By the year 2030, the number of new cancer cases worldwide is projected to rise to 21.3 million annually, up from the estimated 12.7 million cancer cases currently diagnosed.

 Of the 21.3 million new cases every year, approximately 70% will be from low- and middle-income countries (LMICs), many of which lack the healthcare programs required to effectively manage their current cancer burden, much less that predicted for 2030.

 Moreover, the ratio of mortality to incidence will continue to be significantly higher in LMICs (64% to 75%) than in high-income countries (46%).

A significant feature of the demographic transition in LMIC countries is the change in disease epidemiology; the result is a dual burden of cancer in the presence of communicable and noncommunicable diseases.

 A consequence of infectious diseases as well as westernized lifestyles, this “cancer transition” has contributed to a higher average burden of cancer (in terms of disabilityadjusted life-years [DALYs] lost) in these low-resource settings compared with high-resource regions.

 This is largely due to premature mortality (years of life lost), which stems from advanced disease at presentation and variable access to cancer care.

Improvements in prevention, screening, early diagnosis, and treatment have led to reductions in mortality from cancer in high-income countries, following significant

economic investment. However, many countries have reached a plateau, with increased financial investment no longer an assurance of improved outcomes.

In LMICs, the costs of managing such chronic health issues and their risk factors are stretching the already fragile health services infrastructure, or, in many cases, generating a catastrophic impact on health costs and personal finances.

 Many health programs focus solely on communicable diseases through vertical interventions, with little strategic planning for chronic diseases. Cancer treatment in particular is highly challenging and quite distinct from all other service provision planning. The lack of coordination between the plethora of public and private institutions, as well as uncontrolled private enterprise, has contributed to wastage of healthcare resources, gaps in coverage, and wide variations in quality as a result of varying modalities of financing, affiliation, and healthcare delivery.

How Can We Achieve Value in the Management of Cancer?

Despite the burden of cancer in LMICs, only a fraction (2.7%) of global sector investment in cancer research is spent on R&D directly relevant to LMICs.

Research efforts should be focused to meet the unique challenges of cancer care in LMICs and should enable cost-effective treatment pathways with highly significant outcomes.

is not just about creativity—rather, greater emphasis must be placed on achieving equivalent or superior outcomes using prevailing treatments and technology, intermittently or for shorter duration. This will include practices of care that encourage shorter in-patient stays and less extensive use of expensive cancer medicines. LMIC countries need to be encouraged to choose a leadership role in value-based research, but currently, the economic incentives for this are limited, especially where fee-forservice financing of healthcare predominates. With regard to radiation technologies, brachytherapy, hypofractionated radiotherapy (reduced number of treatment

sessions whilst maintaining effective dose), and combination therapy (with chemotherapy agents) provide potentially cost-effective options for radical treatment and palliation.

LMICs cannot sustain pursuing a high-income—country model of cancer management. Their priority should instead be prevention and adequate financing of public systems. Public health campaigns need to focus on prevalent risk factors such as obesity, sedentary lifestyles, and smoking. Taxation has been advocated as an integral component of antitobacco policy,

and food advertising regulation, school-based educational initiatives, and pricing policies on foods have all been considered as ways to tackle obesity.

, human papilloma virus, and hepatitis B virus are mediators of gastric cancer, cervical cancer, and hepatocellular carcinoma, respectively.

These cancers require multimodality management, including radiotherapy, surgery, and chemotherapy. Although expensive, the diseases are potentially preventable through modulation of the causative agent. Vaccinations have been developed for the human papilloma virus, which can significantly reduce the risk of developing a malignancy,

and are being rolled out in LMICs such as Rwanda.

However, primary prevention with vaccination or screening programs will not necessarily be cost-effective in all countries. Instead, programs such as visual inspection with acetic acid for cervical cancer can prove cost-effective in the diagnosis of early-stage cancers.

The structure of the healthcare system will have a direct impact on the ability of individuals and their families to access healthcare, and can potentially widen inequities in outcomes. Inability to pay for specialist diagnostic and treatment services can result in late presentation, diagnosis, and inadequate treatment for cancer care.

 It can also lead to catastrophic or impoverishing health expenditures due to a lack of financial protection afforded by the healthcare system.

 Families may sacrifice expenditure on basic necessities such as food and housing to finance care for chronic disease. Therefore, universal healthcare coverage is essential for ensuring that vulnerable populations are protected from the financial cost of ill health, and the fee for treatment should be determined based on their ability to pay rather than the risk of ill health. However, out-ofpocket payments remain high in many LMICs.

Countries such as Mexico have introduced social insurance schemes to ensure risk pooling and protect from the destabilizing effects and financial implications of ill health, and Mexico is considered a model for other LMICs, especially in the face of the epidemiological transition.

It is essential, given the competing healthcare demands resulting from the epidemiological transition in LMICs, to avoid a zero-sum game (where the loss equals the gain). Management of communicable diseases such as HIV/AIDS and malaria have focused on vertical interventions.

 However, research into biomedical and behavioral interventions show that no single strategy is effective and that what is required is a compre-hensive, multilevel, intersectoral, and culturally sensitive series of interventions that engages both the general population and groups at elevated risk.

Interventions acting on structural factors would provide a horizontal integrated approach. If coordinated effectively and focused on issues such as education, employment, poverty, and healthcare access, these interventions could reduce the incidence and facilitate the effective management of cancer as well as reduce the incidence of other debilitating diseases, contributing to an improvement in overall population health and the achievement of Millennium Development Goals.

The Institute of Medicine states, “Cancer is such a prevalent set of conditions and so costly, it magnifies what we know to be true about the totality of the healthcare system. It exposes all of its strengths and weaknesses.”

While this is true, a horizontal approach takes into account the social determinants of health, which has roots in the economic, political, legal, and cultural environment of a country.

 The impact of these factors in predisposing populations to risk of disease and outcomes from cancer care is as important as the strengthening of health services.

Manpower shortages result in long waiting times, inequities in access, and elevated healthcare costs.

 The western model has largely focused on oncologists being split into 2 categories: medical oncologists, responsible for delivery of systemic anticancer therapies, and radiation oncologists, who deliver radiation therapies, including brachytherapy. Given the shortage of specialty oncologists in LMICs, greater consideration should be given to clinical oncology specialization in LMICs to address these shortages. Clinical oncologists are trained to deliver both systemic and radiation therapies. This is particularly relevant in LMICs, where the disease burden with higher rates of cervical, oesophageal, and prostate cancer necessitates multimodality treatment.

 A dual-training approach provides a flexible workforce,

reduces the number of consultations an individual requires, and potentially ensures greater efficiency in resource consumption. There is also an urgent need to address the chronic shortage and up-skilling of surgeons to tackle cancer.

 In many LMICs, cancer specialization will not be cost-effective and new general cancer surgical training models will need to be implemented.

To conclude, value-based strategies are essential in LMICs to develop efficient, sustainable cancer care programs to meet the projected rise in cancer incidence. A high-income country model is not feasible or appropriate in LMICs. However, through an appreciation of the structural factors which predispose and potentiate cancer—as well as affect access, quality, and affordability of cancer care&mdash;high-value, cost-effective strategies can be developed. Critically, most LMICs do not have sufficient

funds allocated to develop basic cancer care systems or to develop and implement models that would avoid high patient expenditures. Additionally, LMICs should assign funds to adequately compensate cancer healthcare professionals in the public sector. 

: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

: AA, RS: Institute of Cancer Policy, Kings Health Partners Integrated Cancer Centre, Guy’s NHS Foundation Trust & Kings College London; AA: Guys & St Thomas’ NHS Trust, Department of Oncology, London

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. 

2. Soerjomataram I, Lortet-Tieulent J, Parkin DM, et al. Global burden of cancer in 2008: a systematic analysis of disability-adjusted life-years in 12 world regions. 

3. Boyle P, Levin B, eds. World cancer report 2008. Lyon Cedex, France: International Agency for Research on Cancer; 2008.

4. Farmer P, Frenk J, Knaul FM, et al. Expansion of cancer care and control in countries of low and middle income: a call to action. 

5. Boutayeb A. The double burden of communicable and non-communicable diseases in developing countries. 

6. Sankaranarayanan R, Swaminathan R, Brenner H, et al. Cancer survival in Africa, Asia, and Central America: a population-based study. 

7. Murthy NS, Nandakumar B, Pruthvish S, George PS, Mathew A. Disability adjusted life years for cancer patients in India. 

8. Uyl-de Groot CA, de Vries EG, Verweij J, Sullivan R. Dispelling the myths around cancer care delivery: it’s not all about costs. 

9. Fojo T, Mailankody S, Lo A. Unintended consequences of expensive cancer therapeutics—the pursuit of marginal indications and a me-too mentality that stifles innovation and creativity: the John Conley lecture [published online July 28, 2014]. 

10. Frenk J, González-Pier E, Gómez-Dantés O, Lezana MA, Knaul FM. Comprehensive reform to improve health system performance in Mexico. 

11. Knaul FM, Frenk J. Health insurance in Mexico: achieving universal coverage through structural reform. 

12. Goss PE, Lee BL, Badovinac-Crnjevic T, et al. Planning cancer control in Latin America and the Caribbean. 

13. Sullivan R, Purushotham A. Avoiding the zero sum game in global cancer policy: beyond 2011 UN high level summit. 

14. Porter ME. What is value in health care? 

15. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. 

16. Shah C, Lanni Jr TB, Ghilezan MI, et al. Brachytherapy provides comparable outcomes and improved cost-effectiveness in the treatment of low/intermediate prostate cancer. 

17. André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income and middle-income countries? 

18. Jha P, Peto R. Global effects of smoking, of quitting, and of taxing tobacco. 

Articles

Evidence-Based Oncology

Achieving Value in Cancer Care-the Case of Low- and Middle-Income Countries

On June 1, 2014, the penultimate day of the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), the discussion on value in cancer care was rekindled, but this time on a global scale. The session, “ASCO/European CanCer Organisation (ECCO) Joint Session: Value and Cancer Care,” saw participation from physicians and economists from around the world, with individual perspectives on defining value and the programs being developed to address the issue. Regulatory approval does not guarantee patient access to efficient therapies. So where lies the problem?

The first talk was “ESMO-EONS: Value and the Exchange Between Physicians, Nurses, and Patients” by Elisabeth De Vries, MD, PhD, University Medical Center Groningen, Netherlands, a member of the Magnitude of Clinical Benefit Scale task force.

De Vries began with an overview on cancer drug use in Europe, and discussed how the cancer drug development process is influenced by the European Society for Medical Oncology (ESMO).

Similar to what has been demonstrated in the United States, the 5-year relative cancer survival rate in Europe increased between 1999 and 2007. However, the cost of treatment is only burgeoning.

So what is the relevance of the cost of cancer drugs? Using imatinib as an example, De Vries presented a pricing plot that showed that the drug costs the most in the United States, but costs substantially less in Europe and other countries elsewhere around the globe.

She went on to state that there are differences in access to relevantly new anticancer drugs in Europe—differences in price, differences in healthcare costs, and differences in time to access following approval by the European Medicines Agency (EMA). These disparities are associated with various issues, one of which is the cost of the drug and reimbursement.

Among European nations, a 1.8-fold difference in the cost of trastuzumab has been identified. Additionally, a difference in time to availability after EMA approval has been observed. The bottom line: the lack of timely access to anticancer drugs can result in major disparities in cancer outcomes.

With the hope of standardizing policies and easing patient access to novel treatments, ESMO is developing the Magnitude of Clinical Benefit Scale. How will the scale be used? EMA-approved drugs will be scaled by the task force, and drugs with the highest value will then be promoted.

Various factors that contribute to the scale include quality of life (QOL), overall survival (OS), progression-free survival (PFS), prognosis of condition, toxicity, hazard ratio, long-term survival, and rate of response. These factors will be used to determine the magnitude of clinical benefit. “We did not factor costs into the equation due to the heterogeneity that exists across Europe,” clarified De Vries. “We believe the ESMO scale will be constantly evolving with the availability of increasing efficacy and toxicity data as the treatment is used by the wider population.”

The scales, she noted, are distinct for curative versus palliative settings. PFS, for example, can never qualify for a grade 4 score as a primary end point, but could be a secondary end point to be considered concurrent with OS, toxicity, and QOL.

The major heterogeneity in drug price and access across Europe can result in inequality in optimal care. The ESMO scale grades drugs to determine the ideal drugs that should be immediately accessible to patients across Europe.

 The task force plans to develop and further mature this grading scale by collaborating with sister societies to generate as much data as possible to improve patient access.

Next on the panel was Richard Sullivan, MD, PhD, Kings Health Partners Integrated Cancer Centre, London, England, who discussed “Cancer Care in Cost-Restrained Healthcare Systems.” Sullivan, who is also a part of the team that is developing the ESMO scale, conducts a research program whose focus extends from the sociopolitical policy of global cancer (OncoPolicy) to the development of public health systems in highrisk conflict areas focusing on DR Congo, Afghanistan, and Libya. In OncoPolicy, he recently led the first major Lancet Oncology Commission that examined the affordability of cancer in high-income countries.

“All healthcare systems are struggling to deliver affordable and equitable cancer care,” said Sullivan. Cancer care operates as a complex adaptive system, and unlike

• it is non-linear, dynamic, and can even appear chaotic;

• individuals who comprise the system behave according to social and structural norms rather than the needs of the system;

• goals and behaviors are often in conflict; and

“Our global economic systems have become ‘addicted’ to the returns generated by cancer care and treatment,” pointed out Sullivan. Income equality is worsening globally, and we need to gain a better handle on value and equitability. Research has shown that three-fifths of the global population has less than 5% of global wealth. How can that provide equitable cancer care?

Additionally, the cancer research portfolio is extremely narrow when it comes to drug discovery and fundamental biology. The sheer volumes and pace of outputs is outstripping the ability of policy makers. “It’s harder to make costeffective and rational decisions to provide or make available efficient therapy to the population as a whole,” said Sullivan.

Cancer care systems are framed by behaviors and cultures that are not coterminous with affordability and equity. Patients can have very high expectations from their cancer treatment. Therefore, “How we frame the debate becomes as important as the content of the debate,” proclaimed Sullivan.

Identifying sites for fiscal controls and sustainability mechanisms is an uphill battle, and recognizing problem areas to adapt cost-effectiveness is very hard. This is even more difficult in developing nations like India, where 67% of out-of-pocket expenditure with financial hardship and 21% catastrophic expenditure has been documented with cancer care, according to Sullivan.

Most of our societies are reaching limits on affordability or what we are willing to pay. How do we then get value-based pricing?

Balancing costs and benefits with toxicity of new technologies needs consideration. New, extremely efficient drugs (such as the developing immunooncology molecules) could be the stepping stone in this setting.

“Value-based pricing without universality or universal healthcare does not work,” concluded Sullivan. “Reform can never stop, as exogenous factors emerge and societal demands and values change.”

The final presentation in the session, by Lowell E. Schnipper, MD, Beth Israel Deaconess Medical Center, discussed “American Perspective on Globally Defining Value in Cancer Care.”

The United States spends a lot more on healthcare than a lot of European nations, and the data are spotty.

“Why do we emphasize value?” asked Schnipper.

Drug price is a part of the high cost of cancer care, but not the only problem by any means. Outside the United States, clinical aspects are used for assessment first, and then the results are applied for price negotiation.

He reiterated that the physician has an active role to play in value determination and cost regulation, and ASCO is making efforts to help define value in cancer care with the long-term goal of integrating these suggestions in the clinic.

His final thoughts were that the value model must also be adaptable for early disease settings, which is ongoing.

The closing remarks were provided by Clifford Hudis, MD, Memorial Sloan Kettering, and the immediate past president of ASCO. “We are entirely dependent on industry for both innovation and cash flow. But we want to develop a dialogue and generate communication when it comes to drug costs.” 

1. ESMO clinical benefit scale: project background and overview. European Society for Medical Oncology website. http://www.esmo.org/content/download/16414/287782/file/ESMO-Clinical-Benefit-Scale.pdf. Accessed June 2, 2014.

2. World Cancer Congress website. http://www.worldcancercongress.org/prof-richard-sullivan-mdphd. Accessed June 2, 2014.

The Global Perspective on Value in Cancer Care

Some experts argue that overdiagnosis (OD) and overtreatment (OT) of cancer is common and increasingly costly. Others argue that current cure rates are high because of the screening processes that are in place. Both viewpoints were debated during the session “Overdiagnosis and Overtreatment in Cancer: Point/Counterpoint,” conducted on June 1, 2014, the third day of the annual meeting of the American Society of Clinical Oncology (ASCO) held in Chicago.

“Cancer overdiagnosis and overtreatment, or appropriate attention to early disease?” was the question posed by Barbara L. Smith, MD, PhD, director of the breast program at Massachusetts General Hospital, codirector of the Gillette Center for Women’s Cancers, and associate professor of surgery at Harvard Medical School. So far, the goals of cancer care have been minimizing mortality, prolonging life, reducing morbidity of treatment, preventing primary cancers, and providing access to quality care for all. Of late, the discussion has widened to include cost effectiveness and avoiding excess treatment.

“For several years now, death rates from cancer have seen a dip and cancer incidence rates have plateaued—an indicator that the strategy is working. The cornerstones of success of modern care include earlier detection, improved treatments (multimodality care op-tions), a combination of early detection and better treatment, and also

improvement in overall population health. Healthier patients can work through the toughest treatments,” said Smith.

Smith questioned whether diminishing returns could be resulting in overkill. “Are cancer patients being administered more treatment than needed?” More importantly,

can comparable success be achieved with lighter treatment?

She provided an example of the increasing use of bilateral mastectomy in early-stage breast cancer. The numbers were at 3% back in 1998 but are up to 18% in 2007. The question to pose: Is it necessary? Patients want the procedure for peace of mind—to reduce their chances of recurrence. But what about the oncologist?

This is a challenge being discussed across a spectrum of disease states such as hypertension and cholesterol. Some of the questions that oncologists need to ask include:

• What is the optimal way to screen (sensitivity/specificity goals, cost, and limitations of diagnostic technologies)?

• What should the threshold for treatment be?

• What are the morbidity and mortality goals?

An ideal example is that of the recent debate about using the Papanicolaou (Pap) test cytology versus human papillomavirus (HPV) DNA testing. Pap has proved successful in reducing cervical mortality, but the role of HPV in disease has been recognized, and recently the cobas test was approved as a primary HPV screen.

The sensitivity of the screening is ideal—the problem lies in the fact that 10% of patients who are Pap-positive have precancerous lesions, but some cancers are HPV-negative. Additionally, there may be cancer-independent transient HPV infections that could result in falsepositive results. Only 10% of women with high-risk HPV develop persistent infection. The result: unnecessary colposcopies and biopsies following HPV testing.

However, a recent study showed that patients are the ones who want screening and would even overrule their physician in wanting to be screened.

Can improved treatment reduce the need for screening? Not yet, said Smith. We still cannot reliably distinguish between patients with indolent and aggressive cancer. “Cost is the elephant in the room—an unsustainable and sensitive topic that comes up with death panels, rationing, etc,” she said.

The other elephant in the room is liability for malpractice. Delays in diagnosis are common claims in malpractice lawsuits, and variations in guidelines (eg, annual vs biennial screening for breast cancer) can increase a physician’s exposure to such litigations.

What will it take to change practice? A change in physician perspective and a change in patient expectations may be the answer. Additionally, cost constraints need to be modified, guidelines need to be standardized, and medicolegal issues need to be addressed.

Smith concluded by saying that implementing small changes can lead to the bigger goals of:

Rinaa S. Punglia, MD, MPH, associate professor, Department of Radiation Oncology, Harvard Medical School, presented “The Case Against Overdiagnosis and Overtreatment of Cancer.”

OD/OT are inherent in breast cancer screening, and OD is central to the mammography debate in breast cancer. “OD usually leads to OT. A treatment does not necessarily alter outcomes,” said Punglia.

The solution to this problem, she believes, lies in informed decision making (IDM), which is made possible by opening a dialogue. Decision to screen can lead to false positives, but also to early diagnosis and improved outcomes. IDM can be used to reduce OT.

For example, ductal carcinoma in situ (DCIS) has historically been treated with mastectomy, but that approach may be too drastic. Today, patients undergo breast preservation surgery, which can leave patients at risk for a second breast event in the preserved breast, but can be followed with radiation therapy (RT). Meaningful outcomes for a patient after RT include recurrence, treatment of recurrence, and breast preservation. However, on the downside, RT can be expensive.

So how does one decide if a patient receives RT? DCIS overestimates a patient’s risk of recurdrence, and making a decision is difficult for patients. Therefore, individual decision making is key—lay the options down and help patients make the right choice. Punglia shared knowledge on a decision-making tool being actively used at Dana-

Farber (www.onlineDeCISion.org), which helps patients and providers alike.

The final viewpoint in this debate, “The Case for Overdiagnosis and Overtreatment of Cancer,” was presented by Laura Esserman, MD, MBA, director, Carol Franc Buck

Breast Care Center; and coleader, breast oncology program, UCSF Helen Diller Family Comprehensive Cancer Center.

In March 2012, the National Cancer Institute convened a workshop to generate ideas for a research agenda around OD. According to Esserman, a critical shift in philosophy is needed to explain that the previous approach of OD saves lives.

The old paradigm of cancer was of inexorable progression—or of every patient having the same rate of disease progression. That has changed, and we know today that it is far from true. Oncologists recognize that there is variable progression in patients and that there are IDLE (indolent lesions of epithelial origin) lesions that may not affect mortality. Therefore, understanding the biology of the cancer is extremely important.

Although the spectrum of disease has been realized and understood, the definition of cancer has not evolved. If a patient thinks “cancer,” they think they will die if they are not treated.

“A very important question is: what do you know, when do you know, and how do you act on what you know?” said Esserman.

The need of the time is a new approach to cancer treatment rather than arguments on 30-year-old guidelines, Esserman emphasized. However, it is extremely important to understand outcomes before changing guidelines. “Increased detection saves lives” is way too simple: the concept is much more complex, she said.

Recognizing and gaining an improved understanding of IDLE disease is important said Esserman—for example, does a tumor with little potential for metastasis and with little chance of progression or death require aggressive treatment? “IDLE tumor gene signatures could help define ultra-low—risk tumors. This could be validated in various cohorts and used to stratify patients with high- and lowrisk tumors,” according to Esserman.

Esserman closed her argument by recommending that a better-tailored definition replace the word “cancer,” companion diagnostics be coupled with treatment, and observational registries be created to identify IDLE disease. 

Overdiagnosis and Overtreatment: The Cancer Paradigm

Velcade (bortezomib), developed by Millenium Pharmaceuticals Inc, is a proteasome inhibitor (

) currently approved for the treatment of multiple myeloma and relapsed mantle cell lymphoma.

 Several abstracts, presented on May 31, 2014, and June 1, 2014, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago set forth data from trials that are under way to evaluate bortezomib for other indications.

Bortezomib and rituximab in the treatment of iNHL

This study, conducted at multiple trial centers and led by clinicians at Northwestern University, Chicago, was designed to assess the tolerability of bortezomib and rituximab in patients with high tumor burden (HTB) non- Hodgkin’s lymphoma. Treatment in this multicenter phase 2 study consisted of 3 induction cycles of bortezomib and

rituximab, followed by an abbreviated consolidation. All outcomes were analyzed by intent to treat. All 42 patients enrolled in the trial were evaluable. The therapy was well tolerated, with few grade 3/4 toxicities and minimal neurotoxicity. Grade 3 adverse events (AE) included fever, infusion reaction, infection, cardiac, fatigue, diarrhea, hypokalemia, and bowel obstruction; the only grade 4 AEs were neutropenia and thrombocytopenia. Overall response rate (ORR) at the end of therapy was 70%, with a 40% complete remission (CR) rate (follicular lymphoma [FL]: ORR 76%, CR 44%). At a median follow-up of 50 months, 4-year progression-free survival (PFS) was 44%, with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Interestingly, 4-year OS was superior for FL compared with non-FL histologies (97% vs 43%, respectively, P = .003). Altogether, bortezomib/rituximab is a targeted therapeutic regimen that was very well tolerated and resulted in long-term survival rates comparable to prior HTB FL rituximab/chemotherapy series.

Replacing vincristine with bortezomib in R-CHOP regimen in treating mantel cell lymphoma

R-CHOP—rituximab, cyclophosphamide, doxorubicin (Hydroxydaunomycin), vincristine sulfate (Oncovin), prednisone&mdash;is standard therapy for newly diagnosed, bone-marrow transplant (BMT)-ineligible mantle cell lymphoma (MCL) patients. Bortezomib is approved in the United States for relapsed MCL. This study, registered as a collaborative trial between Millennium Pharmaceuticals and Johnson & Johnson Pharmaceuticals, evaluated whether replacing vincristine with bortezomib in R-CHOP

improves outcomes in newly diagnosed, BMT-ineligible MCL patients. Adults with treatment-naïve, measurable stage 2 through 4 MCL and ECOG PS 0 to 2 were

randomized to VR-CAP (velcade, rituximab, cyclophosphamide, doxorubicin, prednisone) or R-CHOP. The primary end point was PFS and secondary end points included time to progression, time to next treatment, OS, response by modified international lymphoma workshop response criteria (LWRC), and safety. Of the 487 patients, 244 were randomized to the R-CHOP arm and 244 to the VR-CAP arm, and were administered a median of 6 cycles. After 40 months median follow-up (298 PFS events), median

PFS was 14.4 months (R-CHOP) vs 24.7 months (VR-CAP). Rates of grade 3 or higher AEs were 85% (R-CHOP) versus 93% (VR-CAP), serious AEs were 30% versus 38%, discontinuations due to AEs 7% versus 9%, and on-treatment drugrelated deaths 3% versus 2%. This trial showed that VR-CAP significantly prolonged PFS and consistently improved secondary efficacy end points versus R-CHOP in newly diagnosed, BMT-ineligible MCL patients, with additional but manageable toxicity.

Phase 3 trial for myeloma comparing different iMiDs

Treatment with immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) has dramatically increased response rates and survival for myeloma patients over the last decade, with triple drug combinations proving more effective than double or single agents. This trial, Myeloma XI—a collaborative study between the University of Leeds, Celgene Corportation, and Merck Sharp and Dohme Corporation&mdash;was a phase 3 randomized trial for newly diagnosed patients of all ages, which compared induction treatment with cyclophosphamide/lenalidomide/dexamethasone (CRD) to cyclophosphamide/thalidomide/dexamethasone (CTD), given to maximum response or intolerance. To evaluate the role of pretransplant consolidation with a proteasome inhibitor, patients achieving less than a very good partial response (VGPR) were randomized to additional cyclophosphamide/bortezomib/dexamethasone (CVD) versus no treatment. Fit patients went on to receive melphalan + autologous stem cell transplant. Of the 1939 patients analyzed, 1104 were on the intensive pathway arm (540 CRD vs 564 CTD) and 835 were on the nonintensive arm (411 CRDa vs 424 CTDa); 274 patients received additional bortezomib. The preplanned intent-to-treat analysis of combined CR+VGPR rates presented a significant difference between CRD and CTD treatment on multivariate analysis in favor of CRD, with odds ratio of 1.27 (95% CI 1.06-1.52, P = .009). Additional bortezomib therapy&mdash;for those with a suboptimal response&mdash;upgraded response in 51% of the patients, demonstrating that PI therapy can be effective in patients intrinsically resistant to IMiDs. Treatment with both IMiDs was well tolerated. The trial demonstrated an important difference in response between the IMiDs thalidomide, and lenalidomide; however, further follow-up is required to see whether this translates into prolonged PFS and OS. 

1. How Velcade (bortezomib) works. Velcade website. http://www.velcade.com/Understanding-velcade/About-velcade. Accessed June 1, 2014.

2. Evens AM, Smith MR, Lossos IS, et al. Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumor burden (HTB) indolent non-Hodgkin lymphoma

3. Cavalli F, Rooney B, Pei L, Van De Velde H, Robak T; on behalf of the LYM-3002 Investigators. Randomized phase 3 study of rituximab, cyclophosphamide, doxorubicin, and prednisone plus vincristine (R-CHOP) or bortezomib (VRCAP) in newly diagnosed mantle cell lymphoma (MCL) patients (pts) ineligible for bone marrow transplantation (BMT). 

4. Pawlyn C, Davies FE, Cairns DA, et al. Optimizing induction and pretransplant consolidation for myeloma: results of Myeloma XI, a phase III trial comparing different IMiDs. 

Velcade: A Progress Report in Various Cancers

May 31, 2014, the second day at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), ended with a session entitled “Health Care in America in 2014: Current and Future Implications of the Patient Protection and Affordable Care Act” (ACA). The presenters provided an overview of the recent and anticipated changes related to the ACA as well as its timeline. The panelists also explored how federal budget sequestration might affect reimbursement, Medicare, and funding of research and drug development.

Rena M. Conti, PhD, a health economist and assistant professor in the section of hematology/ oncology at the University of Chicago, opened the session with, “Bracing

for the Future: Impact of Changes in Healthcare Policy on Drug Development.” Healthcare spending in the United States is already 17.7% of current gross domestic product (GDP), and is projected to rise to 22% in 6 years, she said. About 1 of every 20 healthcare dollars is spent on cancer care, said Conti, although estimates vary among

Conti affirmed that cancer care costs are rising faster than overall healthcare and cancer care is outpacing all other healthcare spending, with the current costs estimated at $125 billion. The ACA will increase that level of spending, and a population that is increasingly older will add to the financial burden.

So where is the problem? It manifests in the skirmish between the average value of new innovations and their application to individual patients. There result: although improvements in survival benefit are observed (due to various contributing factors such as improved screening techniques, treatment advances, and behavioral changes) (

), there is overuse and misuse of therapies. This is in addition to the off-label and unapproved use of drugs.

There is no argument that drug costs have seen a substantial increase, although the newer molecules have improved precision and thus response to therapy. But are these costs sustainable?

“So the fundamental question remains, how do we improve access and cost-effectiveness of these therapies while maintaining innovation?” asked Conti.

Conti laid out the political economy of reform. The cost of a drug is 2-pronged: if patients are well insured, they don’t face very steep bills. Additionally, co-payment assistance is widely available for branded therapies. This, however, acts as a lever to inflate prices.

Consequently, physician practices face significant pressures to find deep discounts on acquisition prices of these therapies, and the 340B drug pricing program, which requires drug manufacturers to provide outpatient drugs to eligible healthcare organizations or covered entities at significantly reduced prices

resulted in a major consolidation of practices.

Conti highlighted the “how” of reform:

1. Change drug reimbursement policy: maintain the current system but make efforts to closely match reimbursements with acquisition costs.

2. Change the locus of risk bearing from physicians and hospitals to pharmacy benefit managers and insurers.

3. Change reimbursement models to include novel drugs.

Use of generic therapies is an obvious opportunity to exploit, she said. For example, Gleevec is going off-patent in 6 months, and replacing it with a generic will cause a drastic drop in drug price. “Each stakeholder—the provider, the payer, and the manufacturer&mdash;has a role to play in bringing about this payment reform,” concluded Conti.

Lawrence N. Shulman, MD, chief of staff and senior vice president for medical affairs at Dana-Farber Cancer Institute, and associate professor, department of medicine, Harvard Medical School, presented his perspective on “The Impact of Accountable Care Organizations on Oncology Practice.” He explained what accountable care

organizations (ACOs) are and what can be done to best position oncologists in that environment.

He started off with the CMS definition of an ACO.

 ACOs are groups of doctors, hospitals, and other healthcare providers who come together voluntarily to deliver coordinated high-quality care to their Medicare patients.

The goal of coordinated care is to ensure that patients, especially the chronically ill, get the right care at the right time, while avoiding unnecessary duplication of services and preventing medical errors. When an ACO succeeds, both in delivering high-quality care and spending healthcare dollars more wisely, it will share in the savings it achieves for the Medicare program.

Shulman then delineated the characteristics of an ACO. Patients participate in an ACO if their primary care physician (PCP) is enrolled in it. Patients are not restricted to

seeking care from predetermined providers, although PCPs may try to direct care. Although the payment is fee-forservice, the actual cost is still determined by CMS.

The question remains, though, “What do patients want? Access to treatment for best chance of survival, an improved quality of life, high ficiently, and of course affordable care,” said Shulman. Payers are interested in high-quality care, at a reasonable cost, and they want affordable premiums that are acceptable to their clients. The third stakeholder in the equation, the oncologist, wants freedom to provide the best care, fair compensation, and freedom from administrative burdens to be better able to focus on care.

Shulman then said that cancer care is different with regard to ACOs. PCPs manage or co-manage patients with diabetes, heart failure, and other ailments with specialists, and influence the cost of care. But they cede care of the cancer patient to a specialist and so are out of the cost equation. However, PCPs would share the risk and benefit of ACO performance when employed by a hospital or by multi specialty practices.

The challenges with cost include noninformed decision making. Oncologists are not very good at measuring patient outcomes, managing cost of care, and factoring in cost of treatment during care. Much of what they do daily in the clinic only provides weak evidence to help decide between treatments. “But,” emphasized Shulman, “that cost must be factored in when making treatment decisions.” Pathways, he said, must include the total cost of care, and the oncologist must carefully evaluate the cost of imaging, the selection of a testing laboratory, and other factors, based on what is absolutely needed.

Shulman’s concluding remarks were that pathway developers need to make tough decisions. Partnerships between providers and payers can control costs and improve

care. “We should aspire to do these things with the patient in mind,” said Shulman. “The current system is not patient centered.”

How oncology practices will fit into and interact with ACOs is not very clear yet. Oncology practices should play an active role in the control of cancer care costs to fit into the quality metrics of care.

“Healthcare Reform 101: Summary of the Recent and Planned Changes Related to the Patient Protection and Affordable Care Act” was presented by Blase N. Polite, MD, MPP. Polite, an assistant professor of medicine in the section of hematology/oncology at the University of Chicago and chair of the ASCO Government Relations Committee, offered an overview of the impact of the PPACA on patients and providers.

Polite discussed ASCO’s policy on Medicaid expansion, which has been the source of controversy in some states due to the US Supreme Court ruling that upheld ACA but allowed states to opt out of extending Medicaid to Americans in the low-income tier just above the poverty level. ASCO’s policy, Polite said, is that “All states should expand their Medicaid program to provide coverage, at least for individuals with incomes below the poverty level, or should come up with an alternate strategy that provides comprehensive subsidized health coverage that ensures, among other benefits, access to high-quality cancer care, measured by cancer-specific quality metrics, delivered by a cancer specialist.”

• expand the list of cancer risk syndromes covered

• clarify that follow-up testing should be covered without cost sharing

• clarify that coverage for risk-reducing surgeries is covered

The clinical trial provisions under ACA state that health plans cannot:

• deny an individual participation in a clinical trial

• deny, limit, or impose additional conditions on the individual associated with participation in a trial

• discriminate against the individual for participation in a trial

However, these provisions are not yet backed by strong regulations. They do not apply to Medicaid patients or those covered by “grandfathered” health plans, and they do not allow out-of-network coverage. Polite emphasized that oncologists need to monitor the implementation of these policies by health plans.

Polite concluded by saying that the ACA-implemented provisions are good news for cancer patients overall, although there are a few concerns with regard to coverage and penalties on physicians caring for the poorest and sickest patients. 

1. 340B Drug Pricing Program. HHS website. http://www.hrsa.gov/opa/. Accessed June 1, 2014.

2. Accountable care organizations. CMS website. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ACO/. Accessed May 31, 2014.

Impact of the Affordable Care Act on Cancer Care

On August 13, 2014, Peter P. Yu, MD, FASCO, the 2014—2015 president of the American Society of Clinical Oncology (ASCO), sat down with 

 at their headquarters in Alexandria, VA, to discuss some of the “value” prospects that ASCO has brought to the table when discussing cancer care.

: How is ASCO defining value in cancer care?

 “Value” is important to talk about in cancer care as it feeds into concerns regarding both the sustainability of and access to cancer care. ASCO’s initial framework for evaluating value in oncology is defined by three key components: clinical benefit, toxicity, and cost.

 How is ASCO helping both providers and patients navigate today’s changing healthcare landscape?

 The cancer patient is bombarded during a time of high emotional stress. There are a lot of discussions occurring within a short period of time—treatment options, side effects to anticipate, prognosis, etc. Layering it with a discussion of cost of care makes it even harder on the patient. Yet if these conversations with the provider do not happen before treatment begins, patients will surely realize the cost burden after the fact: the cost of care, the co-pays, and the unaffordability of it all. This can impact the success of therapies, compliance, and other issues. ASCO is endeavoring to develop a framework that can form the basis to initiate the value discussion. The approach is to look at different kinds of cancer treatments, assess their clinical benefit in terms of quality of life and survival, the economic cost, and the toxicity cost, in a way that can be compared with alternative treatments. This can help compare different regimens on a relative basis without trying to rank-order treatment, based on a single value judgment. We want to establish a basis to conduct a discussion on choosing treatment options, not to restrict patient or physician choice. Outlooks, of course, will vary&mdash;for some patients, certain side effects may be intolerable, while others may accept any degree of side effects as long as there is a significant survival benefit. So it’s not possible to state a single right answer for every patient&mdash;that’s for the doctor and the patient to decide together. But if we can provide a basis for having a consistent discussion across patients and providers, it’d be a significant benefit.

 Can you elaborate on the Choosing Wisely campaign and the role that ASCO seeks to play?

 It’s the first part of a broader effort across the house of medicine to discourage use of therapies or diagnostic tests that have no proven value. This is an effort across medicine to foster a culture for doctors to evaluate the downstream consequences of the things we order. A generation ago, most oncologists ignored the broader considerations of treatment decisions; they did not believe it to be their responsibility. They thought, “My job as a patients advocate is to do everything I can to have the patient survive a day longer—end of story. Anything else is not my responsibility.” They also believed it was unethical for a physician to consider both financial and clinical toxicity cost.” However, with medical events triggering a quarter of US personal bankruptcies, most physicians today recognize that it’s their responsibility to

discuss the relative value of the treatments that they are recommending to their patients. We would like to instill a sense that we need to be mindful of this conversation.

 Can you provide us an overview of CancerLinQ?

 We are rapidly moving to a world of digital heath. All aspects of our lives are captured electronically in a way that can speed communication, enhance coordination

The American Society of Clinical Oncology Annual Meeting, 2014

Achieving Value in Cancer Care-the Case of Low- and Middle-Income Countries

The Global Perspective on Value in Cancer Care

Overdiagnosis and Overtreatment: The Cancer Paradigm

Velcade: A Progress Report in Various Cancers

Impact of the Affordable Care Act on Cancer Care

In Conversation With ASCO President Peter Paul Yu

Clinical Pathway Adherence and Barriers to Coverage

The Oncologist Defines Value of Care

Promising Results in Leukemia From a BCL-2 Inhibitor

Cancer Care in the United States: The Path Ahead

The EGF Receptor (EGFR) Continues to Be a Promising Target in NSCLC