Several studies presented at the 2015 ESMO World Congress on Gastrointestinal (GI) Cancer offered new promise for patients. The new data covered both established and emerging therapeutics.

In updated results from the phase Ib KEYNOTE-012 trial, the PD-1 inhibitor pembrolizumab had an overall response rate of 22% in patients with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction. Also in immunotherapy, adding the investigational agent IMM-101 to gemcitabine showed promising activity while maintaining quality of life in patients with advanced pancreatic cancer.

Results from the phase III RECOURSE trial (page 30) showed a similar survival benefit, regardless of KRAS status, with the oral nucleoside TAS- 102 in patients with KRAS wild-type or mutated metastatic colorectal cancer (CRC). The FDA is currently reviewing a new drug application for TAS-102 as a treatment for patients with refractory metastatic CRC (mCRC), with an approval decision scheduled by December 19, 2015.

In contrast to the RECOURSE results, mutational status was predictive of efficacy with second-line cetuximab in patients with mCRC in the phase II CAPRI-GOIM trial. Participants whose tumors had no mutations in 

 genes experienced significantly prolonged progression-free survival by continuing cetuximab as part of a second-line regimen compared with chemotherapy alone.

Two studies confirmed the benefit of the multikinase inhibitor regorafenib, which is FDA-approved for patients with pretreated mCRC based on results from the CORRECT trial. Findings from a large expanded access program confirmed the overall survival (OS) data from CORRECT, and the CONCUR trial confirmed the OS benefit from CORRECT in Asian patients.

Another promising development coming out of the World GI meeting was a discussion on how novel agents that are revolutionizing the treatment of the hepatitis C virus could also have a significant impact on prevention and treatment outcomes in hepatocellular carcinoma.

For additional insight on the latest groundbreaking developments in GI cancers and all other tumor types go to 

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Several studies presented at the 2015 ESMO World Congress on Gastrointestinal Cancer offered new promise for patients.

World GI Congress: New Data, New Hope

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

		John Theurer Cancer Center at Hackensack University Medical Center

There is no question that we are currently living through one of the most exciting times in medicine, particularly in oncology, as I have frequently alluded to in this column. The new drugs that have emerged continue to transform the landscape and in some cases, will likely replace standard chemotherapy. The ongoing developments include advances with novel small molecules—such as kinase inhibitors in CML and lung cancer, and BCR targeted therapies in B-cell malignancies&mdash;as well as the enormous momentum seen (finally) in immunotherapy with checkpoint inhibitors, BITE antibodies, and cellular therapies (eg, CAR-T cells), which have shown sustainable activity across multiple tumor types.

These novel treatments are often reported as “breakthrough therapies” based on their impressive activity, even in patients refractory to chemotherapy, as well as their frequently being more tolerable than cytotoxic agents and often being administered conveniently as oral agents. Given these advantages, such novel therapies are, not surprisingly, widely adopted by the entire community. Even though some of these new anticancer agents do not induce complete remission, they provide durable responses, which translate into years of clinical benefit for patients and eventually carry the potential promise of making cancer “a chronic disease.”

Over the past few years, however, given the wellrecognized unsustainable cost of healthcare—particularly in cancer (with a predicted 40% increase in incidence by 2030!)&mdash;the cost of these new therapies has come under scrutiny. Though we have become accustomed to novel therapies being more costly for over two decades, their cost has continued to increase at an estimated average of $8,500 a year per patient for the past 15 years. Some extreme recent examples illustrate the current problem, with some breakthrough therapies costing up to $150,000 to $178,000 per patient, with copays that obviously then become prohibitive, leading large groups of oncologists to complain that it has gone too far.

Additionally, the next step with these emerging therapies will naturally be to combine biological agents, with the logical rationale that it will extend clinical benefit. This implies that in some cases, such as with indolent lymphomas, we will generate regimens that will cost over half a million dollars a year (with an endpoint to treat until progression). Needless to say, this becomes unfeasible and needs to be addressed. However, a number of factors might help read through and resolve this difficult equation:

		We need to look at the big picture for every patient and the cost of other procedures or strategies to treat every case. Reducing hospitalizations and complications with an ambulatory therapy can obviously offset a significant part of the cost of novel therapies.

		The use of combinations of new biologicals might help achieve deeper responses and hopefully help shift the field to minimal residual disease (MRD) as an endpoint and potentially be able to stop treatment or customize recommendations based on therapy “needs” through molecular monitoring.

		Nowadays, the FDA approval of a drug is based on proven/suggested clinical benefit in a population with unmet need, which typically refers to a disease subtype having failed X, Y, or Z prior therapies. However, most currently approved drugs in oncology will not work in about 30% to 70% of cases. Having the ability through molecular diagnostic/stratification to offer a given therapy to the right subset of patients is crucial and could save substantial dollars in addition to sparing risk and waste of precious lifetime for these patients. This effort of “precision medicine,” though palpable, still needs a huge amount of work and a stronger commitment from all players.

		In addition, the development of smarter—ie, molecularly relevant&mdash;trials would help identify biomarkers that could guide such decisions. They would also reduce the cost of drug development, which should translate into lower drug costs after FDA approval.

		The “me-too” drugs are sometimes looked at as another company “jumping” on the bandwagon; I would argue that they are critical to competitiveness, as recently shown with the hepatitis C treatment story.

Overall, the unprecedented, soaring price of anticancer drugs (and cancer care) is not sustainable and has truly not been addressed. This leads us to ambivalent situations: amazing stories of new compounds bringing patients back to life and generating appropriately huge hope for cancer patients around the world, while at the same time, the treatment is often accompanied by prohibitive financial toxicity.

I believe that in the pharmacoeconomics complex and deeply misaligned landscape, several forces will have to come forward together to improve the status quo. Countless initiatives are trying to look at outcome of cancer treatment or define the “best” pathways to treat patients. The goal is to identify where the real impact of a given drug or regimen is—ie, which agent, regardless of cost, gives the best mileage for a given patient? At that point, it is suggested that the “cost becomes almost relative.” I would argue that physicians as main prescribers need to be part of both the debate and solution. This solution needs to capture cost and outcome&mdash;as we do in COTA&mdash;in order to maintain quality for patients, while reducing variance in management by providing the appropriate rationale (evolving when needed) to support treatment decisions. This is the best way to render physicians responsible while allowing them to remain patient-centric&mdash;isn’t that the true core of medicine? And smarter medicine is better medicine!

The unprecedented, soaring price of anticancer drugs (and cancer care) is not sustainable and has truly not been addressed.

The Cost of Drugs in Cancer Care: A Story of Misalignment, With Necessary (Positive) Changes!

	Hematologic Malignancies Translational Research Center

	The Tisch Cancer Institute & Division of Hematology/Medical Oncology

A new test reveals which patients with leukemia and other blood disorders are likely to respond to treatment for graft-versus-host disease (GVHD) that develops after a stem cell transplant (SCT), according to a study led by researchers at the Icahn School of Medicine at Mount Sinai and published in 

Patients with fatal blood cancers like leukemia often require allogenic SCT to survive. Donor lymphocytes, which are transplanted along with donor stem cells into a recipient, can seek out and eliminate malignant cells that survived intensive chemoradiotherapy, causing a complete remission of the malignancy. But these lymphocytes cause GVHD, a life-threatening complication and major cause of death after SCT.

The disease, which can be mild to severe, occurs when the transplanted donor cells attack the GI tract, liver, and skin of the patient. Symptom severity, however, does not accurately define how patients will respond to treatment and patients are often treated alike with high-dose steroids. Although SCT cures cancer in approximately 50% of the patients, 25% die from relapsed cancer, and the remaining go into remission but later succumb to the effects of GVHD.

High-dose steroids are the only proven treatment for GVHD. Those with low-risk GVHD are often overtreated and face significant side effects from treatment, such as diabetes or bone disease. Patients with high-risk GVHD are undertreated and the GVHD progresses, often with fatal consequences. The goal is to provide the right treatment for each patient at the right time. This test identifies those patients at higher risk at the onset of their symptoms, allowing clinicians to design an aggressive intervention early on. Equally important is the ability to tailor a less-aggressive approach for those with low-risk disease who may not need a long course of high-dose, systemic steroids.

Along with a multicenter team of researchers, we first developed and tested a new scoring system using almost 500 blood samples from patients with newly diagnosed GVHD in varying grades from two different centers. We created an algorithm using concentrations of three biomarkers previously discovered by our team: The Tisch Cancer Institute at The Mount Sinai Medical Center tumor necrosis factor receptor Type 1 [TNFR1], soluble IL-33 receptor [ST2], and regenerative 3 alpha [Reg3α].

We were able to calculate the probability of nonrelapse mortality (usually caused by GVHD that does not respond to therapy) and divided the patients into three distinct groups to predict the patient’s response to GVHD treatment. The low-risk group had complete responses to treatment 75% of the time, whereas only 25% of the high-risk group showed complete responses.

The acid test was to evaluate the algorithm in a validation set of 300 additional patients from 20 different SCT centers throughout the United States. The algorithm worked perfectly, and the cumulative incidence of nonrelapse mortality significantly increased as the GVHD score increased, and conversely, the response rate to primary GVHD treatment decreased.

This new scoring system will help identify patients who may not respond to standard treatments, and may require an experimental and more aggressive approach, and it will also help guide treatment for patients with lower-risk GVHD who may be overtreated. This test will allow us to personalize treatment at the onset of the disease, where small differences in treatment may make big differences in outcomes. Also, future algorithms may incorporate additional biomarkers or clinical characteristics, proving increasingly useful to develop precision medicine for all SCT patients.

In order to capitalize on this discovery, we’ve created the Mount Sinai Acute GVHD International Consortium (MAGIC), which consists of a group of 10 SCT centers in the United States and Europe who will collaborate to use this new scoring system to test new treatments for acute GVHD. This group will use the biomarker algorithm to direct treatment in patients who volunteer to participate in clinical trials based on their risk assigned by the algorithm.

Preparations are underway to offer this test under the Clinical Laboratory Improvement Amendments (CLIA) certification of the Mount Sinai Clinical Laboratories for these clinical trials. My colleagues and I have also written a protocol to treat high-risk GVHD that has been approved by the FDA. In the future, other SCT centers may be able to send blood samples directly to Mount Sinai for this analysis.

Co-collaborators on the research included the University of Michigan, the University of Regensburg, and the Blood and Marrow Clinical Trials Network.

	Levine JE, Braun TM, Harris AC, et al. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicenter study. 

	The study was supported by grants from the National Cancer Institute; the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the Doris Duke Charitable Fund, the American Cancer Society, and the Judith Devries Fund.

A new test reveals which patients with leukemia and other blood disorders are likely to respond to treatment for graft-versus-host disease that develops after a stem cell transplant.

New Test Could Guide More Precise Treatment of GVHD

The goal of palliative care (PC) is to treat/prevent the noxious effects of cancer via a holistic approach. PC is multifaceted, requiring a cross-disciplinary team equipped to address physical, psychological, social, and spiritual problems. PC does not preclude curative therapies, and multiple reports have shown that it improves quality of life, reduces costs, and does not shorten survival.

 PC is of particular importance in gynecologic cancer. Treatment may require surgery, chemotherapy, radiation therapy or (increasingly) all three modalities. Surgery is often complex, extensive, and includes risks of bleeding, infection, and thrombophlebitis.

Chemotherapy requires intravenous and intraperitoneal infusion of multiple cytotoxic agents. Radiation therapy makes frequent use of painful and debilitating intracavitary applications. Gynecologic cancer disproportionately affects families, as well. Commonly striking mid-life women, gynecologic cancer frequently damages familial cohesion. Low-income communities with numerous matriarchal families suffer particularly devastating consequences from the loss of a mother.

PC issues particularly associated with gynecologic cancer include: lower extremity lymphedema (LEL), sexual function problems, chemotherapy-induced peripheral neuropathy (CIPN), and post-chemotherapy cognitive dysfunction (“chemobrain”).

LEL occurs following pelvic lymphadenectomy and is typically worsened by subsequent radiation. Although the precise incidence, risk factors, and severity are not well defined, in its extreme form, LEL can be crippling. Treatments include lymphatic massage, fitted garments, and mechanical compression. LEL is more easily prevented than reversed, so early intervention is important.

 Current trials will improve understanding of LEL within the next few years.

	Sexual function changes can contribute to stress, depression, and anxiety and may have profound effects on quality of life, relationships, and personal identity. Female sexual function can deteriorate, often dramatically, during menopause, and iatrogenic menopause is often a part of gynecologic cancer therapy. Surgical oophorectomy is commonly performed. Standard pelvic radiation therapy and multiagent chemotherapy typically cause ovarian failure, as well. Characterized by decreased estrogen production, ovarian failure can cause poor vaginal lubrication/elongation, altered genital sensitivity, and decreased libido.

	Treatment options are limited. Estrogen replacement is contraindicated for endometrial and some other cancers. Pharmacologic alternatives include the antihypertensive agent clonidine and the serotonin inhibitor venlafaxine.

 Nonpharmacologics, including acupuncture and yoga, may be effective.

	CIPN is strongly associated with cisplatin and paclitaxel, commonly used agents in gynecologic cancer. Further, patients may receive multiple chemotherapy regimens lasting 6 months or longer, often with repeated use of the same agents. CIPN progresses proximally with a cumulative, dose-related effect that is often difficult to measure objectively.

	Most cases resolve, but some may be persistent. 

 Gabapentin, venlafaxine and analgesics are commonly used, but no consistent, standard treatment has been identified.

 Amifostine has been studied in ovarian cancer, but proved to be unacceptable to patients, as it required tri-weekly IV administration, supine positioning, prophylactic antiemetics, and resuscitation capability.

	Chemobrain includes changes in memory, fluency, motor coordination, and calculations, and may occur in 40% of patients. First described in 1997, chemobrain has been reported in multiple cancer types.

	A recent study of chemobrain in ovarian cancer evaluated processing speed, reaction time, and attention/ memory. Over 30% had a decline in at least one area, most commonly attention/memory, although depression and anxiety may be confounders.

 Interventional trials are in development for this population.

	In summary, PC should address the unique symptom profile of gynecologic cancer and be tailored to individual socioeconomic environments. Benefits from PC innovations in gynecologic cancer may exceed those of traditional therapies.

				Bakitas MA, Tosteson TD, Li Z, et al. Early versus delayed initiation of concurrent palliative oncology care: patient outcomes in the ENABLE III randomized controlled trial. 

				Taplin SH, Weaver S, Salas E, et al. Reviewing cancer care team effectiveness. 

				Hareyama H, Hada K, Goto K, et al. Prevalence, classification, and risk factors for postoperative lower extremity lymphedema in women with gynecologic malignancies: a retrospective study. 

				L’Espérance S, Frenette S, Dionne A, et al. Pharmacological and non-hormonal treatment of hot flashes in breast cancer survivors: CEPO review and recommendations. 

				Frisk J, Källström AC, Wall N, et al. Acupuncture improves healthrelated quality-of-life (HRQoL) and sleep in women with breast cancer and hot flushes. 

				Beijers A, Mols F, Dercksen W, et al. Chemotherapy-induced peripheral neuropathy and impact on quality of life 6 months after treatment with chemotherapy. 

				Avan A, Postma TJ, Ceresa C, et al. Platinum-induced neurotoxicity and preventive strategies: past, present, and future. 

				Moore DH, Donnelly J, McGuire WP, et al. Limited access trial using amifostine for protection against cisplatin- and three-hour paclitaxel-induced neurotoxicity: a phase II study of the Gynecologic Oncology Group. 

				Tannock IF, Ahles TA, Ganz PA, et al. Cognitive impairment associated with chemotherapy for cancer: report of a workshop. 

				Hess L, Huang H, Robinson W, et al. Cognitive function during chemotherapy for front-line treatment of ovarian, primary peritoneal or fallopian tube cancer: a Gynecologic Oncology Group study. Gynecol Tulane Cancer Center at Tulane University School of Medicine Oncol. 2013;130(1):6-7.

Palliative care should address the unique symptom profile of gynecologic cancer and be tailored to individual socioeconomic environments.

August 2015 | Oncology & Biotech News

World GI Congress: New Data, New Hope

The Cost of Drugs in Cancer Care: A Story of Misalignment, With Necessary (Positive) Changes!

New Test Could Guide More Precise Treatment of GVHD

Palliative Care Issues in Gynecologic Cancer