The arrival of robotics in surgery has been a roller coaster ride, offering another lesson in how technology in healthcare, unlike most industries, faces challenges to show it’s better than the status quo.

The use of surgical robotics, especially the well-publicized da Vinci Surgical System, has flourished in the past several years. The name da Vinci is nearly synonymous with the term “robotic-assisted surgery,” as it is the overwhelming market leader. As of 2012, more than 2000 of the 1000-pound devices have been sold around the world. Estimates are that da Vinci systems are used in at least 200,000 surgical procedures each year (mostly prostatectomies and hysterectomies).

According to Intuitive Surgical, da Vinci’s manufacturer, the number of surgeries may have topped 367,000 in 2012.

 However, this roller coaster car may be headed for a long, bone-rattling dip. Today, Intuitive Surgical reports that sales are down, with revenues falling 59% for the first quarter of 2014 compared with that same period in 2013. This drop may be attributable to several things: technical issues and outcomes questions, not to mention high capital (approximately $1.5 million) and maintenance costs (about 10% of the capital costs). This may be a signal of a new wariness among payers and providers regarding the value of robotic-assisted surgery.

Robotic surgery’s promise is straightforward: small incisions and scaled-down surgical movements should mean less damage to surrounding tissue, with improved recovery the result. Yet, evidence to support surgical robotic assistance is tenuous at best.

A recent study from Finland found that when robotic surgery was used in cancer patients who needed hysterectomies, time in the operating room was greater, with patients faring no better than those who had conventional procedures. Furthermore, the cost in Finland was calculated to be at least 50% higher for these patients. These researchers found that when used with patients with benign conditions, the cost of surgical robotic assistance was closer to triple the cost of conventional conditions.

A 2013 investigation by Columbia University researchers found that the use of robot-assisted hysterectomy for benign disorders, among 264,758 women in 441 centers, led to no outcomes benefit, and instead cost $2000 more per procedure compared with conventional laparoscopic hysterectomies.

 However, the use of this modality jumped 19-fold, from 0.5% to 9.5%, in a span of 4 years. At hospitals with the equipment, robotic-assisted procedures accounted for more than 20% of all hysterectomies performed.

Still, it is thought that robot-assisted laparoscopy has real benefit, particularly in pediatric surgeries and nerve-sparing procedures, where precise suturing, better visualization (3-dimensional view of the area of the affected tissue), and finer movements are high priorities.

 In patients with prostate cancer, a large (>22,000 patients), nonrandomized study found that patients undergoing surgically assisted radical prostatectomies had less frequent positive surgical margins (13.8%) compared with laparoscopic procedures (16.3%) and open surgery (22.8%).

Positive surgical margins in prostate cancer are a wellrecognized correlate with biochemical reoccurrence. A study published this year in the J

reviewed records for more than 5900 patients who underwent either open radical prostatectomy (41%) or robot-assisted radical prostatectomy (59%).

 Data points compared were postoperative complications, blood transfusions, prolonged length of stay, readmissions, additional cancer therapies, and costs of care within the first year. Analyses showed that the 2 groups were similar for odds of overall complications, readmission, and additional cancer therapies. The group undergoing robot-assisted surgery had a higher probability of experiencing genitourinary and miscellaneous medical complications at 30 and 90 days postsurgery (P <.02), but they had a lower risk for requiring a blood transfusion and having a prolonged length of stay (P <.001). Even with these benefits, the expenses at 1 year were greater in this group ($13,394 vs $11,940; P <.001).

A review of literature between 2000 and 2013 indicated that there are benefits associated with robotic prostatectomy, including decreased blood loss, fewer blood transfusions, decreased length of hospital stay and preservation of urinary and sexual function, and other quality-of-life measures that appear to be dependent upon the surgeon’s technique.

 However, costs were significantly less for procedures not employing a robotic surgical system.These results somewhat conflict with other studies for safety and length of stay. A study by Hu and colleagues

found more complications in the group undergoing robot-assisted surgery. Pierorazio and associates

showed a longer length of stay in those undergoing robot-assisted procedures. A review of a sampling of Medicare claims files between August 1, 2008, and December 31, 2008, concluded that similar frequencies of problems with continence and sexual function are experienced

by patients undergoing open surgery or robot-assisted prostatectomy surgery.

The number of adverse events (AEs) associated with the da Vinci Surgical System caused the FDA to take notice. In 2013, the FDA sent a warning letter to Intuitive for underreporting AEs and issued an “urgent medical device recall” for 1300 da Vinci robot arms. A lawsuit was filed in March 2014 by Intuitive’s shareholders, claiming that the company underreported AEs and concealed recalls from the FDA.

The number and seriousness of adverse events filed in its Manufacturer and User Facility Experience (MAUDE) database increased by one-third from 2011 to 2012, as the number of robotic procedures jumped 26%, according to Intuitive, da Vinci’s manufacturer, in a Securities and Exchange Commission quarterly filing. Reports in the MAUDE database may be filed by the manufacturer, hospitals, clinicians, and patients. Filings can be related to equipment malfunctions that cause no harm to patients, as well as injuries and deaths that may be related to the device or the surgeons operating the device. Unfortunately, data are not available to determine whether there is a correlation among the procedure, facility, patient demographics,  disease/morbidity, and/or surgeon.

A 2013 study published in the Journal for Healthcare Quality evaluated AEs associated with the use of the da Vinci system over a 12-year period. Cooper and co-workers

 found a total of 245 AEs that were reported to the FDA, including 71 deaths and 174 events that caused injuries but were not fatal. Researchers from Johns Hopkins were concerned that AEs were underreported, and they termed the process for event reporting “haphazard,” calling for improvements in the reporting of these events. The study did not compare AE reporting for robot-assisted surgery with open surgeries of the same type.

Even assuming that AEs associated with robot-assisted surgery are significantly underreported, the frequency would likely amount to a tiny fraction of the total surgeries performed. Robot-assisted prostatectomy is now more common than the open surgical approach in the United States,

 although this certainly varies by geographic region and access to the devices.

The popularity of the procedure means higher billings for providers who are willing to risk the capital outlay (approximately $1.8 million) and perhaps gain a marketing edge over competing hospitals in a given region.

Payment and reimbursement can be a powerful incentive or disincentive to the growth of robot-assisted procedures. At present, payers do not generally reimburse differently for open surgery, laparoscopic procedures, or robot-assisted surgery. According to the medical director of a regional health plan who participated in a recent survey, “There are no CPT codes for robot-assisted

laparoscopic surgeries. This is just another form of laparoscopy. Accordingly, there is no payment differential to the providers for the use of the robot,” according to this payer, who asked not to be identified. “Those providers who try to bill with modifier 22 and claim to have a more complicated surgery with the robot are usually denied additional reimbursement. Some of the contracted facilities do have contract rates for robot-assisted surgery; however, as these contracts come up for renewal, the additional enhancement for robot surgery is being eliminated.”

Furthermore, many payers are concerned about the expanded use of this technology to “marginally indicated” procedures, based on pressure from the C suite to recoup the costs invested in devices like da Vinci. Payers are also concerned that any surgeon who does not come out of a training fellowship program where they had “hands-on” experience in using da Vinci would be subject to an unacceptable “learning curve” in actual practice.

Are surgeons and their hospitals focused on getting the latest and greatest technology? Based on the lack of proven improved outcomes, this may be the case, according to the medical director of a national plan who participated in the survey. “I’m the payer representative on our health system’s robotics committee. At a recent committee meeting, what struck me was the tone of the surgeons, which I felt was very gizmo-ish, if that is a word, in that they were clammering for more access for less-complicated procedures. The general surgeons in our area want to do them for appendectomies and gallbladder removals, and this is being pushed by the manufacturer.”

This executive added, “There was a 20-minute debate regarding one hospital that just got a new robot-assisted surgery device, who was being sold on converting (to) newest version for only $150,000 more!” The amount of training needed on the devices to safely perform the surgeries is also critical. “We’ve been told about the importance of proctoring and mentoring surgeons on the machines: physicians unfamiliar with the machines will turn a 2-hour prostatectomy into a 6- to 8-hour procedure unless properly trained. And we were told that it probably takes 200 procedures for them to become proficient in robotic prostatectomies.”

Thus, it seems the healthcare system is paying more, regardless of whether health plans know it. “The cost of operating room and anesthesia for a 6-hour prostatectomy is not noted—it is just paid,” said this payer. A 2012 technology assessment review by the Center for Evidence-Based Policy at the Oregon Health & Science University for the Washington State Health Authority summarized, “Generally there is low to moderate strength of evidence that robotic-assisted procedures are associated with improved outcomes, such as shorter hospital stays, and reduced blood loss and transfusion for several procedures (eg, prostatectomy, hysterectomy, nephrectomy, and cystectomy).

Where it has been examined, operative times using robotic assistance are generally longer than for conventional surgeries. There is a general lack of study for patient-centered outcomes (eg, quality of life, longer survival). Many studies are limited by small sample sizes, retrospective nature of data collection and analysis, dissimilar control groups, and inadequate control of potential confounders.”

The report continued, “Where it was studied, there were data indicating that there is a ‘learning curve’ for use of robotic equipment and that some outcomes were improved with increasing levels of experience (eg, operative time, length of stay, and complication rates for robotic prostatectomy).”

In other industries in the United States, particularly manufacturing, improved technology often results in improved efficiency, better quality, and lower costs. In the healthcare industry, however, it is rare to cite instances where new medical technologies had positive effects on efficiency, quality, and costs. Robotic surgery seems a prime example of the failure of technology in the healthcare industry to improve efficiency and outcomes, at least in prostate surgery. This may not be the case in other types of surgical procedures that requires precise movements. The problem is that evidence is still lacking.

As Debasish Sundi and Misop Han wrote in an editorial18 accompanying the JCO article, “Do the results of this study prove superiority or safety of one technique over another? The simple answer is no.”

Most robotic-assisted surgeries, particularly done in centers without a great deal of volume, tend to take significantly more time than conventional procedures. With robotic-assisted surgeries, much of this time is taken in the set-up—preparing the patient, the machinery, and properly positioning the device next to the patient (“docking”). This set-up time also includes camera placement, trochar positioning, and draping the patient.

In a center in Ireland, practitioners recorded the procedure set-up time for hysterectomies, from the first few operations performed to having completed more than 500 consecutive  hysterectomies. Setting up the system can take anywhere from 20 to 90 minutes in total, depending again on the user’s experience. Furthermore, actual procedures take longer with robotic assistance (of course, depending on the complexity of the surgery), and this is also characterized by a learning curve.

Source: http://www.robotsurgery.ie/clinicaldata-

1. Babbage Science and Technology. Surgical robots: the kindness of strangers. The Economist. http://www.economist.com/blogs/babbage/2012/01/surgical-robots. Published July 12, 2012. Accessed April 8, 2014.

2. Tanner L. FDA takes a fresh look at robotic surgery. Associated Press. www.usatoday.com/story/news/nation/2013/04/09/robot-surgeryfda/2067629/. Published April 9, 2013. Accessed April 28, 2014.

3. Saxena V. Inuitive’s sales plunge as da Vinci concerns persist. Fierce Medical Devices http://www.fiercemedicaldevices.com/story/intuitives-sales-plunge-da-vinci-concernspersist/2014-04-09. Published April 9, 2014. Accessed April 17, 2014.

4. Tapper AM, Hannola M, Zeitlin R, et al. A systematic review and cost analysis of robot-assisted hysterectomy in malignant and benign conditions [published online March 15, 2014].

Eur J Obstet Gynecol Reprod Biol. 177C:1-10. doi:10.1016/j.ejogrb.2014.03.010.

5. Wright JD, Ananth CV, Lewin SN, et al. Robotically assisted vs laparoscopic hysterectomy among women with benign gynecologic disease. JAMA. 2013;309(7):689-698.

6. Van Batavia JP, Casale P. Robotic surgery in pediatric urology. Curr Urol Rep. 2014;15(5):402.

7. Esteban F, Menoyo A, Abrante A. Critical analysis of robotic surgery for laryngeal tumours [published online March 10, 2014]. Acta Otorrinolaringol Esp. pii:S0001-6519(14)00031-4.

8. Sooriakumaran P, Srivastava A, Shariat SF, et al. A multinational, multi-institutional study comparing positive surgical margin rates among 22393 open, laparoscopic, and robot-assisted radical prostatectomy patients. Eur Urol. 2014;65(6):e89-e90.

9. Gandaglia G, Sammon JD, Chang ST, et al. Comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. J Clin Oncol. 2014;32(14):1419-26.

10. Laviana AA, Hu JC. A comparison of the robotic-assisted versus retropublic radical prostatectomy. Minerva Urol Nefrol. 2013;65:161-170.

11. Hu JC, Lipsitz SR, Barry MJ, et al. Comparative effectiveness of minimally invasive vs. open radical prostatectomy. JAMA. 2009;302:1557-1564.

12. Pierorazio PM, Mullins JK, Ross AE, et al. Trends in immediate perioperative morbidity and delay in discharge after open and minimally invasive radical prostatectomy (RP): a 20 year institutional experience. BJU Int. 2013;112:45-53.

13. Barry MJ, Gallagher PM, Skinner JS, et al. Adverse effects of robot-assisted laparoscopic versus open retropubic radical prostatectomy among a nationwide random sample of Medicareage

14. Wasserman E. Intuitive now faces a pension plan’s lawsuit over its robotic surgical device. Fierce Medical Devices website. www.fiercemedicaldevices.com/story/intuitive-nowfaces-pension-plans-lawsuit-over-its-roboticsurgical-device/2014-03-26. Published March 26, 2014. Accessed April 28, 2014.

15. Cooper MA, Ibrahim A, Lyu H, Makary MA. Underreporting of robotic surgery complications [published online Aug 27, 2013]. J Healthc Qual. doi:10.1111/jhq.12036.

16. Ali A, Nguyen DP, Tewari A. Robot assisted laparoscopic prostatectomy in 2013. Minerva Chir. 2013;68(5):499-512.

Articles

Evidence-Based Oncology

Robotic-Assisted Surgery: A Question of Value

Thousands of tests that give doctors guidance on how to treat cancer or other progressive, chronic illnesses will face FDA scrutiny for the first time, according to a July 31, 2014, announcement from FDA Commissioner Margaret A. Hamburg, MD.

The FDA issued final guidance on its clearance policies for companion diagnostics, which are used in cancer treatment to identify those patients who may benefit from a specific therapy. These tests, often based on genetics, are frequently developed in tandem with the therapy and were already subject to FDA clearance.

The agency had also exercised oversight of all direct-to-consumer tests as well as those whose reliability had to be guaranteed across multiple laboratories, such as those in hospitals. What’s new is the FDA’s movement into the realm of laboratory developed tests, known as LDTs, which are designed, manufactured and used within a single laboratory; tests are performed with a patient’s blood or tissue samples.

“Ensuring that doctors and patients have access to safe, accurate and reliable diagnostic tests to help guide treatment decisions is a priority for the FDA,” Hamburg said in a statement. “Inaccurate test results could cause patients to seek unnecessary treatment or delay and sometimes forgo treatment altogether. Today’s action demonstrates the agency’s commitment to personalized medicine, which depends on accurate and reliable tests to get the right treatment to the right patient.”

The number of tests that could be affected by FDA’s action could be as high as 11,000, and the number of labs involved as high as 2000.

 Forthcoming guidance documents will spell out how manufacturers will provide information about their LDTs, which they can continue to sell and perform pending new rules. For now, the FDA will not move to regulate LDTs for rare diseases and certain tests for which there is no FDA-cleared option.

FDA’s move is not a surprise, as the agency has had its eye on the industry for some time. FDA issued a report in October 2013, “Paving the Way for Personalized Medicine,”

 outlining its possible role in nurturing molecular diagnostics. Some industry experts like Bruce Quinn, MD, PhD, of Foley Hoag LLP, have highlighted the contrast between the FDA’s view of the potential of molecular diagnostics compared with CMS,

 which is being sued by the California Clinical Laboratory Association over reimbursement disputes with Medicare contractors.

The agency has also been pressed by some members of Congress to close the regulatory gap exposed by the sharp rise in genetic and molecular testing, particularly in cancer care. US Rep. Louise M. Slaughter, a New York Democrat who is a microbiologist, hailed the FDA’s move, which came just over a year after she wrote to the Office of Management and Budget calling on the agency to exercise its authority to bring “transparency and accountability” to the field. “Diagnostic testing is an incredible medical breakthrough that holds the key to personalized medicine, but patients can only realize the benefits of diagnostic testing if the tests are safe and effective,” Slaughter said in a statement.

In her June 2013 letter, Slaughter noted that LDTs outside FDA oversight not only lack pre-market approval, but also are not subject to any post-market surveillance or recalls, despite their “interchangeable” nature in clinical settings. The current system, she said, offers “little transparency for patients or even doctors regarding what test has been used.”

There has been debate within the testing industry whether more FDA oversight helps or hurts. While regulation would bring higher costs to enter the market, some believe it could pave the way for fewer reimbursement disputes with insurers and, especially, with CMS.

 said officials would review FDA’s plan before reacting. In an e-mailed statement, Myriad Genetics said the company “looks forward to collaborating with policymakers and stakeholders to provide input and focus on the future of the US regulatory process for LDTs.”

Myriad, which has a reimbursement application pending with CMS for its Prolaris prostate cancer test, also said in its statement, “Myriad has a strong track record of scientific excellence that includes conducting numerous clinical studies in support of the analytical and clinical validity of our diagnostic tests.”

Nanostring CEO Brad Gray said a riskbased system of regulation could work as long as the reimbursement process recognized its value. He discussed the clearance process that Nanostring’s Prosigna breast cancer assay went through, which Gray said “required multiple clinical and analytical validation studies run to the FDA’s exacting standards across thousands of samples. We believe that the results are impressive, with the Prosigna assay outperforming the leading Laboratory Developed Test, Oncotype Dx, in a 1,000+ patient comparative effectiveness study.” (Gray cited a study that appeared in the 

“As a result, we believe the key to making the system work will be recognition by payers of the substantial time and investment required to meet the FDA requirements,” Gray continued. “Many industry participants are watching closely to see how payers react to the Prosigna assay in terms of setting both medical policy and establishing reimbursement. It will be important for them to see that the investment in FDA clearance is worthwhile if others are to follow in our footsteps.”

Gray noted that already, a large national payer has started offering Nanostring reimbursement for Prosigna. 

1. FDA takes steps to help ensure the reliability of certain diagnostic tests [press release]. Silver Spring, MD: FDA Newsroom; July 31, 2014. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm407321.htm

2. Herper M. FDA to regulate thousands of cancer, genetic and other diagnostics. Forbes website. http://www.forbes.com/sites/matthewherper/2014/07/31/fda-to-regulate-thousands-ofcancer-genetic-and-other-diagnostics/. Published July 31, 2014. Accessed August 4, 2014.

3. Simoncelli T. Paving the way for personalized medicine: FDA’s role in a new era of medical product development. http://www.fda.gov/downloads/scienceresearch/specialtopics/personalizedmedicine/ucm372421.pdf. Published October 2013. Accessed March 7, 2014

4. Caffrey MK. When science outpaces the payers: reimbursement in molecular diagnostics. 

5. Overly J. Medicare sued over erratic payment policies. Law360.com. http://www.law360.com/articles/530713/medicare-sued-over-erratic-payment-policies. Published April 22, 2014. Accessed April 25, 2014.

6. FDA heeds Rep. Slaughter’s call for transparency in laboratory diagnostic testing [press release]. Washington, DC: US House of Representatives; July 31, 2014. http://www.louise.house.gov/press-releases/fda-heeds-rep-slaughters-call-fortransparency-in-laboratory-diagnostic-testing/.

7. Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. 

FDA Moves to Regulate Thousands of Diagnostic Tests

If one thinks “cancer” and “New Jersey,” the images that come to mind might be those that have long defined the state: plumes of smoke along the Turnpike, acres of oil refineries, or fleets

An actual map of  cancer incidence reveals something else. For starters, most of the cancer occurs in South Jersey (

), where cornfields have given way to retirement communities. As for images that evoke emerging threats, think sun and sand, not smokestacks.

In line with the recent warning from Acting US Surgeon General Boris D. Lushniak,

 rising rates of melanoma in counties along the famous 126-mile shoreline have drawn attention from both state health officials and leading researchers.

 In summer months, the NJ Department of Health (DOH) sends teams right on to the beaches, both to educate sun worshippers and to screen for early cases of skin cancer, according to spokeswoman Dawn Thomas.

New Jersey’s cancer threats are similar to the rest of the nation’s; the difference is the degree (

). While overall cancer rates have fallen over the past 20 years, the state still ranked seventh in cancer incidence in 2011 with 49,080 cases, according to the American Cancer Society.

 That report stated the “big 4”—lung, prostate, breast, and colorectal cancer&mdash;still account for most of the state’s cancers; 52% of all cancer incidence and 49% of all cancer deaths. Lung cancer, with most cases caused by smoking, is the single biggest killer, accounting for 4100 of the state’s 16,370 cancer deaths in 2011.

 Rising rates of melanoma among the young and overall higher rates of thyroid cancer, which may or may not be explained by better detection,

 are also part of New Jersey’s complicated cancer story, which is one of great strides on some fronts and frustration in others.

If New Jersey once sat in the shadow of New York City and Philadelphia, it doesn’t act that way anymore. In the wake of Lushniak’s warning, the home page for the Cancer Institute of New Jersey (CINJ) was overhauled to highlight the “Call to Action” on melanoma, featuring both the work of CINJ behavioral scientist Eliot Coups, PhD, and of Howard L. Kaufman, MD, FACS, associate director of clinical science, who had just presented important phase 3 results using talimogene laherparepvec to treat melanoma at the American Society of Clinical Oncology in Chicago.

To be sure, New Jersey has come a long way from the 1970s, when it had the highest cancer rates in the country

 and a hard-to-treat case almost certainly meant crossing a river to one of its neighboring cities for treatment. Today, cancer rates among African American men have fallen and disparities between whites and minorities are narrower than in many other states.

Best of all, a state known for its bruising politics has achieved a bipartisan consensus that cancer patients should not have to travel out of state for care. Against a backdrop of state budget cuts and a recession that was deeply felt, cancer care for many has come closer to home, with governors and legislators from both parties overseeing significant investments in infrastructure. A $139 million medical school to serve South Jersey, discussed for decades, opened in Camden in 2012.

 Next door is the $100 million MD Anderson Cancer Center at Cooper, which opened in October 2013, transforming both a section of a beleaguered city and care itself.

More hard-won was a 2012 law, brokered by Republican Governor Chris Christie and Democratic Senate President Stephen Sweeney, who comes from Gloucester County in South Jersey, that restructured New Jersey’s higher education assets.

 Leaders of the major research institutions say this step is finally dismantling the silo effect that for decades prevented research entities from collaborating as fully as they might have and from taking full advantage of their close proximity to leading pharmaceutical manufacturers.Research today emanates from CINJ, a National Cancer Institute-designated center based in New Brunswick, NJ, that became part of Rutgers University in 2013 and had 476 active clinical trials last year, according to spokeswoman Michele Fisher.

Eight medical centers across the state enjoy major partnerships with CINJ, and even more have relationships. In South Jersey, the hub for cancer care is Camden, NJ, where a year-old collaboration between Cooper Medical School at Rowan University and the world-famous MD Anderson Cancer Center is ramping up; spokeswoman Wendy Marano reports that between October 2013 and June 2014, the center experienced 18% growth in patient volumes across all areas, including an 11% increase in complex cancer cases.

The medical school itself is still very new, having accepted its first class in 2012 (third- and fourth-year medical students from Robert Wood Johnson Medical School had previously trained at Cooper).

 At both CINJ in New Brunswick and MD Anderson at Cooper, leading oncologists report that the old pattern of New Jersey patients automatically going out of state for cancer care is quickly ebbing. In some cases, they say, cancer patients cross the Delaware or Hudson rivers into New Jersey to receive care. Marano said between October 2013 and June 2014, MD Anderson at Cooper experienced a 30% increase in cases from outside the traditional service area, including cases from Pennsylvania.

Amid these good signs, however, is a lingering undercurrent: the state’s ongoing financial distress. For more than 20 years, multiple governors have patched over or ignored the growing unfunded retirement obligations for New Jersey’s public employees. This spring, another revenue shortfall caused Gov. Chris Christie to propose cutting $1 million from the New Jersey Commission on Cancer Research and $10 million from CINJ.

 In April, Christie blamed the cost of public employee pensions for the proposed cut.

 Although the Legislature restored all the funding for budget for the fiscal year that began July 1, 2014,

 New Jersey’s ongoing challenge of how to meet the cost of retirement obligations to public employees threat-en every part of the budget, including cancer research, which has widespread support.

Overlooked in the budget debate is the fact that not a dime that New Jersey receives from the 1998 Master Settlement Agreement (MSA) with the 4 largest tobacco companies goes to combat smoking.

 Like 17 other states, New Jersey took the payout from the agreement upfront, and sold bonds that are paid off as settlement dollars arrive, a process called securitization. Unlike some states, New Jersey did not carve out settlement funds for smoking cessation.

 Instead, New Jersey uses $2.2 million in federal dollars for cancer screening and prevention; Generosa Grana, MD, director of MD Anderson at Cooper, had strong praise for the state health department efforts, which DOH’s Thomas said are based in all 21 counties. “We are catching cancer at an earlier stage,” Grana said, attributing this to 3 factors:

• sustained public education efforts, including attention from the media

• better screening and detection services, including broader access

• more access to genetic testing services, and a recognition of the role that testing and genetic counseling play in overall survival.

As with other parts of New Jersey’s cancer story, the onset of the Affordable Care Act (ACA) has been a mixed bag.

While some patients who previously lacked insurance now have it, CINJ’s Kaufman said some patients insured by the exchanges who have tried to get a test or scan out of state had trouble doing so (

The state’s environmental history is strongly connected to cancer’s footprint here, but just how much has been the subject of debate for decades.

Concerns about air and water pollution, and about toxins in landfills in a state where people are abundant and open space increasingly scarce, have driven state planning and environmental policies since the 1980s. New Jersey remains home to one of a handful of cancer clusters tracked by the CDC: the area around Toms River, NJ, where local concerns over possible connections between childhood leukemia and waste from Ciba-Geigy arose in 1996.

But Grana said studies of connections between environmental causes and cancer have not pinpointed a single factor. By contrast, she said, higher rates of smoking in South Jersey undoubtedly contribute to higher cancer rates in those counties, along with the older demographics of the population.

Overall, only 16.8% of New Jersey adults over the age of 18 years smoked in 2011, according to the CDC,

 but Grana said rates are higher in South Jersey, and this is reflected in lung cancer statistics. She said, however, that treatment for lung cancer is improving: CDC figures reflect that of the 4 major cancers, only lung cancer rates are lower than national averages (

The state’s cancer prevention efforts flow through NJ Cancer Control and Early Detection (NJ CEED) program, which operates through the state’s counties to provide education, outreach, and screening for breast, cervical, prostate, and colorectal cancer, according to Thomas. She said in the fiscal year that ended June 30, 2014, the program screened 24,700 women for breast, cervical, and colorectal cancer, as well as 847 men for prostate cancer. Ten task forces that cover 2 counties apiece operate statewide (including 1 through MD Anderson at Cooper). In a state that has long valued local control, this disbursement of screening services matters.

Evelyn Robles-Rodriguez, RN, MSN, APN-C, AOCN, who is the director of Oncology Outreach Programs at MD Anderson at Cooper, offered an example of the kind of program NJ CEED funds. Robles-Rodriguez received a call from an Indian temple in a nearby suburb a decade ago informing her that women at the temple weren’t being screened for cancers, and she was able to get funds for a screening program and a translator to ensure “culturally competent” services. On the very first visit, 38 women were screened, and today that clinic sees women at the temple once a month.

Another effort addresses the needs of Vietnamese women living in Camden, many of whom work as nail technicians throughout the area. A nurse practitioner at the hospital has just received funding to examine data from these 2 initiatives, “to see what inroads we have made,” Robles-Rodriguez said. Could New Jersey do more? Cancer control advocates succeeded in getting the legislature to ban minors under the age of 17 years from using commercial tanning beds, after the infamous case of the “tanning Mom,” whose 5-year-old showed up at school with burns.

Most of the 2013 recommendations from the American Cancer Society advocate getting more money aimed at the war against tobacco.

 A February 2014 report by another national group, the Campaign for Tobacco-Free Kids, criticized several states for the gaps between what they collect in tobacco taxes and MSA funds and what they spend on smoking cessation. In that report, New Jersey was listed with $947.2 million in overall tobacco-related revenue for fiscal year 2014. Instead of spending the CDC-recommended amount of $103.3 million on tobacco prevention, New Jersey was spending zero, according to the group.

A spokesman for the NJ Department of Treasury, Christopher Santarelli, said in an e-mail that $391.5 million in cigarette tax revenues are deposited “for general state use.” Currently, 76% of the MSA funds are used to pay bondholders and the rest goes to the Treasury; Santarelli said that this use is consistent with the purpose of the MSA, which is to repay states for the cost of  tobacco-related illnesses.

“Would it be ideal to have more money?” Grana asked rhetorically. It would always be better to have more, but she and Robles-Rodriguez sounded hopeful about how far they have come, using funds from multiple public and private sources. Said Grana, “The governor’s Office on Cancer Prevention and Control has done a great job of building the infrastructure we have.”

At CINJ, Getting the Right Therapies to Patients

The annual retreat on cancer research, co-sponsored by CINJ and the Commission on Cancer Research (CCR), came on May 21, 2014, at the height of the effort to restore millions in research dollars to the state budget. It was a display of contrasts, which at the time were quite serious. At the check-in table, a CCR commissioner hawked the familiar “Conquer Cancer” license plates while grumbling about Christie’s proposed cuts to research. Meanwhile, keynote speaker Arnold J. Levine, PhD, formerly of Princeton and Rockefeller Universities and today a professor at Rutgers Robert Wood Johnson Medical School, treated medical students to a high-level talk on his decades of work with p53-knockout mice, which has revolutionized the study of how cancer develops.

The breadth of studies at New Jersey’s research retreat was impressive: posters featured everything from preclinical studies on agents to treat pancreatic cancer, to studies of breast cancer among women veterans at the East Orange Veterans’ Administration hospital. With 134 clinical trials in various phases, the East Orange VA is yet another important source of cancer research.

At a session designed for the public, medical oncologist Janice Mehnert, MD, a Rutgers graduate, covered the rising incidence of melanoma along with CINJ’s ability to deliver newer immunotherapies to treat it through clinical trials. Mehnert was among those sounding the alarm about the dangers of too much sun. “Many of my patients come from Monmouth and Ocean counties,” she said.

In a later interview, CINJ’s Kaufman said getting the best, new therapies to cancer patients is among the institute’s main goals. “The division of clinical science is dedicated to identifying the most promising new drugs in development, to looking at new technology, in terms of diagnosis as well as treatment, and to fostering that translation into getting these things to the patient,”

Bringing CINJ into Rutgers, he said, has allowed better integration with the research units that do basic science; for example, the chemistry department has faculty that work on drug  development, but in the past lacked the connections to get their work into clinical trials. “We’re also trying to develop much stronger relationships with Newark, which has a different population of patients and different types of cancer,” Kaufman said. Both Rutgers and the state medical school have long had a presence in Newark, and the integration will open doors for more clinical trials at multiple sites that attract both larger numbers and a more diverse patient population.

Already, Kaufman said, CINJ is expanding its precision medicine program; the program has treated an initial 100 patients and is in the process of treating 500 patients. Of the first 100, Kaufman said, “40% had a change in clinical management based on information identified in genomic analysis.”

Arguments for giving South Jersey its own medical school and cancer center have been around for years. The population is growing. The demographics tilt toward seniors, who don’t want to travel far for care. Putting new medical facilities in Camden would provide jobs and economic development the city desperately needs. But most of all, the case makes sense medically. All one has to do is look at a map.

The southernmost counties that make up the area MD Anderson at Cooper serves have higher rates of cancer incidence and mortality than the rest of the state, according to CDC data. Higher smoking rates and demographics account for most of this, Grana said.

A visit to MD Anderson at Cooper reveals a hospital built from scratch with customers in mind. A wide driveway designed for easy pickups and drop-offs gives way to an airy entrance, and the facility features ample room for families and a healing garden. Patients receiving infusions can do so together or in private rooms. There’s no more hurrying to multiple appointments on different floors; instead, the doctors take turns visiting the patient in a state-of-the-art “pod.”

The relationship between MD Anderson and the medical school is close, with the cancer center’s physicians serving on the Cooper Medical School faculty, according to Grana. She said members of the incoming class were admitted based on both academics and their embrace of Cooper’s service ethic, for the purpose of “populating South Jersey with physicians who are well-trained and committed to the mission of the school.”

Cooper’s third class is highly competitive, according to data supplied by John McGeehan, MD, associate dean for student affairs and admissions. Some 5200 applicants vied for 72 spots in the class of 2018, and 53 members of the incoming class are from New Jersey.

Bringing the MD Anderson name and relationship to Cooper was no small feat, Grana said. Three factors that made MD Anderson interested were Cooper’s “completely employed physician model,” an existing infrastructure that supported clinical research and strong community outreach for cancer prevention and control, Grana said. After initial meetings took place, a 6-month due diligence period followed during which MD Anderson reviewed “every aspect” of Cooper’s program, she said. The agreement was signed in September 2013, and the new facility opened a month later.

There’s plenty of back-and-forth travel between Houston and Camden; faculty from the 2 sites sit on each other’s tumor boards and take part in numerous committees that cover everything from health information technology to patience experiences. Outreach is expanding, too. Robles-Rodriguez is seeing her role grow into new prevention and survivorship programs, which will be measured more than ever under the ACA. Cooper’s historic role as the provider for those without insurance is allowing the hospital to take the cancer screening data on patients who now have coverage, and deliver it to new patient-centered medical homes.

For those who have survived cancer, group sessions are allowing those who have had similar diseases to support one another as they work with Cooper to get nutrition information and develop a treatment plan, a new ACA mandate.

During 17 years at Cooper, Robles-Rodriguez has seen plenty of change, and she sounds optimistic. Years ago, patients fighting breast cancer “only had a handful of medications,” she said. “Now we have an arsenal of weapons. That has made a big difference, especially for those with more aggressive disease.”

More and more people are hearing the message, she said, “The earlier you detect the cancer, the higher your chances of surviving the disease.” 

1. Surgeon general issues call to action to prevent skin cancer [press release]. Washington, DC: HSS; July 29, 2014. http://www.hhs.gov/news/press/2014pres/07/20140729a.html.

2. Bates TB. This deadly cancer is on the rise at the shore. Asbury Park Press. http://www.app.com/story/news/investigations/watchdog/investigations/2014/06/27/skin-cancernj/11506143/. Published June 27, 2014. Accessed August 4, 2014.

3. O’Brien K. Cancer death rates continue to drop. The Star-Ledger. http://www.nj.com/news/index.ssf/2014/01/american_cancer_society_death_rates_continue_to_drop_nj_ranks_7th.html. Published January 7, 2014. Accessed August 4, 2014.

4. Carrascal A, Sciandra R, Hasbrouch E, Horner B. The cancer burden in New Jersey. American Cancer Society, New York and New Jersey. www.acscan.org/ny. Published July 2012. Accessed August 4, 2012.

5. Sayre C. The rising incidence of thyroid cancer. The New York Times. Published Times Essentials, 2011. Accessed June 2014. Also, information from NJ state epidemiologist Christina Tan, MD, via e-mail from NJ Department of Health spokeswoman Dawn Thomas, indicates that better detection techniques may account for some of the reported increase in thyroid cancer in New Jersey.

In New Jersey, Focus in Fight Against Cancer Changes, and Care Comes Closer to Home

In early May, an article reported on an approach undertaken by scientists at the National Cancer Institute (NCI) in which immune cells were isolated from a patient to attack her cancerous cells; the patient was suffering from metastatic cholangiocarcinoma, which had spread from the patient’s bile duct to her liver and lungs despite  chemotherapy.

 Following whole exomic sequencing, they identified CD4+ T helper cells (TH1) among the tumor-infiltrating lymphocytes (TILs) of the patient that recognize a mutation in the ERBB2IP protein expressed by the cancerous cells. The patient was initially subjected to an adoptive-cell transfer (ACT) with 25% mutation-specific TH1 cells, which shrunk the target lesions and stabilized the disease. However, when the disease progressed, the patient was administered >95% mutation-specific TH1 cells,

 Although the patient’s tumors have not disappeared, the treatment provides proof of concept that the body’s own defense system can be harnessed and reprogrammed to attack a solid tumor.

This approach has previously been used in treating patients suffering from leukemia and melanoma. Physicians at Memorial Sloan Kettering Cancer Center in New York treated 5 patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) with their own genetically modified T cells that expressed a CD19-specific CAR receptor.

 Although tumors in all 5 patients were rapidly eradicated, 2 patients died—1 from a blood clot and 1 in whom the cancer relapsed. However, 3 of the survivors received subsequent bone marrow transplants and have a good prognosis. The group recently published results from another study, this time with 16 patients with relapsed or refractory B-ALL who were treated with autologous T cells expressing CAR. The complete response rate was 88% among the 16 patients, most of whom subsequently received stem cell transplants. The group now plans to conduct a multicenter phase 2 study with the therapy.

In 2012, the National Cancer Institute published a report on the success of ACT in melanoma patients.

 Three separate trials treated 93 melanoma patients with their own TILs, which had been grown out in the laboratory, along with the cytokine interleukin-2 (IL-2). Of the 93 patients, the tumor was completely eradicated (complete response) in 20, and 19 remained tumor-free for more than 5 years; some stayed tumor-free more than 8 years. Significant tumor shrinkage was observed in 52 patients. A similar trial at The University of Texas MD Anderson Cancer Center found that 25 of 50 patients had partial or complete tumor responses.

However, according to Michael Kolodjiez, MD, national medical director for oncology strategies at Aetna, although these treatments are very promising, they’d be difficult to adopt in the clinic. In an interview with 

, Kolodjiez said, “CAR T cell therapies are complicated, their administration is complicated—consider what happened with Provenge. It’s definitely exciting therapy, but adopting it in the clinic can be challenging.”

The treatment is coupled with certain issues and side effects, as most cancer therapies are. The required lymphodepletion prior to the treatment, as well as the IL-2 administration, are associated with toxicity. A predicted consequence of rapid and potent antitumor immunity is the development of a generalized proinflammatory immune state. Furthermore, infusion of the large amount of T cells can generate an immune response, the cytokine release syndrome (CRS), that could potentially be fatal.

 CRS has been reported to occur several days to weeks after infusion of T cells. Additionally, both tumor lysis syndrome and macrophage activation syndrome have also been reported with the treatment.

 Efforts are ongoing to improve upon some of these procedural side effects of the therapy.

A research group at the Institute for Cell Engineering at the Johns Hopkins University School of Medicine, led by Jonathan Schneck, MD, PhD, has developed an innovative technique to attack a tumor: nanoscale artificial antigenpresenting cells (aAPCs). A graduate student in Schneck’s laboratory observed that treating the aAPCs with a magnetic field resulted in a clustering of T cells to which the aAPCs bind. Subsequently, naïve T cells were functionalized, which made the active T cells even more active. In turn, the normal immune response increased significantly. When injected into mice that were growing skin tumors, mice treated with nano aAPCs and then treated with a magnetic field presented significantly smaller tumors and longer survival compared with the control untreated mice.

Schneck has pioneered a start-up, NexImmune, based on these nanoparticles; the company has trademarked the process as Artificial IMmune (AIM) Technology.

 The company claims that AIM aAPCs can be precisely engineered to orchestrate a polarized immune attack on the patient’s tumor. The immune cells can be readily designed and are not susceptible to suppression by T

Traditionally, immunotherapy approaches can be classified into: monoclonal antibodies, cancer vaccines, and nonspecific immunotherapies.

Monoclonal antibodies reflect a more specific/targeted approach, since the antibody can be precisely targeted to a tumor-specific antigen.

 The current approach to improving the efficacy and safety of antibody treatment is the use of bispecific and even trispecific antibodies, combining parts of 2 (bi) or 3 (tri) antibodies together. A market research report released late last year identified several pharmaceutical companies (Roche, AbbVie, Pfizer, Sanofi, Amgen, Merck, and others) with ongoing phase

1 and 2 trials for bispecific antibodies.

 Meanwhile, a trifunctional antibody developed by TRION Pharma, Removab (catumaxomab), received approval in the European Union for the treatment of malignant ascites and is undergoing clinical trials in the United States (

Cancer vaccines were developed with the goal of boosting the immune system to attack cancer cells, quite unlike the traditional vaccines administered to prevent infectious diseases. Cancer vaccines can include entire cancer cells, parts of cells, or just the antigens. A more personalized approach involves using a patient’s own immune cells and sensitizing them to the tumor cells in the laboratory to create a vaccine.

 An example of an FDA-approved cancer vaccine is sipuleucel-T (Provenge) for advanced prostate cancer (

The nonspecific immunotherapy approaches include injecting cytokines, such as IL-2, interferons, and GM-CSF, into the body. Cytokines, produced by immune cells, regulate the growth and activity of other immune cells and blood cells, and can be administered either alone or concomitant with chemotherapy.

Immune checkpoint inhibitors (both chemical inhibitors and monoclonal antibodies) are currently receiving much attention. Immune checkpoints are a part of the body’s defense system that prevents immune cells from attacking “self.” Cancer cells, however, use these checkpoints to circumvent an attack by the immune system, and drugs targeting these checkpoints have gained huge strides in the clinic. Some of the immune checkpoint proteins being targeted include cytotoxic T-lymphocyte antigen-4

(CTLA-4), programmed death 1 (PD-1), and programmed death-ligand 1 (PDL1). CTLA-4, expressed on the surface of T cells, keeps T cells from attacking other cells in the body. Cancer cells use this to their advantage to prevent an immune attack. Ipilimumab is a monoclonal antibody that binds to and inhibits CTLA-4 (

). Although approved for melanoma, it is now being evaluated in combination with other antibodies and chemotherapy in the treatment of numerous other cancers. PD-1 is expressed

more often in T cells in inflamed tissues and tumors, where binding of the ligand PD-L1 prevents an immune response.

 Cancer cells have been found to overexpress

PD-L1 and efforts are ongoing to develop an antibody that effectively blocks PD-1 (

Said Kolodziej, “There’s a lot coming out with the new checkpoint therapies, and although it’s very exciting, it’s still too early. Policy decisions regarding such novel therapies are not made (at Aetna) until the FDA has approved them. Additionally, we at Aetna also try to harmonize with the NCCN (National Comprehensive Cancer Network) treatment guidelines.” He added that Aetna has an evidence section led by the senior medical director, which helps draft company policies on coverage by amalgamating FDA approval, NCCN guidelines, and of course the available evidence on the drug or treatment. Initially, coverage will reflect the FDA label indications, which he said are the strongest indications based on evidence. “Expansion of coverage will take into consideration the NCCN recommendations. Once the drug is commercially available, it’s very important to ensure that the right person gets the right treatment.”

 convened a panel discussion that brought together clinicians and payers to address the impact of the increased use of immunotherapy drugs in treating cancer in a managed care setting.

 The panelists agreed that immunotherapy, especially the newer checkpoint inhibitors, offer a promising approach in oncology. The drugs are currently being employed in refractory/relapsed patients, but the panel members expressed hope that immunotherapy would soon be used in curative and adjuvant settings.

Added Kolodjiez, “The sequence of therapies is important, but that’s not very clear yet. We need evidence for determining the sequence of administration of drugs. For example, consider melanoma: you have ipilimumab, B-RAF inhibitors, and the PD-1/PD-L1 inhibitors.” The FDA label could provide recommendations, but he suspects it will not.

The novel approach by researchers at the NCI and at Memorial Sloan Kettering is still at an early stage and considered “experimental” by insurance companies. Aetna’s policy bulletin states that ACT, using TILs or IL-2—treated lymphokine-activated killer cells, is classified as experimental and investigational therapy since there is not yet sufficient evidence that it is more beneficial than IL-2 alone.

 Cancer vaccines, specifically for melanoma and ovarian cancer, are also considered experimental therapy due to insufficient evidence of safety and effectiveness.14 Based on the available information for the drug, ipilimumab is considered necessary for malignant melanomas but experimental and investigational for all other cancers.

Labeled as the “Breakthrough of the Year” in 2013 by Science magazine,

 immunotherapy holds immense promise as an effective treatment—but an expensive one. If expert predictions hold true, employer-sponsored insurance plans have to brace for a big hit, because it is estimated that immunotherapy drugs&mdash;expected to treat nearly 60% of all cancers&mdash;will cost $35 billion per year within 10 years.

 Payers, of course, are developing models and algorithms—including reimbursement incentives, guideline-based coverage, pharmacist medication consults, and early intervention&mdash;to help reduce the cost of treatment with these specialty drugs.

When asked about determining the “value” of a particular treatment, Koldjiez said there are 2 important things that need consideration: “What is the outcome in terms of survival benefit, and the magnitude of the outcome in terms of symptom relief? Consider the PD-1/PD-L1 inhibitors as an example. Some patients have an extremely durable response and don’t need any more treatment for a long time, and the associated toxicities are minimal. But this is an exception and not a rule. In case of renal cell carcinoma patients, these inhibitors have proved extremely toxic and their effect does not last too long.” If a treatment is beneficial, says Koldjiez, the cost does not matter. The cost discussion, according to Kolodjiez, surfaces when the magnitude of benefit is small (a few weeks or months vs years). For treatments that provide greater benefit, there isn’t even a discussion.

Although the debate continues, an even-minded approach remains essential. Open conversation among patients, providers, payers, and the pharmaceutical industry will be what ultimately defines “value”: be it that of the drug or, more importantly, the patient’s life. 

1. Grady D. Patient’s cells deployed to attack aggressive cancer. 

. May 8, 2014. http://www.nytimes.com/2014/05/09/health/doctors-use-patients immune-cells-toshrink-cancer-tumors.html?_r=1. Accessed May 21, 2014.

2. Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. 

3. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. 

4. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. 

5. Phillips C. A transfer of power: harnessing patients’ immune cells to treat their cancer. NCI Cancer Bulletin. 2012;9(9). http://www.cancer.gov/ncicancerbulletin/050112/page4. Published May 1, 2012. Accessed May 22, 2014.

6. Kalos M, June CH. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. 

7. Nanoparticles and magnetic fields train immune cells to fight cancer in mice [press release]. Baltimore, MD: Johns Hopkins Medicine; February 24, 2014. http://www.hopkinsmedicine.org/news/media/releases/magnetic_medicine.

8. The next generation of immunotherapy. NexImmune website. http://www.neximmune.com/ home. Accessed May 22, 2014.

9. Types of cancer immunotherapy. American Cancer Society website. http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherap/immunotherapy-types. Accessed May 22, 2014.

August 2014

Robotic-Assisted Surgery: A Question of Value

FDA Moves to Regulate Thousands of Diagnostic Tests

In New Jersey, Focus in Fight Against Cancer Changes, and Care Comes Closer to Home

A New Method to Fight Cancer: The Body's Own Immune System

A Glimpse Into Managed Care of Diagnostics

Patient-Centered Physician Selection: A Necessary First Step for Accountable Care

Digital Technologies Gain Popularity for Smoking Cessation: Evidence Strongly Supports Some

Studies See Value of Prostate Cancer Diagnostic Test, but Will CMS Pay for It?

Reducing Risk and Improving Efficacy of Clinical Trials: the Adaptive Design

How Do You Establish Value in Cancer Care?

MMRF Efforts Attack the Disease From Every Angle; "Transformation" on the Horizon

AJMC Panel: Advances in Multiple Myeloma Therapy Extend Survival for Patients, Raising Cost Concerns

WellPoint Initiative May Challenge Some Practices

WellPoint Hopes a Name Change Will Ensure a New Tide of Consumers

AJMC Panel Asks: Does it Pay to Use Pathways?

ASCO's Initiative to Define Value In Cancer Care