I often find myself in awe of physicians who travel around the world seeking out the 2 most desirable aspects of medicine—patients in desperate need of medical care and patients with genuinely novel pathology.

The downside of this pursuit is putting yourself in harm’s way, through exposure to endemic infections or dangerous sociopolitical situations. If there were a place where it was possible to safely deliver care to those truly in need and encounter fascinating clinical pathology, then that would be an ideal location to practice medicine. Fortunately, I have found this medical Shangri-La at Boston Medical Center (BMC). As the running joke goes, patients step off the plane at Logan Airport, ask for the nearest hospital, and arrive at BMC. While we may not be the closest hospital to Logan physically, we certainly are the nearest hospital to these patients philosophically. On principle: we don’t turn anyone away.

As a fellow, my first clinic patient was a young man from Honduras who appeared fatigued. Upon examining him, I noted that he had a large spleen. As it turned out, the patient was coinfected with human immunodeficiency virus and leishmaniasis; his lab work also showed pancytopenia.

There was a serious concern that the patient had visceral leishmaniasis. A bone marrow aspirate and biopsy were indicated to help confirm the diagnosis and determine the etiology of his pancytopenia. Before long, we had the pathology results, which revealed leishmania promastigotes. The patient was treated with antiretroviral therapy and liposomal amphotericin B. As of this writing, he is still receiving maintenance amphotericin B treatments on an outpatient basis.

Later in the month, I had the opportunity to make a rare diagnosis, even for a hematologist. A middle-aged Haitian man presented with pancytopenia. His initial lab work revealed that he had a non-autoimmune hemolytic anemia as well as severe iron deficiency. During a return visit, the patient was asked about any source of bleeding and he confirmed that he had been suffering from hematuria for several months. Fluorescein-labeled proaerolysin variant testing confirmed the suspected diagnosis: paroxysmal nocturnal hemoglobinuria (PNH). Because of the large clone of CD59 deficient cells (60%), the patient was initiated on eculizumab therapy. Since beginning therapy, he has shown a vast improvement in his symptoms and cytopenias.

Each of these patients immigrated to the United States in search of a better life. While here, both patients were diagnosed with incurable diseases. Although the first patient may have been diagnosed in his home country, it is unlikely that he would have been able to receive the maintenance amphotericin B that is keeping him alive. The second patient never would have been diagnosed with PNH, let alone received costly infusions of eculizumab on a biweekly basis.

These cases were interesting from a clinical standpoint, but were made even more important by our ability to intervene and improve the length and quality of life for both patients. This is something we would not have been capable of if we had encountered these men in their respective countries.

Later in the year, I rotated on the inpatient service. Here, I had the pleasure of meeting 2 male Haitian patients with adult t-cell leukemia/lymphoma (ATLL) who presented classically with profound hypercalcemia. As my attending at the time said, “ATLL usually comes in threes.” I cannot imagine another place in this country that sees ATLL “in threes”—except, perhaps, Kings County Hospital in Brooklyn.

One of these men was older and had an aggressive lymphomatous subtype. He had comorbid conditions and had failed first-line therapy with zidovudine/interferon. He completed 1 treatment cycle of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with little response, and passed away after several hospital admissions.

The other gentleman was younger, and his course was particularly complex and heartbreaking because he was a Jehovah’s Witness. Consistent with his religious wishes, he refused blood products. This limited our supportive care and therapeutic options. Initial therapy with zidovudine/interferon was aborted due to cytopenias. Ultimately, he was started on CHOP and was able to tolerate 5 cycles before succumbing to his disease.

Our impact on these patients was not as obvious. They each presented with severe disease that likely would have ended their life immediately if they presented in Haiti, due to severe, refractory hypercalcemia. The first patient lived for several months with his disease but never achieved a durable remission. The second patient did not achieve a durable remission either, but lived for almost a year with his disease. Although the desired outcome of a cure or durable remission was not achieved for either of these patients, it was satisfying to be able to care for them and provide them the best chance of survival. This is the particularly gratifying part of working at Boston Medical Center. We take care of very sick patients, who have limited resources, in a fully state-of-the- art academic facility. Even when we fail, we know we provided our international patients with the best that modern medicine has to offer.

For a truly international medical experience, you don’t need to buy a ticket to South America, Africa, or the Far East. You will not need an active passport or a series of exotic vaccinations. You can simply hop on a plane to Boston and ask for the nearest hospital for those in need. You will be taken to Boston Medical Center, and will not be turned away.

Articles

I often find myself in awe of physicians who travel around the world seeking out the 2 most desirable aspects of medicine-patients in desperate need of medical care and patients with genuinely novel pathology

An International Experience at Home

I have no basic science research experience, but when the opportunity to join a laboratory project was offered to me as a clinical fellow, I joined simply because I was interested in the experience and what I could potentially learn from it. Currently, I am involved in a research project assessing whether or not microRNAs (miRNAs) can predict brain metastases in patients with triple-negative and HER2-positive breast cancer. The question originated from observations in the clinic that brain metastases are more common in patients with this subtype of breast cancer.

The concept of miRNA is relatively new. MiRNAs are short, non-encoding ribonucleic acids (RNAs) that regulate the transcription of messenger RNA. As I began working in the lab, I quickly gained insight into the other side of medicine: the laboratory! There, I extracted total RNA with pipettes for accurate measurement of different reagents and used a stopwatch to determine the multiple incubation periods in varying temperatures. As with any scientific endeavor, challenges have arisen. Difficulties obtaining older tissue samples is one. Obtaining suboptimal final products on polymerase chain reaction after several hours of working is another. However, approaching these challenges with perseverance and resourcefulness has made this project move forward, albeit slowly.

I do not have results to share yet, but later goals include identifying the individual targets and mechanisms of miRNAs that give rise to brain metastases. Future implications include identifying higher-risk patients by using miRNA as a biomarker in serum or tissue, and perhaps using these as targets for treatment. It’s bedside to bench and back again! Reverse translational medicine is not novel. Perhaps the best examples in oncology are those involving the epidermal growth factor receptor (EGFR).

In May of 2003, the FDA approved gefitinib, an orally administered EGFR tyrosine kinase inhibitor, as therapy for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who were refractory to established cancer treatments (both a platinum drug and docetaxel). Tumor response rate was used as a surrogate marker. The overall response rate to gefitinib was around 10%.

In other words, most patients treated with gefitinib did not respond. However, in about 10% of patients, a dramatic and rapid response was observed. Subsequently, a phase 3 trial was designed to determine the survival advantage of gefitinib in the NSCLC population as a whole. The ISEL (Iressa Survival Evaluation in Lung Cancer) trial enrolled 1692 patients with previously treated, locally advanced, or metastatic NSCLC, and randomized the patients to gefitinib or placebo.

The results were disappointing. Gefitinib provided no significant survival advantage over placebo (5.6 months vs 5.1 months), although further analysis did reveal improved median survival in 2 subgroups in favor of the gefitinib arm: 1) never-smokers (8.9 months vs 6.1 months; P = .012), and 2) Asian patients (9.5 months vs 5.5 months; P = .01).

Following a second clinical trial that failed to demonstrate a survival benefit, the FDA revised the labeling for gefitinib in 2005. This limited the use of the drug to patients currently receiving and benefitting from, or who previously received and benefitted from, gefitinib.

Researchers were curious why gefitinib produced a survival advantage in particular subgroups (never-smokers and patients of Asian origin).

 For this reason, Lynch and colleagues examined the molecular mechanisms behind these results and noted somatic mutations in the tyrosine kinase domain of the EGFR gene in 8 of 9 patients with gefitinib-responsive lung cancer; such mutations were found in 0 of the 7 non-responders. The results of their work suggest that screening for such mutations in patients with lung cancer may help identify those who will respond to gefitinib.

 Other groups of investigators have published similar results independently.

The Iressa Pan-Asia Study (IPASS) was designed to compare gefitinib against carboplatin-paclitaxel as first-line treatment in clinically selected East Asian patients with advanced NSCLC. The patients were never-smokers or former light smokers, and therefore more likely to have EGFR mutations. EGFR mutation status was assessed in patients who consented to have their tumors checked for this and other biomarkers. EGFR mutation status could only be evaluated in 36% of patients. In the subgroup of patients who were positive for the EGFR mutation, progression-free survival (PFS) was significantly higher in those who received treatment with gefinitib rather than with carboplatin-paclitaxel (hazard ratio [HR], 0.48; P <.001). However, in the subgroup of patients without EGFR mutation, chemotherapy conferred a PFS benefit over gefitinib (HR, 2.85; P <.001).

Cetuximab and panitumumab are monoclonal antibodies that inhibit EGFR activation. Both cetixumab and panitumumab have demonstrated single-agent efficacy in metastatic colorectal cancer when compared against supportive care. However, response rates are low.

 Is it the EGFR status or the level of EGFR expression that predicts a response to one of these agents?

Chung et al reviewed medical records and identified 16 colorectal cancer patients who had irinotecan-based chemotherapy-refractory disease, were EGFR-negative, and received cetuximab in a non-research setting. An objective response was noted in 25% of these patients. The authors concluded that the current routine practice of using the results of EGFR immunohistochemistry testing for patient selection may exclude patients who could potentially benefit from anti-EGFR therapy with cetuximab.

If not the EGFR status, what factors predict clinical benefit from anti-EGFR inhibition? For the answer, a group of researchers further assessed the question in the lab. Lièvre et al hypothesized that genetic alterations in EGFR-related pathways affect the response to cetuximab. The researchers tested tumor specimens from 30 patients with cetuximab- treated metastatic colorectal cancer for EGFR copy number as well as mutations in the protein-coding genes KRAS, BRAF, and PIK3CA. Among the 11 patients who responded to cetuximab, none tested positive for a KRAS mutation. On the other hand, a KRAS mutation was detected in 13 of the 19 non-responders. It was concluded that the KRAS mutation bestows resistance to anti-EGFR therapy.

Based on these findings, Amado et al looked at the role of KRAS as a selection marker in chemotherapy-refractory metastatic colorectal cancer patients who enrolled in a phase 3 trial that compared panitumumab against supportive care. The investigation was done retrospectively. KRAS mutations in codons 12 and 13 were identified by real-time polymerase chain reaction testing conducted on formalinfixed, paraffin-embedded tumor sections collected for the trial. KRAS mutations were detected in 43% of patients. PFS, the primary end point of the trial, was significantly greater in the wild-type (WT), or nonmutated, KRAS population compared with that in the mutant KRAS population (12.3 weeks vs 7.4 weeks). Response rates were also much better in the WT-KRAS group (17% vs 0%). The authors concluded that WT-KRAS is required for panitumumab efficacy. In addition, the investigators noted, “These are the first results arising from a randomized, controlled trial showing that the state of a signaling molecule downstream of a target plays a crucial role in predicting clinical benefit to a targeted therapeutic.”

Similar findings were published in the same year by Karapetis et al, who retrospectively determined the KRAS status of patients who participated in the phase 3 CO.17 study. The CO.17 study’s primary objective was to assess the effect of cetuximab on overall survival (OS) and PFS in patients with advanced colorectal cancer who had failed multiple lines of chemotherapy. The retrospective analysis by Karapetis et al showed that in WT-KRAS tumors, treatment with cetuximab improved OS (9.5 months vs 4.8 months) and PFS (3.7 months vs 1.9 months) compared with best supportive care. In the mutant KRAS population, cetuximab provided no benefit over supportive care.

The results of these studies were practice changing. Based on these retrospective analyses, the FDA changed the product labels of cetuximab and panitumumab in 2009.

 My research project is currently not as ambitious, and I am definitely not going to be a physician-scientist after this experience. However, it is exciting to know that I may be able to contribute to the growing pool of molecular knowledge in oncology.

			Information for healthcare professionals: gefitinib (marketed as Iressa). FDA website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/ ucm085197.htm. Accessed July 21, 2014.

			Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced nonsmall- cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). 

			Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-smallcell lung cancer to gefitinib. 

			Ledford H. Translational research: the full cycle. 

			Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. 

			Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. 

			Lièvre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. 

			Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. 

			Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced cancer. 

			Cetuximab (Erbitux) and panitumumab (Vectibix). FDA website. http:// www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProducts andTobacco/CDER/ucm172905.htm. Accessed July 27, 2014.

Based on a current laboratory research project, Zarah Dulce
F. Lucas, MD, discusses microRNAs and their potential to
predict brain metastases in patients with triple-negative and
HER2-positive breast cancer.

From Bedside to Bench

On a recent day in hematology clinic, I stood dutifully by my attending as he sorted through bone marrow slides. Upon opening the slide carrier he sighed and asked, “Why did they do all these unnecessary stains? It just drives up the cost, and that affects the patient.”

Although this comment may have seemed offhand, it was just as instructive to me as learning to read an aspirate. Everywhere around us, people are talking about costs in healthcare. The growing concern about soaring expenditures in oncology is hardly news: Google “rising cost of cancer care,” and you’ll find nearly 23 million search results. The hottest topics in medicine today are “cost-conscious” and “high-value” care.

Costs in oncology are rising faster than costs in many other sectors of medicine: cancer care costs increased from $72 billion in 2004 to $125 billion in 2010, and are projected to reach $173 billion by 2020.

 The increasing number of new cancer cases, the costs of emerging therapies, survivorship care, and unnecessary or ineffective testing are all important factors.

Despite advances in cancer prevention, by 2030 the number of new US cancer cases is expected to increase by 45%—from 1.6 million to 2.

 million cases annually—driven largely by our nation’s rapidly aging population.

 Although targeted drugs and immunotherapies show great promise, they are extremely expensive. Eleven of the 12 cancer drugs approved by the FDA in 2012 cost more than $100,000 per year.

 The use of novel cancer therapies in combination with other drugs is costly, even for those who are insured, and high costsharing has already demonstrated negative impacts on medication adherence and health outcomes.

The costs of cancer survivorship also play an emerging role. As care improves, so does survivorship, and currently there are 14.5 million survivors in the United States

 However, it is important to recognize that in addition to the possibility that cancer may recur, survivors are at risk for treatmentrelated comorbidities such as diabetes and cardiovascular disease.

For this reason, multiple healthcare professionals may play a role in a patient’s care, which can affect overall costs of care. One study estimated the economic burden of survivorship to be more than $16,000 annually per patient.

	Discussing “Financial Toxicity”: Is It Equivalent to “Do No Harm?”

Unnecessary testing contributes to excessive costs as well, and may be harmful to a patient. A recent study analyzing outcomes in lung cancer patients demonstrated that physicians who failed to follow established clinical guidelines when providing care to their patients used more invasive testing and had higher rates of complications.

A 2009 guidance statement by the American Society of Clinical Oncology (ASCO) about the overall cost of cancer care advised that physicians “must understand the unique needs of each patient when making treatment decisions, including consideration of out-of-pocket costs.”

 This sentiment was echoed in a 2013 Institute of Medicine report which recommended that oncologists “provide patients and their families with understandable information about cancer prognosis, treatment benefits and harms, palliative care, psychosocial support, and costs.”

Providing patients and their family members with information about costs, perhaps not coincidentally, falls at the end of this long list. Yet, medical debt remains a critical issue for cancer patients and their families.

A recent Kaiser Family Foundation study noted that 1 in 3 Americans reported difficulty in paying medical bills. Although the risk of medical debt is greater for the uninsured, many insured patients also experience difficulty paying their bills.

 Another study demonstrated that cancer patients were 2.65 times more likely to file for bankruptcy than those without cancer.

Medical debt can lead to credit card debt, bankruptcy, barriers to receiving necessary healthcare, and difficulties in paying for basic necessities such as meals and housing. Additionally, cancer can affect a patient’s ability to work, or can prompt a working family member to quit or reduce their hours worked in order to become a caregiver.

Many patients and family members, already struggling with the emotional burden of cancer, don’t know where to seek financial help. Although 75% of pre-retirees believe that their top fear in retirement is uncontrollable healthcare costs,

 only 21% of patients surveyed in a recent analysis actually chose to discuss their fears with a professional.

So why aren’t we talking about it? Both patients and physicians may feel uncomfortable discussing the cost of a potentially lifesaving or life-prolonging treatment option. This in turn presents an ethical challenge: as physicians, shouldn’t we worry about the patient in front of us, and not society as a whole? Taking into account the looming financial burden our patients may face, however, financial toxicity is becoming an important “side effect” to discuss.

Cost concerns are driving the demand for clear evidence of value. However, the difficulty lies in aligning these factors with the best possible patient outcomes. ASCO recently formed a task force to develop a scoring system for evaluating drugs based on their cost, value, efficacy, and side effects. The scoring system is expected to be presented for public comment later this year.

Additional cost-saving measures, such as the use of evidence- based clinical pathways, can minimize variations in cancer care and generate savings by decreasing or eliminating the use of low-value services. The results of an analysis by Neubauer et al demonstrated that outpatient costs in non-small cell lung cancer were nearly 35% lower for patients treated according to an established pathway, with no differences in 12-month overall survival.

Appropriate drug pricing represents a much greater struggle, but physicians are taking a stand. Currently, traditional market forces are largely absent from pricing decisions for new cancer drugs, so there are few competitive pressures to control their costs. One option would be to simply refuse to prescribe drugs based on pricing. Last fall, Memorial Sloan Kettering Cancer Center in New York rejected a new drug for advanced colon cancer because it was twice as expensive as another equally effective drug.

 While this move is admirable, it is not easily (or ethically) reproducible. Attention has turned to debates about funding for comparative effectiveness trials.

	Championing Fellows as the Future Oncology Workforce As fellows in training, what can we do to bend the cost-care curve?

A recent editorial in the New England Journal of Medicine compared ketoconazole with abiraterone in patients with metastatic prostate cancer. The editorial highlighted the cost differences of each drug (costs of ketoconazole were $500-$700 per month, while costs of abiraterone were more than $70,000 per month) and suggested the need for a comparative effectiveness trial. However, the editorial explained that although treating patients with the less expensive drug could generate $1 billion in annual savings, the purchase price of abiraterone (nearly $70 million) would make funding this type of study difficult.

 Another potential solution that has recently become popular in cancer care is to rate the value of treatments based on their cost per quality-adjusted life-year, a method now used by many health economists.

There are a number of ways to become a “Champion of Change.” First, we have to be sensitive to the concerns of our patients and create an open environment where all “toxicities” can be addressed.

To address financial barriers, we must educate ourselves about patient resources such as pharmaceutical programs and nonprofit foundation support that can help enable informed discussions. ASCO provides information to help advise patients on managing the costs associated with cancer care at Cancer.net, and websites such as GoodRx.com can help physicians price drugs available at multiple pharmacies.

We must also think critically about unnecessary testing and therapies. The Choosing Wisely campaign, launched by the American Board of Internal Medicine (ABIM) Foundation, provides resources to help clinicians make informed practice decisions.

In partnership with ABIM’s campaign, ASCO has issued 2 “Top Five” lists designed to raise awareness about costly procedures in oncology practice that should be reconsidered or questioned.

 Additionally, the American Society of Hematology released a similar list in December of 2013, and is currently producing its second list.

 Both societies acknowledge that current challenges include effective implementation and outcomes measurement,

 which represent opportunities for fellows to engage in novel educational programming, use case-based teaching examples where cost and overuse can be readily demonstrated, and design quality-improvement projects within their home institutions.

Most importantly, fellows must familiarize themselves with this important issue and engage patients (and colleagues) in these critical discussions. Becoming a “Champion of Change” will ensure less financial toxicity, more meaningful cancer care, and stewardship of the profession to which we are all committed.

			Institute of Medicine. Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. Washington, DC: The National Academies Press; 2013.

			American Society of Clinical Oncology. The state of cancer care in America, 2014: a report by the American Society of Clinical Oncology. 

			Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. 

			Oncologists: cancer drugs have become too expensive. The Advisory Board Company website. http://www.advisory.com/daily-briefing/ 2013/04/30/oncologists-cancer-drugs-have-become-too-expensive. Published April 30, 2013. Accessed July 7, 2014.

			Eaddy MT, Cook CL, O’Day K, Burch SP, Cantrell CR. How patient cost-sharing trends affect adherence and outcomes: a literature review. 

			American Cancer Society. Cancer Treatment and Survivorship Facts & Figures 2014-2015. Atlanta, GA: American Cancer Society; 2014.

			Guy GP Jr, Ekwueme DU, Yabroff KR, et al. Economic burden of cancer survivorship among adults in the United States. 

			Almeida FA, Casal RF, Jimenez CA, et al. Quality gaps and comparative effectiveness in lung cancer staging: the impact of test sequencing on outcomes. 

			Meropol NJ, Schrag D, Smith TJ, et al. American Society of Clinical Oncology guidance statement: the cost of cancer care. 

			Pollitz K, Cox C, Lucia K, Keith K. Medical debt among people with health insurance. The Henry J. Kaiser Family Foundation website. http://kff.org/private-insurance/report/medical-debt-among-people- with-health-insurance. Published January 7, 2014. Accessed July 7, 2014.

			Ramsey S, Blough D, Kirchhoff A, et al. Washington State cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis. 

			More boomers “terrified” of future health care costs. Nationwide Insurance website. http://www.nationwide.com/about-us/120913- nf-healthcare-survey.jsp. Published December 9, 2013. Accessed July 7, 2014.

			Zafar Y, Abernethy AP, Tulsky JA, et al. Financial distress, communication, and cancer treatment decision making: does cost matter? 

			ASCO at work on a scoring system to weigh cost vs. potential benefits of pricey cancer treatments. MedCity News website. http://medcitynews. com/2014/04/asco-scoring-system-cost-effectivenesscancer- treatments. Published April 17, 2014. Accessed July 7, 2014.

			Neubauer MA, Hoverman JR, Kolodziej M, et al. Cost effectiveness of evidence-based treatment guidelines for the treatment of nonsmall- cell lung cancer in the community setting. 

			Bach PB, Saltz LB, Wittes RE. In cancer care, cost matters. The New York Times website. http://www.nytimes.com/2012/10/15/ opinion/a-hospital-says-no-to-an-11000-a-month-cancer-drug.html. Published October 14, 2012. Accessed July 7, 2014.

			Mailankody S, Prasad V. Comparative effectiveness questions in oncology. 

			Woodward RM, Menzin J, Neumann PJ. Quality-adjusted life years in cancer: pros, cons, and alternatives. 

			2012 top five list. Choosing Wisely: ASCO identifies five key opportunities in oncology to improve value of patient care. American Society of Clinical Oncology website. http://www.asco.org/practiceresearch/ 2012-top-five-list. Accessed July 7, 2014.

			ASCO’s 2013 top five list in oncology. American Society of Clinical Oncology website. http://www.asco.org/practice-research/ascos- 2013-top-five-list-oncology. Accessed July 7, 2014.

			Hicks LK. Update on the 2013 ASH Choosing Wisely initiative. American Society of Hematology website. http://www.hematology.org/ Thehematologist/Features/2688.aspx. Published April 10, 2014. Accessed July 7, 2014.

On a recent day in hematology clinic, I stood dutifully by my attending as he sorted through bone marrow slides

September 2014 | Oncology Fellows

An International Experience at Home

From Bedside to Bench

Becoming a Champion of Change: Educating Fellows on the Costs of Cancer Care