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Sunday, April 13, 2014

BY CAROLYN B. HENDRICKS, MD

Center for Breast Health

Bethesda, Md.

 

I have been in a small or solo suburban medical oncology practice since 2001. My practice is breast cancer dedicated. I have terrific staff and phenomenal patients. I love it.

 

But right now, I am seriously considering closing my practice.

 

Why? Over the past several years, the increasing cost of chemotherapy drugs has risen and the reimbursement for chemotherapy has fallen to the point where my practice is at the tipping point. In addition to the high drug costs, giving chemotherapy is complex and expensive. In my practice, it requires two highly trained nurses, a nurse practitioner, and a really top notch biller. Because chemotherapy drug prices are tied directly to how much chemotherapy is purchased, small practices like mine -- whether urban, suburban, or rural -- pay more for the same chemotherapy drugs than larger practices do. But we still have the same safety and staffing requirements.

 

In 2013, I purchased $3.4 million in chemotherapy, about average for oncologists, but in my case that high cost is due to a handful of very expensive drugs for breast cancer.

 

I have worked hard to increase my practice efficiency including a complete transition to an electronic health record, but quality oncology care is time intensive, so it isn’t possible to dramatically increase the number of new patients that I see.  I won’t compromise on quality.

 

For the past two years, my practice has lost a significant amount of revenue. Oncologists like me purchase chemotherapy on credit and then scramble to get reimbursed. I have assumed a significant amount of debt (too much to not publicly) and had a significant reduction in my own income down to the same amount I took home 10 years ago. 

 

Since it went into effect in April 2013, the sequester has resulted in a loss of $12,000 in Medicare revenue for my practice -- that amounts to one payroll or one month’s rent.

 

I experienced a significant staff shortage last year because of overlapping staff maternity leaves, and ended up sending my patients to my local hospital for three months. They received good care but were very distressed to receive much higher bills for their out-of-pocket expenses than for the exact same chemotherapy administered in my office. 

 

What are my options? Purchase, merge, sell, or close?

 

I negotiated with an academic medical center for a year and a half for purchase, merger, or sale of my practice.  Last month, they withdrew from the negotiations explaining that the economic climate for outpatient oncology is too precarious in Maryland.

 

I am considering attempting merger with other oncology groups, locally and regionally. It is a daunting task. I am also seriously considering closing my practice. Both of those decisions would have a very significant impact on my staff and patients. I really want to preserve the small, nurturing, and high-quality practice environment that I have cultivated. 

 

I sincerely hope that the changes outlined in ASCO’s State of Cancer Care in America report will be enacted.  Small practices like mine would benefit directly from:

  1. lifting the sequester;
  2. introduction of new payment models that don’t rely on buying and billing for expensive chemotherapy drugs, and
  3. an eventual transition to payment for quality and not quantity or location of care be it urban, suburban or rural. 

These changes would go a long way towards alleviating the workforce issues I have described -- that is, early retirement, burnout, increasing scarcity of oncologists in rural areas, and the steep decline in the number of small practices. Hopefully, these changes will occur rapidly enough that I won’t have to close my practice doors in the near future.

 

Adapted from remarks delivered at a Capitol Hill briefing in March where the American Society of Clinical Oncology released  its comprehensive report on the state of cancer care in the U.S., “Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis” (OT 4/10/14 issue)


Monday, January 13, 2014

I reviewed with great interest the recent article on the AACR’s 2013 Cancer Progress Report highlighting advances in immunotherapy (OT, 10/25/13 issue). As a clinician who closely follows this area of research, I share the AACR’s concern about the current oncology research funding crisis, and I echo AACR’s call for greater patient participation in cancer clinical trials. Such participation is crucial to the continued advancement and adoption of immunotherapy, a treatment modality that has been shown to produce meaningful and durable responses in a subset of patients, and which is “beginning to revolutionize the treatment of certain cancers,” in the words of AACR President Charles L. Sawyers, MD.

 

Whereas immunotherapeutic agents such as ipilimumab and interleukin-2 (IL-2) are thought to modulate “natural immunity,” the nature of their clinical effector process is not well understood. When we have therapies capable of durable response but such benefits are limited to a select group of patients, greater effort needs to be applied to identifying the predictive and prognostic markers of response. Understanding such biomarkers will enhance response rates (i.e., by enabling selection of appropriate patients) and limit toxicity (i.e., by facilitating appropriate dosing). In addition, biomarker studies tied to clinical trials will provide a basis for rational combinations.

 

Registration databases have been established for ipilimumab and IL-2, and clinical trials such as the ongoing PROCLIVITY program are advancing understanding of combination immunotherapy. However, the lack of significant funding outside of industry has limited understanding of biomarkers. While the registration databases are collecting valuable clinical information, they lack annotated tissue samples needed for biomarker studies. Ideally, every patient undergoing immunotherapy should receive immunologic assessments just as they have CT scans and other blood tests. Yet we lack the basic understanding that would allow immunologic assessments. Consequently, we are administering costly therapies to patients who may only experience toxicity.

 

Policymakers should increase support for translational research focused on understanding the expanding number of tools available to the treating clinician. One such tool is the immune score, a proposed classification system that quantifies the density and location of immune cells within a tumor, and which purportedly has a prognostic value exceeding that of the AJCC/UICC TNM-classification.1 The immune score is emblematic of the huge strides we have made in translational research, and may eventually be regarded as the immunotherapeutic equivalent of molecular targeting, which has led the way to personalized cancer care. Indeed, enhanced understanding of these potentially valuable tools may someday lead us to the era of personalized immunotherapy.

 

Gregory A. Daniels, MD, PhD

Moores UCSD Cancer Center

La Jolla, CA

 

Reference

       1. Galon J, Pages F, Marincola FM, et al. The immune score as a new possible approach for the classification of cancer. J Transl Med. 2012;10:1. http://www.translational-medicine.com/content/10/1/1


Wednesday, January 08, 2014

I am writing to salute Dr. Jedd Wolchok for his inspirational “Voices” column in the November 10 issue, and to echo his call for more clinical trials to evaluate combination immunotherapies.

 

As he points out, the rapid and durable responses observed in patients with melanoma and kidney cancers suggest a potential role for combination immunotherapy in treating other types of cancer, and I applaud efforts to pursue this approach more broadly. Numerous research initiatives are investigating the purported synergistic effects of combining immunotherapeutic agents with molecularly targeted therapies, PD-1 antibodies, or other checkpoint inhibitors as a means to improve outcomes and potentially individualize anticancer treatment. Other investigations are evaluating whether sequential treatment with two complementary immunotherapies may yield improvements in clinical endpoints over those seen with single-agent immunotherapy, while preserving other downstream treatment options.

 

While other cancer types appear to be fertile ground for investigating combination immunotherapy, much remains to be learned about this approach in advanced melanoma and kidney cancer. That is the rationale for the PROCLIVITY clinical trial program, which is investigating the use of high-dose interleukin-2 (HD IL-2) in combination with various inhibitors of BRAF, CTLA4, and tyrosine kinase in patients with metastatic melanoma or metastatic renal cell carcinoma. The PROCLIVITY investigators aim to assess whether HD IL-2-based combination therapy provides a more robust and durable response, compared with HD IL-2 monotherapy, and to identify the optimal sequencing of individual agents in combination regimens.

 

Findings from these and other trials may help refine the administration of combination immunotherapy as a means to improve treatment outcomes across various cancer types. To paraphrase Dr. Wolchok and his patient, Mary Elizabeth Williams, we can and should be making these malignancies more treatable for all cancer patients.

 

Joseph I. Clark, MD, FACP

Professor of Medicine

Loyola University Stritch School of Medicine

Maywood, Illinois


Wednesday, January 08, 2014

Two articles caught my attention in the Nov. 25 issue -- one, about evidence that whole brain irradiation can be eliminated in patients with CNS lymphoma (here); and the other that hippocampus-sparing radiotherapy supports preservation of memory (here). The latter article contains the word PCI -- i.e., prophylactic cranial irradiation.

 

Briefly, prophylactic cranial irradiation was introduced several decades ago to reduce the risk of metastatic disease in the brain in patients with limited small-cell lung cancer, whose cancer is in complete remission after treatment with chemotherapy and thoracic irradiation. Meta-analysis of trials have shown that prophylactic cranial irradiation can improve overall survival at three years from 15 percent to 18 percent and 15 percent to 20 percent.1,2 However, because this prophylaxis is associated with substantial side effects and impact on quality of life, the question arises whether the benefits outweigh the risks. The prophylaxis, though, has for years been offered to patients with limited small-cell lung cancer.

 

Regarding hippocampus sparing, though: Although it may help preserve memory, the result is not absolute and does not prevent other side effects of prophylactic cranial irradiation.

 

High response rates have been reported in patients with small-cell lung cancer with various systemic therapies.3 It was encouraging to read in the OT article that chemo-immune therapy can replace whole brain irradiation in CNS lymphoma.

 

Prophylactic cranial irradiation was brought to my attention in the middle of last year and, reviewing treatment for limited small cell lung cancer, it is noteworthy that little has changed in the past 20 years. Moreover, the question arises whether patients always receive an informed consent at the time of discussion of this prophylaxis. Among survivors are patients who declined the prophylaxis and who were treated with effective local control at diagnosis of brain metastatic disease.

 

In changes to therapy, it is crucial to ascertain that systemic upfront therapy is adequate.

 

References

1. Arriagada et al: Annals of Oncology 2002;13:748-754.

2.  Auperin et al: NEJM 1999;341:476-484.

3.  Crivellari et al: The Oncologist 2007;12:79-89.

 

Marlies Van Hoef, MD, PhD, MBA

mvanhoef@transplantcreations.com


Sunday, December 01, 2013

Massimo Cristofanilli

By Massimo Cristofanilli, MD

Director, Jefferson Breast Care Center, Kimmel Cancer Center and Thomas Jefferson University and Hospitals

 

In recent years we have seen substantial research into the role of the HER2 gene and development of HER2-targeted therapies to treat breast cancer. The HER2 story has become one of the shining examples of progress toward personalized medicine for our patients.

 

In October, the American Society of Clinical Oncology and the College of American Pathologists issued a new guideline on the use of standard laboratory HER2 testing with immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). IHC identifies the relative amount of protein expression of the HER2 gene while FISH reveals the presence and abundance of the gene itself. These tests are recommended because they are considered to be the most evidence-based. The new guideline is expected to reduce some of the confusion when physicians are faced with equivocal IHC and FISH results.

 

In recent years, we have also learned through genomics that breast cancer is a highly heterogeneous disease. IHC and FISH cannot identify molecular subtypes of breast cancer and the numerous pathways that cancers hijack to promote their growth and metastasis. It was disappointing to read the statement from the guideline committee that “there is insufficient evidence to support use of mRNA or DNA microarray assays to determine HER2 status in unselected patients.”

 

This is a missed opportunity. Hopefully we will not have to wait another five years to consider genomic profiling of breast cancer as a standard of practice. I believe most oncologists and pathologists will agree that the current guideline and the new update represent the minimum standard pathology assessment required for selection of patient candidates for HER-2 targeted therapies and these guidelines are usually developed on the bases of data and outcomes collected in a retrospective fashion.

 

Without the use in clinical practice of mRNA or DNA microarray assays, tumor heterogeneity remains a major challenge for clinicians. Tumor complexity will never be completely captured by single gene testing. Tumor heterogeneity associated with the availability of multiple targeted agents requires that we continue to investigate and apply more modern molecular biology and diagnostic technologies to our patients.

 

At our institution and in my practice, I routinely employ molecular subtyping with breast cancer patients, because it provides more information and better guidance than IHC/FISH alone. The newer molecular tests excluded from the guideline have great promise to complement and possibly replace standard diagnostics. While it is true that we lack confirmatory data from prospective, comparative clinical trials, substantial evidence from recently published and emerging new studies is available for consideration by practicing physicians.

 

These new studies show that molecular subtyping of breast cancer more accurately classifies breast cancer into one of four molecular subtypes – Luminal A, Luminal B, HER2-type, and Basal-type – while also providing better guidance about neoadjuvant and adjuvant treatment and risk recurrence. One can argue that genomics is still coming of age, but it is maturing rapidly. There are several studies worth noting that were not discussed in the new guideline:

 

Molecular subtyping of early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy – and who should not have to endure its side effects and potential longer-term complications. A study published in July 2013 in Breast Cancer Research and Treatment analyzed data from four clinical trials and 437 patients using genomic testing (MammaPrint and BluePrint). The researchers found a group of 90 women (21%) who showed little if any benefit from chemotherapy and who had good outcomes five years after surgery. That group could not be identified using IHC or FISH. They had a five-year metastases-free survival rate of 93 percent -- the best of any group in the study.

 

Another effort, the MINDACT trial, is a multi-center, prospective, Phase III randomized study comparing MammaPrint with a common clinical-pathological prognostic tool (Adjuvant! Online) in selecting patients with negative or one to three positive nodes for adjuvant chemotherapy in breast cancer. Recruitment has finished with 6,700 breast cancer patients enrolled from 119 participating institutions in nine European Countries. It is anticipated that the results will further validate this genomic test as an important prognostic and predictive tool in cancer treatment.

 

The primary objectives of MINDACT are to confirm that breast cancer patients with a “low risk” molecular prognosis by MammaPrint and “high risk” clinical prognosis can be safely spared chemotherapy without affecting Distant Metastases Free Survival (DMFS), and to compare different chemotherapy regimens and hormonal therapy.

 

The I-SPY II Breast Cancer Clinical Trial is a model for integrating biomarkers, adaptive trial designs and bioinformatics to quickly, inexpensively, and simultaneously test multiple drug candidates. The goal is to help accelerate the development and commercialization of compounds for locally advanced breast cancer.

 

Finally, the Neoadjuvant Breast Registry – Symphony Trial (NBRST) (pronounced “N-breast”) -- is a prospective neoadjuvant registry trial linking four commercially available tests (MammaPrint, BluePrint, TargetPrint, and TheraPrint) and possible additional gene-expression profiles of interest to treatment response, recurrence-free survival (RFS), and DMFS.

 

For this project, approximately 20 to 30 institutions in the U.S. are contributing clinical patient data from enrolled patients after genomic testing has been successfully performed and the patient has started neoadjuvant therapy. New results will be presented this month at the San Antonio Breast Cancer Symposium (SABCS).

 

Research by myself and others at numerous leading institutions – some of it also to be presented at SABCS -- indicates that in a significant number of cases, molecular subtyping results in the reclassification of HER2 and other breast cancers types (as identified by IHC/FISH) into different subtypes. Molecular subtyping provides more information about both recurrence risk and treatment choices.

 

Targeted therapies cannot be effective unless they reach patients with the right cancer. Gene-expression profiling more accurately reflects tumor biology by evaluating not only a single gene, but also dependent and related pathways.

 

The question for oncologists is should they simply follow this new guideline, or along with this guideline, should they consider more recent scientific publications and presentations about the greater accuracy and utility of molecular subtyping? I believe the latter is a better course.

 

//////////////////////////////////////////////////

 

Recommendation of the New ASCO/CAP Report

The ASCO/CAP Guideline for HER2 Testing recommendation is as follows: “The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing. (J Clin Oncol doi: 10.1200/JCO.2013.50.9984  and Arch Pathol Lab Med doi: 10.5858/arpa.2013-0953-SA)