The rise of oral anticancer agents is revolutionizing cancer treatment for both patients and cancer care providers. Patients can take their medications in the comfort of their own homes without the need for needles, long stints in infusion chairs or intensive nursing oversight. They often require fewer office visits and feel a greater sense of control of their treatment.

But oral chemotherapy and targeted drugs taken orally are often no less potent than infused chemotherapies, and patients still experience side effects that need to be managed. UC Davis Comprehensive Cancer Center has started a program to help monitor patients on these medications.

The Medication Adherence Program, created in 2013 by the UC Davis Departments of Pharmacy and Internal Medicine, and the Division of Hematology and Oncology, is designed to ensure patients receiving any oral anticancer drug stick to their treatment regimens to safely maximize the drugs’ effectiveness and minimize or manage side effects.

A pilot study involving 44 patients enrolled in the program demonstrated that 92% of participants adhered to their regimens, and the UC Davis Comprehensive Cancer Center now employs a full-time pharmacist to administer the program to all interested patients.

The pilot program design was the result of fusing various components of different pharmacy services at UC Davis. To ensure patients understand their oral chemotherapy regimens, for example, the program borrowed a patient education component from the UC Davis Anticoagulation Clinic, which has demonstrated that one-on-one counseling is effective in helping patients adhere to medications for anticoagulation, hypertension, congestive heart failure, and related conditions. The pilot also was influenced by the UC Davis Pharmacy Prescription Renewal Clinic. Implemented at the Cancer Center in 2013, the clinic served as an invaluable model for designing a standardized and efficient method for processing prescription renewals and prior authorization requests.

Oral anticancer agents span the spectrum of hormonal therapies, molecularly targeted therapies, and cytotoxic chemotherapy. In addition, many traditional chemotherapy drugs are also being developed in oral formulations, allowing for more continuous exposure of the drug in the patient over time, which can be more effective and less toxic.

However, studies show adherence to oral chemotherapy drugs varies from 16% to 100% in adult populations and these rates often drop over time with longer treatment regimens. Many patients on oral anticancer drugs either stop taking them because of unwanted side effects, or forget to take them regularly. Stopping the medication or not following the directions correctly can affect treatment efficacy, produce misleading results, and cause higher mortality. It’s important that oncologists have confidence the drug is being taken.

The Medical Adherence Program uses education, monitoring, and one-on-one counseling to help patients manage their medication regimen and help oncologists determine the effectiveness of prescribed cancer treatments.

Pharmacists call patients monthly, asking them how many pills they have left, when they will be back at the cancer center for refills, or whether they would like their medications mailed. They ask about side effects and talk about what to expect. Pharmacists go over drug regimens and offer practical tips, such as how to maintain a medication calendar or handle a missed dose.

Often the pharmacist will follow up by contacting the patient’s oncologist to discuss a possible medication change when symptoms or side effects warrant. Patients enrolled in the program also can make an appointment with a pharmacist or a nurse practitioner at any time to ask a question about their drug regimens.

Patients enrolled in the program say they like the extra layer of protection the program affords them. One 71-year-old patient with metastatic kidney cancer said he appreciates the calls and reminders because his medication regimen already is complicated, with oral chemotherapy in addition to 11 additional medications for other health conditions.

And at UC Davis, where many patients travel as many as 100 miles for cancer care, the program provides a sense of security. Said one 80-year-old metastatic breast cancer patient who lives nearly 60 miles outside of Sacramento, “just knowing someone is checking up on me is comforting.”

The Medical Adherence Program also works with medical insurance companies to ensure patients have access to the drugs they need in a timely manner. Unlike coverage for other medications, administration of insurance benefits for oral chemotherapy agents can be complex, requiring longer prior authorization processes, payments of higher deductibles, and additional steps that can often delay access to critical medications. The pilot program dedicates staff members to serve as liaisons between the patient and the insurance company to expedite medication approvals and to find solutions for patients if they are unable to cover the cost. Staff will contact various resources on the patient’s behalf to fund the medication if the patient is uninsured or unable to make the copayment.

Articles

The rise of oral anticancer agents is revolutionizing cancer treatment for both patients and cancer care providers. Patients can take their medications in the comfort of their own homes without the need for needles, long stints in infusion chairs or intensive nursing oversight.

Oncology Pharmacy Program Ensures Medication Adherence

		Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC

		Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates

In hematology, including in lymphoma, circulating clonal cells are part of the disease, including in Hodgkin lymphoma, as we showed recently.

 Circulating tumor cells (CTCs) in hematology help us for diagnostic purposes, but also to evaluate response as a tracer of depth of remission either by flow negative complete remission (CR) in chronic lymphocytic leukemia or molecular CR in lymphomas or leukemia, which likely will become the next endpoint in most lymphoproliferative disorders.

There is now also clear evidence of shed naked clonal DNA representative of the tumor that can be used for the same purpose and predict early recurrence. A liquid biopsy, or blood sample, can also provide the genetic landscape of all cancerous lesions (primary and metastases), as well as offering the opportunity to systematically track genomic evolution.

The first description of CTCs was made in 1869, but more recent significant technical steps forward have dramatically helped our ability to detect and isolate those cells. CTCs have now been documented in epithelial tumors, particularly in breast,

CTCs in peripheral blood originate from solid tumors and are involved in the process of hematogenous metastatic spread to distant sites for the establishment of secondary foci of disease. They have been associated with outcome reflecting tumor burden and invasiveness of the disease. More recently, studies are going beyond detection and enumeration, exploring the CTCs as a means to better understand the mechanisms of tumorigenesis, invasion, metastasis, and the value of CTC characterization for prognosis and tailoring of treatment.

CTCs can allow for early detection of recurrence but could obviously be a precious tool for cancer screening far beyond standard screening technology that is now routinely used. CTCs, which are relatively rare and require sensitive collection and enrichment technology

 provide information at both the genetic and cellular level. However, cell-free tumor DNA is emerging as an effective alternative to CTCs, with the benefits of easier collection and analysis.

An example of clinical implementation of CTCs in breast cancer from a large multicenter study was recently reported in Lancet Oncology.

 Interestingly, a detection of at least one CTC (65% of the patient population) impacted progression-free survival (PFS). However, when they increased the threshold to a CTC count of 5 per 7.5 mL or higher at baseline, this became a significant predictor for both PFS and overall survival. In addition, the changes on treatment after 6 to 8 weeks had significant impact on outcome. Finally, there were strong correlations between the burden of CTCs and performance status, tumor burden, and bone and liver metastases. CTCs were much better than conventional tumors markers (CEA and CA-15.3) at baseline and during therapy to predict outcome.

One of the most promising aspects of CTCs and the emergence of modern CTC technologies is enabling serial assessments to be undertaken at multiple time points along a patient’s cancer journey, offering new capabilities for pharmacodynamic, prognostic, predictive, and intermediate endpoint biomarker studies. Additional validation is needed, but CTCs seem to reflect the original tumor heterogeneity. Technology looking at ex vivo growth for potential drug screening is being developed,

 though I believe the ability to look at dynamic changes in vivo while a patient receives a novel therapy, for example, might be more relevant and useful to detect response or resistance. Given the difficulties encountered from a regulatory standpoint, as well as practical and logistical issues when one tries to add correlative studies in clinical trials, the impact CTCs could have and will have is truly amazing. I regularly write in this column about the need to push forward and embrace precision medicine in oncology. There is no doubt that CTCs as liquid biopsies will help fill a big piece of the puzzle to help in this endeavor!

			Gharbaran R, Park J, Kim C, Goy A, Suh KS. Circulating tumor cells in Hodgkin’s lymphoma - a review of the spread of HL tumor cells or their putative precursors by lymphatic and hematogenous means, and their prognostic significance. Crit Rev Oncol Hematol. 2014;89(3):404-417.

			Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781-791.

			Sastre J, Maestro ML, Puente J, et al. Circulating tumor cells in colorectal cancer: correlation with clinical and pathological variables. Ann Oncol. 2008;19(5):935-938.

			Schilling D, Todenhöfer T, Hennenlotter J, et al. Isolated, disseminated and circulating tumour cells in prostate cancer [published online July 10, 2012]. Nat Rev Urol. doi:10.1038/nrurol.2012.136.

			Krebs MG, Metcalf RL, Carter L, et al. Molecular analysis of circulating tumour cells-biology and biomarkers. Nat Rev Clin Oncol. 2014;11(3):129-144.

			Alix-Panabières C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014;14(9):623-631.

			Bidard FC, Peeters DJ, Fehm T, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;15(4):406-414.

			Alderton GK. Therapy: using CTCs to test drug sensitivity. Nat Rev Cancer. 2014;14(9):576.

How CTCs and Circulating Naked Tumor DNA-as Liquid Biopsies-Will Transform Diagnostic and Management of Oncology Patients

The Invisible Revolution

	Assistant Professor, Division of Oncology

	University of Washington School of Medicine

	Assistant Member, Clinical Research Division

Colorectal cancer (CRC) is increasingly being recognized as a heterogeneous disease, with molecular features defining emerging subtypes. Understanding which tests to order in which cases can better direct care for our patients. Increasingly, panel testing has advantages over individual genetic testing.

Approximately 15% of CRCs will have microsatellite instability (MSI). Tumors with MSI have a better prognosis overall. In addition, MSI can influence treatment decisions. Retrospective data show that individuals with stage II (T3-4 N0 M0) tumors with MSI have no benefit (or even detriment) from adjuvant 5-fluorouracil chemotherapy. On the other hand, microsatellite stable (MSS) patients have a trend toward a survival benefit. For high-risk stage II patients, the recommendation is to consider adjuvant chemotherapy in MSS cases only.

One-third of MSI cases are due to a germline genetic change in the mismatch repair proteins; the remaining cases are due to sporadic changes in the tumor. The hereditary cases are referred to as Lynch syndrome (LS; previously referred to has Hereditary Non-polyposis Colon Cancer).

Patients with LS have up to a 90% lifetime risk of CRC, in addition to increased risk of endometrial, genitourinary, pancreatic, and other cancers. Screening for LS was previously recommended based on clinical criteria (the Amsterdam and/or Bethesda criteria).

Now, however, universal screening for LS is the recommendation of the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group and other groups. Furthermore, it is the recommendation that patients with CRC undergo both polymerase chain reaction (PCR)-based MSI testing and immunohistochemistry (IHC) screening tests. The PCR-based test evaluates changes in areas of repeated DNA sequences, while IHC utilizes tumor tissue staining to evaluate for loss of expression of the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). A universal screening strategy has been found to be cost-effective because recognizing undiagnosed LS patients may prevent future cancer occurrences in the individual and their family members. This strategy has been adopted by Seattle Cancer Care Alliance in the multidisciplinary Colorectal Cancer Specialty Clinic.

In summary, MSI and IHC are useful screening tools for hereditary cancer and MSI is recognized as both a prognostic and predictive marker for CRC treatment.

In stage IV CRC, KRAS serves as a biomarker for determining benefit from cetuximab and panitumumab, therapies that target EGFR. The manner and extent of mutation testing is key to interpreting results. Standard methods evaluate codons 12 and 13 of exon 2. However, there is evidence from the PRIME (N Engl J Med. 2013;369[11]:1023-1034) and FIRE-3 (Lancet Oncol. 2014;15[10]:1065-1075) trials of clinical benefit from also testing exons 3 and 4 of KRAS, so as not to miss rare mutations that can also predict lack of benefit from anti-EGFR therapy. These retrospective analyses note that NRAS mutations in exons 2 to 4 additionally are predictive. BRAF, which is also in the EGFR pathway, appears to be a prognostic feature, but is not useful for anti-EGFR treatment prediction. Thus, the newer strategy that is advocated is “expanded RAS” testing, including sequencing of exons 2, 3, and 4 of both KRAS and NRAS. Given the expense of individual genetic tests, panel testing is a better streamlined approach to mutation analysis.

	Cheaper, Faster Screening With Panel Testing

With the advent of better testing technology, next-generation sequencing has allowed for cheaper and faster genetic screening of multiple genes simultaneously. This can be used both on tumor tissue (to screen for somatic changes) or germline DNA (to screen for hereditary gene changes and/or genetic changes that may influence treatment response). Developed at the University of Washington (UW), the UW-OncoPlex panel is a 194-gene panel of genes with known or emerging relevance to cancer development. UW-OncoPlex is indicated for tumors of any type where driver genes are of interest.

Notable for CRC, the panel can be used for expanded RAS testing. It includes testing of the four mismatch repair genes, as well as all exons in KRAS, NRAS, and BRAF. Novel technologies are on the horizon for MSI analysis. The ColoSeq and BROCA panels, also from UW, have been designed to analyze a wide variety of germline gene mutations to screen for hereditary syndromes.

In summary, CRC testing technologies and strategies have become more complex. However, with an understanding of what to test in which situations, these molecular tests can personalize care for our patients. The physicians at SCCA welcome new patients to be seen in the Colorectal Cancer Specialty Clinic and, if there is a concern for a hereditary syndrome, the Gastrointestinal Cancer Prevention Program.

		Contact Seattle Cancer Care Alliance at (206) 288-SCCA (7222).

		Contact MEDCON, the toll-free education and referral service at the UW School of Medicine at (800) 326-5300 or medcon@washington.edu. The phone line is open 24 hours a day, seven days a week. A MEDCON operator will connect you with the appropriate expert.

November 2014 | Oncology & Biotech News

Oncology Pharmacy Program Ensures Medication Adherence

The Invisible Revolution

Colorectal Cancer: Right Test, Right Time