PREVAIL study. J Clin Oncol. 2014;32(suppl):abstr LBA1.

 Medivation. Safety and efficacy study of enzalutamide in patients with nonmetastatic castration-resistant prostate cancer (PROSPER). 

https://clinicaltrials.gov/ct2/show/NCT02003924

 Aragon. A study of ARN-509 in men with non-metastatic castration-resistant prostate cancer (SPARTAN). 

https://clinicaltrials.gov/ct2/show/NCT01946204

 Bayer. Efficacy and safety study of BAY1841788 (ODM-201) in men with high-risk non-metastatic castration-resistant prostate cancer (ARAMIS). 

https://clinicaltrials.gov/ct2/show/NCT02200614

 Moilanen AM, Riikonen R, Oksala R, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007.

 Rathkopf DE, Morris MJ, Fox JJ, et al. Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2013;31:3525-30.

 Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379:39-46.

 Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737-46.

 Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242-5.

 Ryan CJ, Crawford ED, Shore ND, et al. Effect of abiraterone acetate and low dose prednisone on prostate-specific antigen in patients with non-metastatic castration-resistant prostate cancer: the results from impact of abiraterone acetate in prostate-specific antigen core study. Presented at the American Urological Association Annual Meeting; May 15-19, 2015; New Orleans, LA.

 Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016 Jan 25. [Epub ahead of print]

 Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Natl Cancer Inst. 2014;106.

 Gardner JR, Livingston PM, Fraser SF. Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: a systematic review. J Clin Oncol. 2014;32:335-46.

https://clinicaltrials.gov/ct2/show/NCT02256111

 Harrison MR, Jones LW. Exercise as treatment for androgen deprivation therapy-associated physical dysfunction: ready for prime time? Eur Urol. 2014;65:873-4.

Men with high-risk nonmetastatic CRPC should if possible be enrolled in a clinical trial and that patients with low-risk disease can be safely observed. 

Novel Androgen Receptor Signaling Inhibitors for Nonmetastatic Castration-Resistant Prostate Cancer: The Light at the End of the Tunnel-or an Oncoming Train?

Since the relatively recent discovery in 1992 that mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma, significant therapeutic advances have lengthened the expected median survival time for the majority of patients, from 3 to 5 years to more than a decade.[1] Despite progress, cure remains elusive, and this unfortunate fact underlies many of the controversies in management of this malignancy. The review article by Chen and colleagues in this issue of ONCOLOGY provides valuable insight and updates regarding diagnostic, prognostic, and clinical trial data in MCL.[2] However, a few issues warrant further discussion as we evaluate how to incorporate the relevant data into daily practice.

First, as Chen and colleagues describe, a variety of prognostic tools are embedded within therapeutic trials, including the Mantle Cell Lymphoma International Prognostic Index (MIPI), the five-gene (

) panel, and proliferation indices obtained via gene expression profiling. However, these are prognostic but not predictive tools, limiting their utility in individual patients. The tool with the greatest potential for individual applicability is minimal residual disease (MRD), which has been assessed via flow cytometry, quantitative polymerase chain reaction (PCR), and next-generation sequencing (NGS) of DNA and RNA. MRD negativity is a potent independent predictor of favorable prognosis, trumping both MIPI score and the specific treatment administered.[3] Given the robust prognostic role of MRD status, can therapy be intensified, extended, or halted based on MRD results? Studies to date have been promising but have also uncovered limitations of various MRD detection techniques. For example, one study of preemptive rituximab therapy for MRD relapse could only identify a PCR marker in half of enrolled patients; among the patients with a detectable marker, one-third had concurrent clinical relapse necessitating more intensive therapy, rendering identification of MRD moot.[4] Several planned and ongoing trials will prospectively implement “MRD-based” treatment algorithms. A US Intergroup study in active development will use MRD status to allocate therapy, likely informing practice patterns in the near future. The most important aspect of any MRD assessment will require a rapid, reliable, and reproducible assay that is sensitive enough to detect disease prior to clinical relapse; NGS holds significant promise in this regard.

A second issue raised by Chen and colleagues is the concept of maintenance therapy. In a disease for which relapse is inevitable, maintenance strategies are an attractive means to achieve prolonged control over progression. However, it is important to note that maintenance rituximab has only shown improved progression-free survival (PFS) and a trend towards improved overall survival (OS) after patients have been treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Since both RB (rituximab and bendamustine) and VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) have been shown to be superior to R-CHOP in separate randomized trials, the added value of maintenance rituximab after patients have been treated with these regimens is unknown. In addition, prolonged lymphopenia with increased viral and mycobacterial infections is more common with RB than with other regimens, and maintenance therapy with rituximab can be associated with increased neutropenia and infections with prolonged B-cell depletion.[5] Complicating the questions of indicators for, and duration of, maintenance therapy is the advent of ibrutinib, a highly active single-agent drug. Currently, several trials are evaluating ibrutinib maintenance, including a planned US Intergroup study, a National Cancer Institute–sponsored trial, and a Swiss trial (ClinicalTrials.gov identifier: NCT02356458). The TRIANGLE study (ClinicalTrials.gov identifier: NCT00209222), ongoing in Europe, will explore the effect of transplant vs maintenance therapy on OS and PFS. The trial, which will help clinicians to further delineate the role of maintenance with novel agents, randomizes patients with MCL to one of three arms: R-CHOP/R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin), followed by autologous stem cell transplantation (ASCT); R-CHOP/R-DHAP with ibrutinib, followed by ASCT with ibrutinib maintenance; and R-CHOP/R-DHAP with ibrutinib, followed by ibrutinib maintenance.

A third issue highlighted by Chen et al is that the inevitable likelihood of relapse challenges the need to use aggressive tools such as ASCT universally in all young patients. While ASCT yields a clear and robust prolonged PFS, there are currently no randomized trials comparing ASCT against a non-transplant approach. Furthermore, MCL remains incurable despite upfront ASCT and there is no proven overall survival advantage to this approach over non-transplant approaches. Biologic doublets, as reflected by the promising activity of combination therapy with lenalidomide and rituximab, may offer patients with MCL an alternative to both transplant and chemoimmunotherapy.[6] The TRIANGLE study, which includes an arm replacing ASCT with ibrutinib, will directly address the value of high-dose chemotherapy in patients with MCL who respond after intensive chemotherapeutic induction.

Recent registry data from the Center for International Blood and Bone Marrow Transplant Research evaluating use of ASCT in MCL at relapse adds complexity to the debate on timing and value of intensive therapy in the front-line setting.[7] Although patients undergoing ASCT as part of initial therapy had the best outcomes, among 132 patients with MCL who underwent ASCT at relapse, the rate of relapse/progression at 5 years was approximately 50% and the 5-year OS rate was 44%. Considering that these patients had received multiple lines of prior therapy, these data are provocative. The ability to achieve long-term disease control in relapsed MCL challenges the role of upfront transplant, suggesting that some patients can derive benefit if ASCT is postponed to the relapsed setting.

Finally, despite impressive single-agent activity observed with ibrutinib, the reported salvage rates after failure of ibrutinib are alarmingly poor. Two separate series have shown a dismal median OS of 8 months and 3 months after ibrutinib discontinuation, with low rates of response to almost any salvage regimen.[8,9] However, it is important to note that all analyzed patients were heavily pretreated and may not be reflective of post-ibrutinib outcomes that might be achieved if ibrutinib were used earlier in the disease course. In addition, insight into mechanisms of ibrutinib resistance has improved, and drug development-targeting Bruton tyrosine kinase (

) mutations, phosphoinositide 3-kinase (PI3K)/AKT activation, and other BTK-related resistance mechanisms-is underway.

Overall, the future of patients with MCL is promising, since therapeutic options have widened. The implementation of universal aggressive treatment is challenged by novel regimens, targeted agents, the use of MRD to guide treatment decisions, and new trials that will directly compare transplant vs non-transplant approaches. The ability to put these results into daily practice is on the horizon and will move us closer towards personalized treatment approaches for our patients with MCL.

Dr. Smith serves as a consultant to Celgene, Genentech, and Pharmacyclics. Dr. Tallarico has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article

 Howlader N, Noone AM, Krapcho M, et al, editors. SEER Cancer Statistics Review, 1975–2012, National Cancer Institute. Bethesda, MD, 

, based on November 2014 SEER data submission, posted to the SEER website, April 2015.

 Chen R, Sanchez J, Rosen ST. Clinical management updates in mantle cell lymphoma. Oncology (Williston Park). 2016;30:353-60.

 Pott C, Macintyre E, Delfau-Larue MH, et al. MRD eradication should be the therapeutic goal in mantle cell lymphoma and may enable tailored treatment approaches: results of the Intergroup Trials of the European MCL Network. Blood. 2014;124:abstr 2147.

 Andersen NS, Pedersen LB, Laurell A, et al. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. J Clin Oncol. 2009;27:4365-70.

 Cheson BD, Wendtner CM, Pieper A, et al. Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: treatment recommendations from an international consensus panel. Clin Lymphoma Myeloma Leuk. 2010;10:21-7.

 Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373:1835-44.

 Fenske TS, Zhang MJ, Carreras J, et al. Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of transplantation timing and modality. J Clin Oncol. 2014;32:273-81.

 Cheah CY, Chihara D, Romaguera JE, et al. Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes. Ann Oncol. 2015;26:1175-9.

 Martin P, Maddocks K, Leonard JP, et al. Post-ibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016 Jan 13. [Epub ahead of print]

Overall, the future of patients with MCL is promising, since therapeutic options have widened. The implementation of universal aggressive treatment is challenged by novel regimens, targeted agents, the use of MRD to guide treatment decisions, and new trials that will directly compare transplant vs non-transplant approaches. 

From Minimal Residual Disease to Maintenance Therapy: Optimizing Tools for Treatment of Mantle Cell Lymphoma

Acute myeloid leukemia (AML) is an aggressive hematopoietic cancer characterized by recurrent genetic lesions and clonal expansion of immature and ineffective myeloid lineage cells, and is associated with a high morbidity and mortality. Recent genomic studies have shown that AML is a highly complex and heterogeneous disease.[1] The most recent edition of the World Health Organization classification addressed the increasing awareness of AML heterogeneity by significantly increasing the number of AML subcategories.[2] Prognostic variables in AML include age and such biologic features as recurrent cytogenetic abnormalities and certain genomic mutations.[3] In fact, recent analyses have demonstrated the value of incorporating gene mutations beyond 

) into AML risk classifications.[4] Despite these advances in our understanding of the pathogenesis of AML, treatment strategies have not significantly changed over the past 40 years, and age-adapted remission induction with chemotherapy and post-remission consolidation with chemotherapy and allogeneic hematopoietic stem cell transplant remain the standard of care.

In this issue of ONCOLOGY, Khaled, Al Malki, and Marcucci contribute a timely and comprehensive review of recurrent genomic abnormalities, current treatment paradigms, and emerging targeted therapeutic approaches in AML.[5] The authors review the incidence and biologic and prognostic impact of both established and emerging recurrent cytogenetic and molecular abnormalities, as well as the current treatment paradigms in both untreated and relapsed and refractory AML. Importantly, the authors review many of the emerging therapeutics for AML, including several novel therapeutics that target recurrent mutations or abnormal biological processes in AML cells. The impact of minimal residual disease (MRD) analysis on post-remission strategies in AML is also discussed. The authors summarize these advances and propose updated treatment algorithms that incorporate newer mutations and MRD testing, and in which patients are stratified by age and fitness for intense therapy.

As highlighted by the authors, our therapeutic approach to AML must evolve to match our increasing understanding of AML pathogenesis and potential associated therapeutic vulnerabilities. Since the advent of next-generation sequencing (NGS), the mutational profiles of large numbers of AML genomes have been described, resulting in a well-characterized AML mutatome.[6,7] This information has increased our understanding of AML pathogenesis. For example, data suggest that AML development is often a stepwise process that follows the development of clonal hematopoiesis as early as the fifth decade of life.[8,9] Furthermore, mutational profiling has led to the isolation of phenotypically and functionally normal preleukemic hematopoietic stem cells that serve as a reservoir for the development of AML clones, both at presentation and at relapse.[10,11] Transformation of these preleukemic hematopoietic stem cells leads to the development of AML, and while the field of AML leukemic stem cells is relatively mature, knowledge of AML mutations adds to the potential targets that might be used to eliminate leukemic stem cells (and potentially preleukemic hematopoietic stem cells) and thus improve therapeutic outcomes.[12] In addition, the process by which secondary AML develops and established AML evolves, termed clonal evolution, has been better described now that NGS has facilitated the characterization of AML-associated mutations.[6,13] Similar work has described the role of 

 mutations in the very-poor-risk therapy-related AML subtype, and has made it possible to identify which patients have a secondary or secondary-like AML based on mutational profiling.[14,15] Overall, the rapid increase in our molecular understanding of AML has led to refinements in our prognostic models, in addition to paving the way for the development of very promising novel targeted agents, such as FLT3 inhibitors, isocitrate dehydrogenase (IDH) inhibitors, and BCL-2 inhibitors.[16-18] The impact of AML mutational profiling on MRD analysis is also rapidly evolving. The presence of MRD after initial therapy, detected by either flow cytometry or molecular-based approaches, has significant and independent prognostic value in AML.[19-22] Determination of the optimal method for MRD detection in AML, the choice of molecular or antigen targets, and the significance of MRD cutoff levels remain critical questions in incorporating MRD analysis into AML management.

As highlighted in this review, the antileukemic activity of intensive chemotherapy has likely been maximized, after decades of trials optimizing the choice of chemotherapy, dose intensity, and duration of treatment. The rapid advances in our understanding of AML molecular pathogenesis and in novel targeted drug development provide a unique opportunity to change the design of future clinical trials and to individualize treatment algorithms to improve outcomes for all subgroups of AML, including older unfit patients. For example, two major recent studies have demonstrated that the addition of the tyrosine kinase inhibitors sorafenib and midostaurin improved survival and outcomes for unselected and 

-mutated younger patients with AML, respectively.[16,23] Furthermore, the addition of the BCL-2 inhibitor venetoclax to standard hypomethylating agent therapy led to promising overall response rates in elderly unfit AML patients.[18] As a field, we now have the opportunity to change the paradigm of clinical trial development by embracing risk-adapted designs that allow us to answer many questions in a single clinical trial. To this end, the treatment approaches suggested by Khaled et al for younger, older fit, and older unfit AML patients suggest a roadmap for risk-adapted prospective clinical trials with limited selection at baseline, randomization to specific mutationally or biologically based treatment arms incorporating novel agents, and further randomization based on MRD response. Alternative trial endpoints that might be used in place of overall survival, such as MRD negativity, can be readily incorporated into these studies. Such “personalized medicine” trials will require large multi–cooperative group efforts in order to adequately power subset arms. This approach will also require AML clinician-scientists to embrace changes to current trial and academic paradigms, as well as necessitating buy-in and cooperation from multiple pharmaceutical companies and other funding sources. In agreement with Khaled et al, we are ready to move beyond a “one-size-fits-all” approach in AML and join our colleagues treating other malignancies, such as lung cancer, in moving towards a personalized medicine approach.

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

Dr. Jonas has been supported by a grant from the National Institutes of Health (K12CA138464). 

 Jonas BA, Medeiros BC. Clinical presentation of acute myeloid leukemia. In: Garza JM, editor. Acute myeloid leukemia: signs/symptoms, classification and treatment options. Hauppauge, NY: Nova Science Publishers, Inc; 2015. p. 1-34.

 Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937-51.

 Mrozek K, Marcucci G, Nicolet D, et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012;30:4515-23.

 Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079-89.

 Khaled S, Al Malki M, Marcucci G. Acute myeloid leukemia: biologic, prognostic, and therapeutic insights. Oncology (Williston Park). 2016;30:318-29.

 Walter MJ, Shen D, Ding L, et al. Clonal architecture of secondary acute myeloid leukemia. N Engl J Med. 2012;366:1090-8.

 Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059-74.

 Genovese G, Kahler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477-87.

 Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488-98.

 Jan M, Snyder TM, Corces-Zimmerman MR, et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med. 2012;4:149ra18.

 Corces-Zimmerman MR, Hong WJ, Weissman IL, et al. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA. 2014;111:2548-53.

 Reinisch A, Chan SM, Thomas D, Majeti R. Biology and clinical relevance of acute myeloid leukemia stem cells. Semin Hematol. 2015;52:150-64.

 Jan M, Majeti R. Clonal evolution of acute leukemia genomes. Oncogene. 2013;32:135-40.

 Wong TN, Ramsingh G, Young AL, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518:552-5.

 Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367-76.

 Stone RM, Mandrekar S, Sanford BL, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]) [abstract]. Blood. 2015;126:6.

 Stein E, DiNardo C, Altman J, et al. Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 that promotes differentiation of myeloid cells in patients with advanced hematologic malignancies: results of a phase 1/2 trial [abstract]. Blood. 2015;126:323.

 DiNardo C, Pollyea D, Pratz K, et al. A phase 1b study of venetoclax (ABT-199/GDC-0199) in combination with decitabine or azacitidine in treatment-naÃ¯ve patients with acute myeloid leukemia who are ≥ 65 years and not eligible for standard induction therapy [abstract]. Blood. 2015;126:327.

 Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374:422-33.

 Terwijn M, van Putten WL, Kelder A, et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol. 2013;31:3889-97.

 Kayser S, Schlenk RF, Grimwade D, et al. Minimal residual disease-directed therapy in acute myeloid leukemia. Blood. 2015;125:2331-5.

 Chen X, Xie H, Wood BL, et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol. 2015;33:1258-64.

 Rollig C, Serve H, Huttmann A, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16:1691-9.

We are ready to move beyond a “one-size-fits-all” approach in AML and join our colleagues treating other malignancies, such as lung cancer, in moving towards a personalized medicine approach.