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Charles L. Loprinzi, MD may have landed somewhat accidentally into the world of symptom management research, but once he arrived, he was there to stay.

Loprinzi has dedicated his medical career to oncology, including more than 3 decades at the Mayo Clinic in Rochester, Minnesota, where he currently serves as the Regis Professor of Breast Cancer Research. Underpinning much of his work, both at the bench and the bedside, is a dogged pursuit of interventions to provide patients with relief from the debilitating symptoms that often accompany a cancer diagnosis and its treatment.

“I was going to become a surgeon when I was in the first year or 2 of medical school ... but the very first clinical rotation I had was Internal Medicine, and I found that that was much more fun than sitting in medical school classes,” Loprinzi explained.

He said that he liked all of Internal Medicine’s subspecialties, and oncology offered him a way to touch upon many of them. Moreover, oncology was a field where the challenges were plenty: “We needed progress—there were a lot of questions that needed answering.”

Throughout his life, Loprinzi relished such challenges. Then he met Charles “Chuck” Moertel when he arrived at the Mayo Clinic in the mid-1980s. Moertel also chaired the North Central Cancer Treatment Group and was looking for someone to lead symptom-control research under the auspices of the Community Clinical Oncology Program (CCOP) because, as he told Loprinzi, “the treatment people don’t want to deal with such research.”

Loprinzi described the prevailing sentiment at the time more bluntly recalling what a highly respected colleague said to him during his days as an oncology fellow at the University of Wisconsin: “We don’t do puke studies here.”

Nevertheless, symptom management into the CCOP’s work in the area of cancer prevention and control, and Moertel saw in Loprinzi a promising researcher well suited to lead the effort.

Loprinzi agreed and has never looked back.

A native of Portland, Oregon, and the second of 10 children born over a span of only 11.5 years, Loprinzi said he learned early how to make his own way and to figure things out. He worked at a young age, learned to save the money he needed for his education, and set off for college at Oregon State University, sight previously unseen, with only 2 “banana boxes” of belongings.

These early experiences helped to set the stage for a career dedicated to problem solving and tackling the side effects that patients with cancer often confront and that, for some, persist long after their therapy ends.

Symptom-management trials were virtually nonexistent when Moertel first approached him, but Loprinzi has since authored hundreds of studies focusing on oral mucositis, anorexia/ cachexia, hot flashes, and chemotherapy-induced neuropathy, to name a few areas.

Randomized clinical trials he conducted early in his career demonstrated that megestrol acetate can improve appetite and lead to weight gain in patients with anorexia/cachexia. The research also illuminated the agent’s toxicity profile. Additional research Loprinzi led showed that megestrol acetate was helpful at low doses at relieving hot flashes in women with breast cancer, another principal focus of his research over the years.

Loprinzi also sought to find a solution to oral mucositis, a frequent and debilitating side effect of 5-fluorouracil (5-FU) and other chemotherapies. Following up on a suggestion of one of the nurses he was working with in the early 1990s, he led a study giving patients snow cone-like ice chips starting 5 minutes prior to 5-FU administration and continuing for 30 minutes.

The result: a 50% reduction in mucositis, according to patient-reported outcomes; ensuing studies replicated the benefit. Cryotherapy is now recommended in guidelines from the Multinational Association of Supportive Care in Cancer—not only for patients receiving 5-FU, but for other chemotherapeutic agents as well.

Currently, Loprinzi’s research is largely focused on chemotherapy-induced peripheral neuropathy (CIPN), a big problem, he said, that can be particularly hard on patients when it persists after treatment ends. He has led multiple randomized clinical trials testing promising agents for prevention of CIPN and/or treatment of established CIPN, but, “unfortunately, neuropathy remains a major clinical problem.”

“There is a substantial minority of patients who have problems [with CIPN] later on, which can be crippling for them,” he explained, which means it is very important to watch these patients closely as they are receiving potentially neurotoxic chemotherapy and identify those more prone to it early on. At times, stopping neurotoxic chemo- therapy is in order.

Loprinzi and colleagues have explored “scrambler therapy,” a nerve stimulation process that showed some promise in initial CIPN studies. His research team also evaluated minocycline, a potentially effective drug traditionally used in the treatment of acne, which they tested in a pilot, placebo-controlled, randomized trial of patients receiving paclitaxel for breast cancer; the drug did not appear to prevent CIPN, but may reduce acute pain syndrome associated with paclitaxel.

Since those nascent studies he conducted with Moertel, the field of symptom control research has grown steadily. Grounding those trials in strong science is essential, stressed Loprinzi. This means employing scientifically rigorous methodology, pursuing findings that are publishable in prominent clinical journals, and keeping their practice-changing potential top-of-mind—not only by defining new syndromes and treatments, but also by delineating those interventions without benefit or those that may actually cause harm.

Loprinzi has received numerous awards for his research, including the Susan G. Komen Foundation Brinker Award in 2002 and the 2005 Clinical Research Award from the Association of Community Cancer Centers. He has also been appointed as an ASCO fellow and he delivered the Charles G. Moertel Lecture, established in honor of his mentor, in 2013.

Loprinzi came to understand early in his career that cancer treatment was both a science and an art. He found a forum to showcase the latter in the “The Art of Oncology” section of the 

 (JCO). Now in its 17th year, the section remains a favorite among oncologists—offering succinct, compelling glimpses into the human side of the oncologist’s everyday practice. He is the section’s founding editor, having served in that role from 2000 to 2011.

Loprinzi said that at first he hesitated when JCO recruited him to be the section’s consulting editor: “I was thinking, ‘I am too busy,’ but then I realized this was an offer too good to be true, and I should just do it. It turned out to be a very educational and rewarding experience.” In addition to the regular feature in JCO, Loprinzi has edited 2 anthologies of selected essays from the series, 

Art of Oncology: Honest and Compassionate Responses to the Daily Struggles of People Living with Cancer

Loprinzi’s office at Mayo is on the 10th floor, but he rarely uses the elevator to get there. He said that he does some of his best thinking while being physically active, preferably outdoors. In recent years, he has vacationed with Margie, his wife of more than 30 years, and other couples on week-long walking tours in Great Britain.

The father of 3 grown children who all live nearby him—2 following his footsteps into healthcare careers&mdash;also likes to split firewood.

“I cut all of my own firewood, even in the middle of winter when it is below zero degrees outside. This is good thinking time.” He notes that when it is really cold outside, the wood splits better. It is often on these occasions that Loprinzi finds he can reflect on some of the practice and research challenges he faces every day.

Breaking issues down is a strategy that has helped him throughout his career. A case-in-point: how to determine—and convey to the patient and family&mdash;what treatment approach is right for each individual. For some individuals, the goal of treatment is to try to cure the patient. For other patients, this is not a realistic goal. But Loprinzi noted that in oncology, you “never say ‘Never’ and never say ‘Always.’” When cure is not the objective, he says that the goal is to have the patient “do as well as is possible for as long as is possible.” He further notes that this can be broken down into 4 items:

“First, we want you to have the fewest side effects as possible from the cancer for as long as possible. Second, we want you to have the fewest side effects as possible from the treatment. Third, we want you to have the longest life, and fourth, we want you to have the best quality of life.”

Loprinzi said that he does not determine which one of these 4 components is most important for each of his patients, but rather sees this approach as a framework to help guide these conversations for physicians. Importantly, it explains the issues in a way that patients and families can understand. It also can stimulate reflection on the risk—benefit profile of certain therapies—not only when to start them, but also when to stop.

“I think that there is a tendency for some physicians to treat too many patients, for too long, for too little benefit, without patients knowing it and without physicians admitting it,” he said. “There is a time for stopping cytotoxic therapy. I am convinced there is a time when chemotherapy causes net harm if it is used for too long, causing survival to be shorter than it would be without it; we do not know exactly when that is.”

The lodestar for Loprinzi’s work in caring for his patients when cure is not a realistic option is one of “compassionate honesty.” This means sitting down with his patients in the clinic, where he still spends about 20% of his time, to ascertain what their goals are as he provides a realistic assessment of their prognosis.

Loprinzi currently leads the symptom control program of the Alliance for Clinical Trials in Oncology Group. Among its latest projects is a new multisite trial led by Jennifer Temel of Massachusetts General Hospital. Temel was the lead investigator on the seminal study, published in 

 in 2010, that demonstrated a survival benefit when early palliative care was provided to patients with metastatic non—small cell lung cancer (NSCLC).

The trial (NCT02349412), noted Loprinzi, is examining the effect of early palliative care beyond the NSCLC setting to include patients being treated for other advanced lung and gastro- intestinal cancers.

“When I started my career, very few people were focusing on symptom management,” recalled Loprinzi, “but now, it has become more popular. I can tell you that a number of practicing oncologists are very happy to hear the results of many symptom-control studies, which influences their clinical practice.”

Still, he underscored, one trial will not give a researcher all of the answers, and as one question gets answered, 10 more are likely to emerge, which is one of the features of oncology research and practice that attracted Loprinzi in the first place. “I have been very fortunate to have been associated with a number of clinical trials that have described interventions that have actually influenced clinical practice,” he said.

Articles

Making the Cancer Journey Tolerable: Loprinzi Puts Focus on Symptoms

It was little more than 3 years ago that ibrutinib (Imbruvica) became the first Bruton tyrosine kinase (BTK) inhibitor to gain the FDA’s approval with a second-line indication for patients with mantle cell lymphoma.

Today, ibrutinib is broadly approved in chronic lymphocytic leukemia (CLL) and WaldenstroÌˆm macroglobulinemia, and efforts continue to expand its uses in other hematologic malignancies.

Meanwhile, the drug development pipeline is stocked with several promising candidates that attack the same target.

Although a new generation is chasing ibrutinib, the original BTK inhibitor continues to demonstrate its paradigm-changing value in CLL and its potential to make an impact in other blood cancers. An application is pending with the FDA for an indication in marginal zone lymphoma.

The progress that has been made in targeting BTK was evident at the 2016 American Society of Hematology (ASH) Annual Meeting held in December, where the latest research into ibrutinib and several novel candidates was presented.

BTK is a downstream component of B-cell antigen receptor signaling; its inappropriate activation has been demonstrated to be involved in the maintenance of a wide variety of malignancies including CLL, acute lymphoblastic leukemia, chronic myeloid leukemia, and even in solid tumors such as colorectal carcinoma.

At 2016 ASH, findings from the longest follow- up to date evaluating up to 5 years of ibrutinib in patients with CLL and small lymphocytic lymphoma (SLL) show that the agent is safe and effective, with 89% of both treatment-naiÌˆve (TN) and relapsed patients experiencing a complete (CR) or partial response (PR) to the therapy (Abstract 233).

“These 5-year results suggest that both previously treated or untreated CLL/SLL patients may achieve robust and long-lasting responses with single-agent ibrutinib, with more patients developing a complete response over time,” said lead investigator Susan O’Brien, MD, associate director for clinical science at the Chao Family Comprehensive Cancer Center, University of California Irvine Health. “Our data suggest that starting treatment with ibrutinib as early as possible in CLL/SLL has promising clinical potential for long-term progression-free and overall survival.”

The data are from the phase Ib/ II PCYC-1102 trial, which evaluated single-agent ibrutinib in TN patients with CLL/SLL and relapsed/ refractory (R/R) patients. O’Brien reported long-term findings based on 132 patients with CLL/SLL: 31 were TN and 101 participants were R/R. Patients received either 420 mg or 840 mg once daily until disease progression or unacceptable toxicity.

Median duration of response had not been reached for TN patients and is 45 months for R/R patients. “Ninety-two percent of treatment-naiÌˆve patients are progression-free at 5 years,” O’Brien stated, adding that CR rates have increased over time to 29% for TN patients and to 10% in the R/R group. Median progression-free response (PFS) has not been reached in the TN group; for R/R patients, median PFS is 52 months.

A long-term extension study (PCYC-1103), collected data on grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation. “Ibrutinib is well-tolerated,” O’Brien said, “with onset of most new grade ≥3 AEs decreasing over time.”

In a separate study, ibrutinib demonstrated encouraging findings as a treatment for patients with chronic graft-versus-host-disease (cGVHD) that was not resolved by corticosteroids. Ibrutinib showed clinically meaningful and durable responses in patients who failed at least 1 prior treatment for cGVHD (Abstract LBA3).

Of the 42 participants who experienced GVHD, 67% responded to ibrutinib, and 71% had sustained improvements over a 5-month period. According to the researchers, the results are encouraging for a subset of patients with limited treatment options beyond corticosteroids.

“Clinicians will find these data support the use of ibrutinib in patients with steroid-refractory chronic GHVD, who currently suffer a range of symptoms that can be chronic and debilitating,” said David Miklos, MD, PhD, associate professor of Blood and Marrow Transplantation at the Stanford University Medical Center.

Preclinical laboratory studies suggested that ibrutinib might also inhibit immune cells involved in cGVHD. Supported by earlier findings, ibrutinib was granted a breakthrough therapy designation by the FDA for cGVHD after failure of 1 or more lines of systemic therapy.

Combination induction therapy with ibrutinib and obinutuzumab (Gazyva) after bendamustine debulking induced a 100% response rate in patients with CLL, according to findings from the phase II CLL2-BIG trial (Abstract 640). The minimal residual disease negativity rate in the peripheral blood at final restaging was 47.5%.

“The BIG regimen showed very promising efficacy in a heterogeneous CLL population,” lead study author Julia von Tresckow, MD, of the Department of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University of Cologne, Germany, said when presenting the data at 2016 ASH.

The data reported at ASH were for 61 of 66 patients recruited to the trial; 5 patients were excluded because they completed fewer than 2 cycles of induction therapy (1 death, 2 due to AEs, and 2 patient self-withdrawals).

The overall response rate (ORR) with bendamustine debulking was 65.9%, including an unconfirmed CR rate of 9.1% (n = 4), an unconfirmed CR rate with incomplete recovery of the bone marrow (CRi) of 6.8% (n = 3), and a partial remission (PR) rate of 50% (n = 22). The stable disease rate was 25% (n = 11) and the progressive disease rate was 4.5% (n = 2).

The investigational next-generation BTK inhibitor acalabrutinib has shown promise as a treatment for patients with CLL. In previously reported findings, monotherapy with acalabrutinib at 100 mg twice daily resulted in an ORR of 95% for patients with relapsed/refractory CLL/SLL. In findings from the frontline CLL setting that were presented at the 2016 ASCO Annual Meeting, the ORR was 97% with acalabrutinib.

Acalabrutinib is currently being compared with ibrutinib in a phase III study for high-risk patients with relapsed CLL (NCT02477696). Additionally, the agent is being explored alone or in combination with obinutuzumab versus chlorambucil and obinutuzumab (NCT02475681).

In the ACE-CL-001 study, only one-third of patients who were ibrutinib-intolerant and subsequently treated with acalabrutinib had a recurrent adverse event, reported Farrukah T. Awan, MD, associate professor, division of hematology, department of internal medicine, Ohio State University (Abstract 638). In addition, acalabrutinib generated a 79% ORR in ibrutinib-intolerant patients.

The study included 33 patients with confirmed CLL and intolerance to ibrutinib. They were treated with acalabrutinib, 100 mg twice daily (n = 30) or 200 mg daily (n = 3), until disease progression or discontinuation.

“Acalabrutinib was fairly well tolerated. There were very few grade-3 or higher adverse events, and those were primarily hypertension, fevers, and myalgia,” said Awan. “The majority of the events were grade 1, and those were most commonly diarrhea and headache.”

Two grade 5 events that occurred while patients were on acalabrutinib, stroke and disseminated systemic fungal infection, were both deemed unrelated to study drug.

Acalabrutinib produced an ORR of 38.1% as a monotherapy for patents with Richter transformation (RT), according to the phase I/II ACE-CL-001 study presented at the 2016 ASH (Abstract 60). In the ongoing trial, the median PFS with acalabrutinib was 2.1 months.

“Acalabrutinib induced complete response and partial responses in a heavily pretreated group of patients with Richter transformation, which is a poor-prognostic group of patients,” said lead investigator Peter Hillmen, MD, PhD, Department of Haematology, Churchill Hospital Cancer Centre, Oxford, United Kingdom. “Initial data of acalabrutinib monotherapy in Richter transformation suggest that further investigation in combination with chemoimmunotherapy or other targeted therapies is warranted.”

The phase I/II study enrolled 29 patients with RT, with primary histologies of diffuse large B-cell lymphoma (DLBCL) with underlying CLL (n = 25), CLL transformed to prolymphocytic leukemia (PLL; n = 3), and follicular lymphoma to DLBCL (n = 1). During the study, acalabrutinib was administered at 200 mg twice daily, which is double the standard dose used in other studies. This higher dose was used to counter the aggressiveness of RT, Hillmen explained.

The CR rate was 9.5% and the PR rate was 28.6%. An additional 23.8% of patients had stable disease. In patients with CLL-related DLBCL, the ORR was 32%. Both CRs were in patients with DLBCL, 1 of which received a stem cell transplant. A second patient with a PR also received a stem cell transplant.

A relative newcomer to the BTK inhibitor scene, BGB-3111 is under exploration in 3 phase I clinical trials focused on establishing its safety and efficacy for patients with B-cell lymphoid malignancies as a single agent and in combinations. The agent is being combined with obinutuzumab (NCT02569476) and BGB-A317, an early-stage PD-1 inhibitor (NCT02795182).

In phase I research presented at 2016 ASH, BGB-3111 demonstrated a 96% ORR among patients with CLL and SLL, consisting entirely of PRs (67%) and PRs with lymphocytosis (28%) (Abstract 642). In those with high-risk molecular characteristics (del17p and/or del11q; n = 17), the ORR was 100%. Additionally, treatment with the agent was well tolerated, despite higher selectivity of targets such as TEC thought to induce greater AEs.

In all, 66 patients with CLL/SLL received BGB-3111 at escalating doses starting at 40 mg daily to 160 mg twice daily. The analysis included 46 patients with at least 12 week of follow-up. The median duration of follow-up in the study was 8.6 months.

“No patients had progressive disease or Richter transformation to date. With limited follow-up, efficacy appears independent of molecular risk features,” said lead investigator Constantine S. Tam, MBBS, Peter MacCallum Cancer Centre, Melbourne, Australia. “Late-stage clinical trials will reveal whether BGB-3111’s excellent tolerability and high target occupancy will translate into improvements in disease control, rates of drug resistance, and rates of treatment-limiting adverse events.”

BGB-3111 has similar BTK selectivity as ibrutinib; however, the agent is more selective for EGFR, ITK, JAK3, HER2, and TEC. In plasma studies conducted on peripheral blood and lymph nodes, the optimal dose, based on BTK occupancy, was defined 160 mg twice daily (

For complete abstracts, visit https://ash.confex.com/ash/2016/webprogram/start.html.

It was little more than 3 years ago that ibrutinib became the first Bruton tyrosine kinase (BTK) inhibitor to gain the FDA’s approval with a second-line indication for patients with mantle cell lymphoma.

BTK Inhibitors Mushroom in Blood Cancer Field

 has quickly become a buzzword in the oncology field and, as a result, its meaning is getting blurry. As Pulitzer Prize-winning oncologist Siddhartha Mukherjee described it in a recent 

 interview, Big Data means “the very deep annotation of patients, their individual cancers, the genetic components of their cancers, and how these cancers are behaving over time.”

The power of that ability to analyze cancers over broad populations has generated much excitement in the drug development arena and it’s not hard to understand the reasons. In “Big Hopes for Big Data,” our cover story in this issue of 

, leading researchers discuss the real-world implications for putting this concept into action.

Perhaps the best example so far is the rapid growth of the American Society of Clinical Oncology‘s CancerLinQ initiative. In just 4 years, CancerLinQ has grown from a prototype to a database with information on more than 1 million patients and the participation of more than 1500 oncologists.

The possibilities for using such a remarkable tool to improve patient care are endless. The data could be mined for patterns of responses to therapy, incidences of adverse events, and targets for new and existing drugs—just to name a few potential uses.

Imagine the same power on an even grander scale as envisioned by the Cancer Moonshot initiative: the building of a nationwide pool of data. If the federal government can appropriately safeguard patient privacy, we may be able to unlock many of the genomic secrets of cancer.

It is important to remember, of course, that the promise of Big Data still resides in the realm of possibility. As a cautionary tale, we might want to remember that it wasn’t that long ago that excitement ran amok about the sequencing of the human genome. The outsized expectations for the benefits of genome sequencing eventually soured the public view of what truly was a remarkable achievement.

This time, the oncology field has an opportunity to lead the way again. Judging by how this effort is shaping up so far, we are quite optimistic.

The power of that ability to analyze cancers over broad populations has generated much excitement in the drug development arena and it’s not hard to understand the reasons.

The Big Data Buzz

Amid a rising incidence of thyroid cancer, endocrine surgeons have increasingly explored minimally invasive approaches for operating on patients with the disease. At Tulane Cancer Center, we are pioneering the use of transaxillary robotic-assisted thyroid and parathyroid surgery to deliver optimal outcomes to appropriately selected patients without the visibly disfiguring scarring that results from conventional techniques.

There is no doubt that new strategies are needed. Thyroid cancer is now the fastest- growing major cancer in the United States; the incidence of the disease rose by 209% from 2001 to 2013.

 Currently, thyroid cancer is the most common tumor type among women younger than 35 years. In 2014, almost 63,000 new cases of thyroid cancer and 1900 related deaths were reported in the United States, and the incidence is expected to rise to nearly 90,000 cases in 2019.

Historically, the first acceptable surgical techniques for thyroid cancer were developed in the late 19th century by the German surgeon Theodor Billroth and his onetime protégé Theodor Kocher, who won a Nobel Prize in 1909 for his work on the thyroid gland.

 Since then, mortality from thyroid operations has become extremely rare.

However, the current gold standard for thyroidectomy, the conventional cervical approach, results in visible scarring that is upsetting to many patients. During the past 20 years, the focus in surgical management of thyroid cancer has shifted to improved cosmetic outcomes, shorter hospitalizations, and faster recovery timeframes.

Minimally invasive options that have been introduced include endoscopic approaches with CO2 gas insufflation. In 2001, South Korean surgeons first described and adopted the gasless endoscopic thyroidectomy using a nonrobotic transaxillary approach. Although this represented an advance, endoscopic approaches have not been widely adopted in the United States due to technical limitations and disadvantages.

An important next step has been the introduction of robotic technology without the use of gas insufflation. In 2009, Woong Youn Chung, MD, PhD, of Younsei University Hospital in Seoul described the use of an axillary incision to access the thyroid space with robotic assistance.

With this method, surgeons gain the ability to control a magnifying 3-dimensional high-definition camera system with multiarticulated tremor-free endoscopic arms and a stable platform, thus restoring the fundamentals that were lost in the transition from conventional to endoscopic neck surgery.

This novel approach offers surgeons as excellent an operative view as the conventional strategy; it also allows easy manipulation of the upper and lower thyroid poles and leaves the incision well hidden in the axillary fold or retroauricular crease.

Thus, the gland and cancerous lymph nodes can be removed without leaving with a disfiguring visible scar in the anterior cervical area, a much preferred outcome, especially for young female patients.

The Department of Surgery at Tulane has a strong collaboration with Professors Chung and Sang-Wook Kang, MD. They have performed more than 5000 operations, and we have conducted hundreds of these procedures with excellent outcomes at our center.

Compared with the conventional method, the Tulane team and others have demonstrated that the transaxillary robotic approach has equal oncological outcomes and provides additional benefits such as identification and preservation of the recurrent laryngeal nerve and parathyroid glands.

 After performing hundreds of these robotic cases, our team started doing oncological neck dissections through these hidden incisions under the arm. Tulane has the largest experience with these operations in the United States.

Similarly, robotic facelift using a retroauricular approach also allows surgeons to gain remote access to the thyroid space without the need of a cervical incision. Other types of robotic thyroid surgeries include thyroid lobectomy, total thyroidectomy, central compartment neck dissection, and radical neck dissection for benign and malignant thyroid diseases.

Outcomes related to transaxillary robotic approaches were comparable with the open conventional thyroidectomy in all postoperative complications. Due to the definite learning curve associated with robotic thyroid surgery, it is the surgeon’s responsibility to ensure that the procedure is performed without compromising the patient’s safety.

Chung has emphasized the importance of selecting the appropriate patients for robotic surgery, starting with a preoperative workup that includes imaging through high-resolution ultrasonography and neck computed tomography and tissue analysis via fine-needle aspiration cytology.8 The tumor characteristics to be considered are size, site, presence of extrathyroidal invasion, multiplicity, bilaterality, and the presence of cervical lymph node metastasis.

Individuals with follicular proliferation with tumor size ≤5 cm and differentiated thyroid cancer are considered candidates for robotic thyroidectomy.

 Exclusion criteria include previous head and neck surgery or radiation, uncontrolled thyrotoxicosis, lesions in the dorsal thyroid area, suspected perinodal infiltration to adjacent structures or major nerves, or distant metastasis.

Although robotic approaches for thyroid surgery have proved to be feasible and safe in a select group of young patients, the technique remains a novel procedure that should only be performed by high-volume thyroid and parathyroid surgeons.

Sosa JA, Hanna JW, Robinson KA, Lanman RB. Increases in thyroid nodule fine-needle aspirations, operations, and diagnoses of thyroid cancer in the United States. 

. 2013; 154(6):1420-1426; discussion 1426—1427. doi:10.1016/j.surg.2013.07.006.

Aschebrook-Kilfoy B, Schechter RB, Shih YC, et al. The clinical and economic burden of a sustained increase in thyroid cancer incidence. 

. 2013; 22(7):1252-1259. doi:10.1158/1055-9965.EPI-13-0242.

Hannon SA. The magnificent seven: a history of modern thyroid surgery.

. 2006;4(3):187-191. doi:10.1016/j. ijsu.2006.03.002.

Kandil EH, Abdelghani S, Noureldine SI, et al. Transaxillary gasless robotic thyroidectomy: a single surgeon's experience in North America. 

Kang SW, Jeong JJ, Nam KH, et al. Robot-assisted endoscopic thyroidectomy for thyroid malignancies using a gasless transaxillary approach.

. 2009;209:e1-e7. doi: 10.1016/j. jamcollsurg.2009.05.003.

Perrier ND, Randolph GW, Inabnet WB, et al. Robotic thyroidectomy: a framework for new technology assessment and safe implementation. 

. 2010; 20(12):1327-1332. doi:10.1089/thy.2010.1666.

Noureldine SI, Jackson NR, Tufano RP, Kandil E. A comparative North American experience of robotic thyroidectomy in a thyroid cancer population. 

. 2013;398(8):1069- 1074. doi:10.1007/s00423-013-1123-0.

Lee J, Chung WY. Robotic surgery for thyroid disease. 

. 2012;2(2):93-101. doi:10.1159/0003560209.

Amid a rising incidence of thyroid cancer, endocrine surgeons have increasingly explored minimally invasive approaches for operating on patients with the disease.

Robotic Surgery Represents a Notable Advance in Thyroid Cancer Care

The passage of the 21st Century Cures Act

 sparked unusually robust holiday celebrations throughout the cancer research community, which harbors high hopes for both the newly funded initiatives and future budget increases.

The act will provide the National Cancer Institute (NCI) an extra $1.8 billion to fund the Cancer Moonshot, an effort to make 10 years of research gains in just 5 years by directing new money to 10 potentially transformative research areas (

). It also gives the FDA the ability to consider real-world clinical data in determining drug indications.

The Moonshot money is the first major boost in federal spending on cancer research in many years, but researchers see reason to hope that it won’t be the last. The surge in new cancer drugs

, and the often incredible results from immunotherapy trials seem to have increased enthusiasm for research spending among politicians and the public.

“As with everything in cancer research, there are some caveats. The vote in December only allocated the first year of funding, and the extra money could go away next year. All that duly noted, the 21st Century Cures Act is very exciting,” said Daniel F. Hayes, MD, president of the American Society of Clinical Oncology (ASCO). “It should provide both an increase in funding for the National Institutes of Health, and therefore the NCI, as well as additional funding for [former] Vice President Biden’s Cancer Moonshot initiative.

“NCI funding has been flat for a decade now, and inflation has decimated real spending to the point that only a tenth of research proposals get funded. If this new initiative is a harbinger of steady increases, then it’s very good news for cancer researchers trying to get support and, more importantly, for our patients who will benefit from it,” said Hayes, who is also co-director of the Breast Oncology Program at the Michigan Comprehensive Cancer Center. “Even if it turns out to be a onetime deal, at least it directs a significant amount of money to many areas that promise big returns.”

Asked to name the most promising of the Moonshot’s 10 research foci, Hayes replied that doing so would be as hard as naming the most promising of his children. Asked what tied the various aspects of the Moonshot together, he answered with a single word: data. Most of the specific research recommendations envision the aggregation of huge amounts of data and the extraction of important discoveries from those collection points.

More than 50 years have elapsed since data analysis produced one of the biggest ever breakthroughs in the war against cancer: indisputable proof that smoking dramatically increases cancer risk.

 Observers have been predicting for decades now that increasing computer power and digital storage would enable many more analytical triumphs. Although those predictions have yet to come true, many see more promise than ever in Big Data.

The importance of information analysis to the Moonshot becomes apparent in the very first focus area: offering comprehensive tumor profiling to a large number patients who agree to participate in a national network that will track what strategy works on what tumor and provides researchers an easy way to instantly find people who qualify for particular clinical trials.

Other goals that explicitly seek to use Big Data analysis or to encourage such studies include the creation of a national data ecosystem that allows sharing between many existing and all future datasets, the retrospective analysis of biospecimens from patients treated with existing standards of care, the generation of 3-D tumor atlases that map the development of every tumor, and the creation of a bank of tumors categorized by responses generated with various forms of immunotherapy.

The raw technology for most of these initiatives has been available for years now, but a lack of digital data and the inability—or unwillingness&mdash;to share what data existed have always limited the impact of data mining on health research.

Many industries had switched entirely to electronic records by the mid-1990s, but less than 30% of all office-based physicians were using electronic health record (EHR) systems just a decade ago.

 The percentage of US physicians using some sort of EHR didn’t break 80% until 2014. Even then, most doctors used only basic systems. Nearly 40% of doctors had yet to start storing and viewing imaging results electronically.

That information that was stored electronically, moreover, has been mostly unavailable to researchers hoping to mine it for hidden treasure. Privacy laws, turf wars, and the technical incompatibility of different collection and storage systems have made it nearly impossible to aggregate truly huge amounts of information in ways that would maximize its value for would-be analysts.

The federal government and private organizations have been working for several years now to increase the ability to securely share data, often information that has been anonymized, across multiple platforms. The government has attempted to create standards with programs such as the Health Information Exchange.

Private organizations have sought to build datasets that lend themselves to research, datasets such as ASCO’s CancerLinQ program, which already has enrolled more than 1500 physicians and accumulated more than 1 million patient records.

 Hayes voiced particular enthusiasm about CancerLinQ, predicting that it “will be a game changer, both for individual practice quality control and for highly granular observational research in the future.”

Supporters of the Moonshot hope that the new money, along with the publicity surrounding it, create a sense of urgency about breaking down the remaining barriers to data aggregation, all while protecting patient privacy and intellectual property.

“We must agree to a radical new approach to sharing data. Not only should there be more team scientific research, but those researchers should share their data and learnings more broadly with outside researchers and the patients involved in the clinical trials for new products,” said Jeffrey Bluestone, PhD, president and CEO of the Parker Institute for Cancer Immunotherapy, speaking in a statement about the 21st Century Cures Act. “It is time to break down the silos and barriers to advancing knowledge for the best interests of patients who are waiting for new cures.”

Bluestone, a professor and noted immunologist at the University of California San Francisco, is charged with implementing the collaborative mission of the institute, which technology entrepreneur Sean Parker launched last year with a $250 million grant. The institute brings together more than 300 scientists at 6 of the nation’s top cancer centers to share in immunotherapy studies including the administration of intellectual property. One early project calls for a first-in-human trial using CRISPR/Cas9 gene-editing technology.

The data mining advocated by the new act isn’t just about facilitating the development of new cures. It’s also about helping clinical physicians and their patients make better use of existing treatments by giving them unprecedented amounts of information about how people with genetically similar tumors have responded to various treatment options.

The explosion in treatment options for many cancer types has already made it financially impossible to run trials large enough to compare all the possible combinations to determine which therapies should be used in which order against tumors with particular genetic mutations. Analyzing outcomes among thousands of real-world patients, even if it doesn’t provide the sort of definitive answers that randomized trials do, may well be the only way to gather data on a variety of regimens for different tumor types. Such analysis might narrow the field enough to make randomized clinical trials for the top contenders feasible, or it might determine standards of care on its own.

Under provisions contained in a different portion of the 21st Century Cures Act, data from real-world patients can also be weighed by the FDA in expanding the indication of an already approved medication. Regulators can use such information to supplement trial results, or, if they find the real-world outcomes compelling enough, they can approve new indications based on that data alone.

This provision, which applies to all types of medication, not just cancer drugs, is probably the most controversial component of the new act. Opponents say it is a dangerous gift to drug makers that will lead to unwarranted indications. Proponents say that, used properly, it may be the best part of the act: a scientifically valid method to greatly speed the rollout of drugs with multiple uses.

Existing clinical data may be enough to win expanded approvals for some medications in the relatively near future, but opportunities will multiply for developers of cancer drugs as the Moonshot gets underway and exponentially more clinical data become available to them. These data will come not only from the government, academia, and clinical practitioners but also, the designers of the Moonshot believe, from pharmaceutical companies themselves.

“Pharmaceutical companies have historically been reluctant to share data. Their model has been to use their considerable financial resources to generate proprietary information and use that information to develop drugs. As we move to precision medicine, though, they’re going to need more data to make new targeted medications than any single company can collect. Pharma has already experimented some with data sharing, and I think it will jump in with both feet when it becomes clear how much the benefits of seeing outside data outweigh the costs of sharing their own data,” said Elizabeth M. Jaffee, MD, who co-chaired the blue-ribbon panel that chose the Moonshot’s 10 areas of concentration.

Indeed, Jaffee believes that the unexpected success of much less ambitious efforts to harness Big Data will lead to widespread public, private, and academic participation in the new efforts.

“There was a controversy a few years ago about sequencing cancer genes. Some people argued that it wasted money to compile data that no one would ever use, and it turns out that everyone uses it. If you want to know what percentage of pancreatic cancers express a particular pathway, you can look it up in 30 seconds, and that’s hugely valuable for testing hypotheses,” said Jaffee, the deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

“Thanks to that success, there’s overwhelming support for the Moonshot plan to move from these one-dimensional tumor models that focus only on genes to 3-dimensional models that provide a complete view of tumor proteins and immunology as well,” she said. “It’s a similar story with the other data initiatives. There seems to be widespread support for finally getting these things done.”

Many of the Moonshot’s 10 areas of concentration are very broad but there are several more targeted initiatives besides the development of the 3-D cancer atlas. Jaffee’s panel specifically recommended more research into childhood cancers. The panel believes that a better understanding of the onco-proteins that produce childhood cancers will uncover potential pathways for inhibiting them.

Another area of specific focus for the Moonshot is early detection and prevention, which currently gets a very small share of cancer research money. Many types of projects could qualify for funding, ranging from the development of more effective antismoking campaigns, to experiments designed to determine what genetic profiles warrant extra cancer screening to the development of cancer vaccines.

All the additional funding will not go to research topics that were not attracting big money before the passage of the 21st Century Cures Act. A sizeable chunk of the money will go directly to the research area that’s already attracting billions of dollars of investments per year: immunotherapy.

“As an immunotherapy specialist who remembers how difficult it was to get any research money just a decade ago, I’m obviously delighted that this field is now getting resources and making breakthroughs. I also believe that, for all the money immunotherapy is getting now, it will still be possible to generate major returns with this additional investment, if NCI takes the rather vague language of the legislation and creates a system that awards the grant money judiciously,” said Howard L. Kaufman, MD, assistant director for Clinical Science at the Rutgers Cancer Institute of New Jersey.

“Also—and this is going to sound odd coming from a guy who focuses on immunotherapy&mdash;we need to make sure that this one area doesn’t get too big a percentage of the research dollars. No one strategy is the answer and there’s a part of me that thinks the pendulum may have swung a bit too far away from targeted therapies,” Kaufman said. “I’d like to see more research into how targeted therapies and immunotherapies can be better used in conjunction because that is, I suspect, where treatment is headed for a number of tumor types.”

Kaufman, along with everyone else interviewed for this story, had no forecasts about whether the new legislation would prove to be an exception in the ongoing trend of declining public research dollars or whether it would prove a harbinger of better times ahead. All three expressed the feeling that technological advances, along with an improved understanding of disease, have created the opportunities for significant breakthroughs in the battle against many maladies, especially cancer. Increased investment in medical research at this particular moment would therefore create exponential returns, if politicians, philanthropists, pharmaceutical executives, and the public decide to make such an investment.

“The mortality numbers don’t show it yet, but I think we’re already in a period of very significant gains in oncology, sort of like cardiovascular medicine was when statins were first introduced. They knew they had something pretty important, but it took almost 20 years for the mortality figures to show the full extent of the impact,” Kaufman said. “There are just so many conditions in cancer now where people are living dramatically longer, such as advanced melanoma where they used to live 6 to 9 months and currently live for 24 months or more... And significant discoveries keep coming. It’s a good time to invest.”

H.R.34—21st Century Cures Act. Congress.gov database. https://www.congress.gov/bill/114th-congress/house-bill/34?q=%7B%-22search%22%3A%5B%22HR34%22%5D%7D&r=2. Passed December 13, 2016. Accessed January 6, 2017.

Buffery D. The 2015 oncology drug pipeline: innovation drives the race to cure cancer. 

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Information Technology in Bio- and Medical Informatics

. Basel, Switzerland: Springer International Publishing; 2015(9267):56-70. doi:10.1007/978-3-319-22741-2_6.

Proctor RN. The history of the discovery of the cigarette—lung cancer link: evidentiary traditions, corporate denial, global toll [published correction appears in Tob Control. 2012;22(1):62]. 

. 2012;21(2):87-91. doi:10.1136/tobaccocontrol-2011-050338.

Centers for Disease Control and Prevention. Use and characteristics of electronic health record systems among office-based physician practices: United States, 2001—2013. https://www.cdc.gov/nchs/ data/databriefs/db143.htm#x2013;2013%3C/a. Published January 17, 2014. Accessed January 6, 2017.

Heisey-Grove D, Patel V. Any, certified, and basic: quantifying physicians HER adoption through 2014. Washington, DC: Office of the National Coordinator for Health Information Technology. ONC Data Brief No. 28. https://www.healthit.gov/sites/default/files/briefs/oncdatabrief28_certi ed_vs_basic.pdf. Published September 2015. Accessed January 6, 2017.

Jensen PB, Jensen LJ, Brunak S. Mining electronic health records: towards better research applications and clinical care. 

. 2012;13(6):395-405. doi:10.1038/nrg3208.

Health information exchange (HIE): standards and interoperability. HealthIT.gov website. https://www.healthit.gov/providers-professionals/standards-interoperability. Updated February 27, 2014. Accessed January 6, 2017.

CancerLinQTM platform hits milestone of having more than one million patient records in system [news release]. Alexandria, VA: American Society of Clinical Oncology; October 20, 2016. http://www.asco.org/about-asco/press-center/news-releases/cancer-linq-platform-hits-milestone-having-more-one-million. Accessed January 6, 2017.

The ambitious goals of the Cancer Moonshot initiative, now incorporated into the recently enacted 21st Century Cures Act, are generating excitement among oncology leaders.


Big Hopes for Big Data: Digital Information Focus Underpins Cancer Moonshot Goals

Researchers are seeking to determine whether adding the PARP inhibitor veliparib to a chemotherapy combination will improve outcomes for patients with HER2-negative, germline 

-associated metastatic or locally advanced breast cancer.

The international Brocade 3 trial, which is currently enrolling participants at more than 200 locations, seeks to randomize an estimated 500 patients in a 2:1 ratio to either veliparib with carboplatin and paclitaxel or a placebo plus the 2 chemotherapy agents (NCT02163694).

The phase III study is open to patients whose tumors are triple negative as well as those with estrogen receptor (ER)- or progesterone receptor (PR)-positive disease because the biomarker of interest is not the hormone receptor, it is the 

 mutation itself, according to principal investigator Shannon L. Puhalla, MD.

“What we’re hoping to learn is whether, irrespective of hormonal status, the 

 mutation is driving the response, as opposed to other factors,” said Puhalla, who is director of the breast cancer clinical research program at the University of Pittsburgh Cancer Institute, and assistant professor of medicine at the University of Pittsburgh School of Medicine.

If successful, the addition of veliparib to a chemotherapy regimen would provide another option for a sizable subgroup of patients with the mutation. Germline 

 mutations account for 5% to 10% of all breast cancers, and from 20% to 25% of hereditary breast cancers.

 “Where this study will fill a void is for the patient who requires chemotherapy, but also has a 

 mutation,” said Puhalla. “Then there would be an advantage to giving the PARP inhibitor with chemotherapy.”

As a PARP inhibitor, veliparib targets a group of enzymes important in repairing DNA damage, blocking the proteins from allowing cancer cells to proliferate and enhancing the cytotoxicity of chemotherapy that also damages DNA.

Nearly 78% of patients who were treated with a combination of veliparib and carboplatin/paclitaxel responded to treatment in phase II clinical trial results presented at the 2016 San Antonio Breast Cancer Symposium.

 However, progression-free survival (PFS) and overall survival (OS) did not meet the threshold for statistically significant improvement compared with the same chemotherapy regimen plus placebo.

The median PFS was 14.1 months (95% CI, 11.5-16.2) for the veliparib arm and 12.3 months (95% CI, 9.3-14.5) for the placebo group (HR, 0.789; 95% CI, 0.536-1.162; 

 = .231). The median OS was 28.3 months (95% CI, 26.9-not reached) with veliparib versus 25.9 months (95% CI, 20.4-31.8) with placebo, respectively (HR, 0.750; 95% CI, 0.503-1.117; P = .157), although these data were not fully mature.

Puhalla and colleagues believe there were enough positive signals in the results to remain optimistic about the prospects for success in the Brocade 3 study. “In part, the hazard ratio that was being evaluated in the phase II study was a high bar to meet; the study was aggressively powered in a way that I think made the PFS harder to attain,” said Puhalla.

The phase II study did demonstrate that the backbone treatment of carboplatin and paclitaxel, which is not listed as a recommended dual therapy in the National Comprehensive Cancer Network guidelines for breast cancer, is extremely effective as first- or second-line therapy for patients who are 

 mutation carriers. Puhalla indicated. “The control arm had a response rate upward of 60%,” she said.

However, Puhalla noted that it is difficult to administer the chemotherapy doublet for an extended period of time since patients are at risk for bone marrow toxicity, generally after 6 to 9 cycles, and would have to halt treatment. The phase III trial allows for veliparib/placebo monotherapy (depending on which arm the patient is on) if there is toxicity with combination treatment which is a key difference between the phase II and phase III trials.

In the phase II trial, the addition of veliparib to chemotherapy did not notably increase the incidence of adverse events (AEs). All-grade AEs occurred in 100% of the veliparib arm and 97.9% of the placebo arm; serious AEs occurred in 34.4% and 27.1% of the veliparib and placebo arms, respectively. The most common hematologic treatment-emergent all-grade AEs included anemia, febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia.

The Brocade 3 trial is being conducted by AbbVie, which is also the company developing the drug. The study is expected to be completed in March 2018.

BRCA1 and BRCA2: cancer risk and genetic testing. National Cancer Institute website. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet#q2. Updated April 1, 2015. Accessed December 30, 2016.

Researchers are seeking to determine whether adding the PARP inhibitor veliparib to a chemotherapy combination will improve outcomes for patients with HER2-negative, germline BRCA-associated metastatic or locally advanced breast cancer.

Vol. 18/No. 02 | Oncology Live®

Making the Cancer Journey Tolerable: Loprinzi Puts Focus on Symptoms

BTK Inhibitors Mushroom in Blood Cancer Field

The Big Data Buzz

Robotic Surgery Represents a Notable Advance in Thyroid Cancer Care

Big Hopes for Big Data: Digital Information Focus Underpins Cancer Moonshot Goals

Veliparib Facing Phase III Test in BRCA-Positive Breast Cancer

Challenges Persist in Deploying ADT in Prostate Cancer

When Values Collide: The Individual Versus the Common Good