documentary did a great job of capturing the innovative genius of mankind and the heroism of both oncologists and the patients who participated in their research. There has certainly been a miraculous evolution in cancer care, from nearly uniform hopelessness to genetically targeted treatments that in some cases, eradicate the disease.

The film was not just inspirational for the story it told, but also for the reaction it generated in the oncology community. Each of the 3 nights it aired, social media lit up with enthusiastic tweets from patients, caregivers, family members, and even those who were learning the story of oncology for the first time. Several oncologists even tweeted that it felt as though they were viewing the film together with their colleagues in their living room.

It is this communal effort, this unified front in the oncology community, that will lay the foundation to forge continued advancement in cancer care. Keywords in the next chapter in oncology will not only be 

is “Bringing the Oncology Community Together.” We understand the significance of collaboration and promote interaction through our affiliate’s scientific meetings (

), and several other platforms. Progress in the 

, requires a unified effort among caregivers, patients, researchers, industry, regulators, and donors.

experience has demonstrated is that we are “a community in unity.” Now, we must sustain this spirit to evolve beyond the history that was so eloquently captured in the film. I have full faith in our limitless capacity to do just that. As 

author Siddhartha Mukherjee, MD, PhD, concluded in the film’s final words, “If the cancer cell is evolving, then so are we.” 

Articles

The Emperor of All Maladies documentary did a great job of capturing the innovative genius of mankind and the heroism of both oncologists and the patients who participated in their research.

A Community in Unity

Chairman and Director Chief of Lymphoma Director, Clinical and Translational Cancer Research

		John Theurer Cancer Center at Hackensack University Medical Center

Cancer has been around longer than the human race, with fossils of dinosaur bones showing evidence of cancerous cells dating back >80 million years ago. Signs of cancer have been found in Egyptian mummies from 3000 BC and in 1600 BC, breast cancer was already being treating with cauterization in Egypt. Around 400 BC, Hippocrates is said to have named masses of cancerous cells karkinos, which is Greek for “crab,” likely for the abnormal shapes of growing tumors. Thus, cancer is not a new phenomenon and as its history has shown, progress in medicine has always been a central focus for any society over the centuries.

Thanks to this focus, tremendous progress has been made in oncology, as illustrated in the recent 6-hour Ken Burns and Barak Goodman television documentary on cancer, which was based on the best-selling 2010 book by Siddhartha Mukherjee, 

The Emperor of All Maladies: A Biography of Cancer

. The book focuses on the last 70 years, with stories of real people whose lives are upended by a cancer diagnosis. It shows how scientific breakthroughs have helped us understand how a normal cell becomes malignant and led to the development of numerous novel therapies.

The documentary was presented from multiple perspectives, such as stories and interviews with the first patients treated successfully using intensive and highly toxic regimens in pediatric ALL, as well as interviews with some of the doctors involved in their treatment. Other milestones covered include the first radical surgery, known as Hallstead (total mastectomy), performed in 1898; the first use of radiation in 1928; and the first chemotherapy (nitrogen mustard) administered to humans in 1943. Modern combination chemotherapy was launched in the 1940s-1950s, the first BMT was performed in the late 1950s, and the first concept of cure appeared in the early 1960s. The first monoclonal antibodies (rituximab) and the first kinase inhibitor (launching the era of new biologicals or targeted therapies) both appeared in mid 1990s.

Since then, an enormous number of new drugs have been added to our oncology armamentarium and today, more than 75% of the pipeline of medicine is in oncology. The most recent addition is the dramatic development of immunotherapy (cell therapy and checkpoints inhibitors, particularly) developed over the last 2 years, which definitely justifies the emerging field of immuno-oncology.

The “War on Cancer” was launched in 1973 and while its success and impact have been debated by some, others see unprecedented changes and accomplishments. Undoubtedly, one of the most significant advances was the completion of human genome sequencing in 2003, which has helped us understand cancer cells’ biology and started shedding light on their enormous diversity, offering a logical rationale for precision medicine (tailored therapy).

The enthusiasm of the science and hope it generates in patients and caregivers is wonderful and should encourage our society to invest further into research (not less, as is the current trend in public funding), while many issues should not be overlooked.

First and foremost, real scientific discovery is usually random and most advances in cancer are still incremental. Though the outcome of many cancers has dramatically improved over the years, for many others, treatment has changed very little, with outcomes that remain disappointing, such as in metastatic colon cancer, lung cancer, or pancreatic cancers.

The current model of funding does not typically encourage “outside-the-box” thinking or support not-yet established young scientists with novel ideas. Clinical trials are not encouraged enough (only 3%-5% of patients enrolled in the United States) for a number of reasons, including the complexity of the bureaucracy associated with clinical research. Furthermore, such trials, by their limitations and restrictions (eg, “unmet need target population” for regulatory purpose), become difficult to enroll, while drugs with really promising activity early on are never approved as compassionate use.

Providing a rationale basis to a trial (with companion test) rather than a “defined” unmet group of patients should be our focus. This might help develop drugs faster— ie, a drug is approved based on molecularly defined, small phase II cohorts, instead of large, randomized phase III studies that often fail due to a dilution effect. This, in turn, would (should) help reduce the cost, which is currently established using a non-sustainable model, particularly in light of many novel agents given orally for years, let alone future use of “chemotherapy-free” combinations that are currently being developed.

The abandonment of chemotherapy is definitely an overstatement. In many aggressive cancers, chemotherapy enables the achievement of a complete remission that, for a significant number of patients, translates into cure. An emphasis should be made on continuing the manufacturing of “old chemotherapy” drugs, which too often, as they became generic, have been literally abandoned over the years. Our goal should be to build on already known results (“old regimens”) by using combination or maintenance/consolidation strategies to improve the “mileage” for every patient.

On the other hand, novel therapies might help develop new regimens (biological combinations) that might change the paradigm as we are starting to see with BCR inhibitors in CLL, particularly for elderly patients or patients with known chemorefractory disease (eg, those with p53 deletion).

Finally, while treatments are, of course, of paramount importance to anyone with cancer, from a global perspective, prevention efforts should also be emphasized. It is estimated there will be a 46% increase in cancer incidence in the next 30 years, and almost half of these incidents are preventable.

On a positive note, the strongest memory of one of the first pediatric ALL patients successfully treated decades ago had to do with his first experience watching TV shows (he had TV access only in the hospital), reminding us that there is a human being behind all of our research, and we must never forget that.

Thanks to the focus on progress in medicine, tremendous progress has been made in oncology, as illustrated in the recent 6-hour Ken Burns and Barak Goodman television documentary on cancer.

"The Emperor of All Maladies"-The Amazing Biography of Cancer...Can We Do Even Better?

	UT Health Science Center San Antonio, TX

Primary brain tumors are a cause of marked debility and are characterized by poor survival. In 2015, an estimated 23,180 new cases of primary malignant brain tumors will be diagnosed and 16,570 patients will die from these tumors.

 Glioblastoma (GBM, grade IV astrocytoma) is the most common and most aggressive of the primary malignant brain tumors in adults, with historical 1-year and 5-year survival rates of 29.3% and 3.3%, respectively.

Currently, frontline treatment consists of a multimodality approach that includes maximal surgical resection and adjuvant radiation therapy with concurrent temozolomide. This multimodal approach has been the standard of care since the EORTC phase III trial demonstrated a median survival of 14.6 months in the temozolomide group versus 12.1 months in the radiation alone group.

 While this was a significant improvement, it is clear that radiation remains the most effective component of the combined approach on median survival with multiple randomized studies showing a 5-month improvement in survival with XRT alone

 compared to an additional 2.5 months with the addition of temozolomide.

Theoretically, any tumor can be controlled if a sufficient dose of radiation is delivered to the tumor. The main limiting factor in delivering a tumoricidal dose is the toxicity to surrounding normal tissue. As the traditional x-ray radiation beam passes through the skull and brain to reach the tumor it is absorbed by the body and shows exponential decrease in the dose delivered with tissue depth. Even using highly conformal applications such as TomoTherapy or Intensity Modulated Radiation Therapy, doses are limited to less than 80 Gy

 due to progressive toxicity with increasing dose. With brachytherapy, the most successful example has been in the use of radioactive iodine to treat thyroid cancer, which can be completely ablated with doses of nearly 1000 Gy with almost no toxicity to surrounding normal tissue. The reason that other therapeutic radionuclides have not been successfully developed for other types of cancer is due to an inability to specifically deliver these isotopes.

Re) is a reactor-produced isotope with great potential for medical therapy if it can be successfully delivered. It is in the same chemical family as technetium-99m (

Tc), which is a commonly used isotope for diagnostic imaging. The average 

Re beta particle path length in tissue of 2 mm is ideal for treatment of solid tumors and the half-life of 90 hours is clinically meaningful. However, a carrier is needed to deliver the isotope to the brain and maintain its localization at the desired site, as it would otherwise quickly disperse and be carried away from the site of injection by the circulatory system.

Liposomes, spontaneously forming lipid nanoparticles, have rapidly evolved as carriers of cancer therapeutics. They consist of naturally occurring lipid bilayers that are nearly identical to the lipid membranes of normal cells. The list of FDA-approved liposomal drugs includes Doxil (liposomal doxorubicin) and Depocyt (liposomal cytarabine) to just name two.

For treatment of locally invasive tumors, liposomal encapsulation of radiotherapeutics holds significant promise. To achieve this, we have developed a proprietary encapsulation method using a custom lipophilic molecule that carries radionuclides into the aqueous compartment of the liposomes. The final investigational product is BMEDA-chelated- 

Rhenium encapsulated within liposomes. These rhenium-labeled nanoliposomes (RNL) have shown great promise in preclinical studies for the treatment of cancer by regional and local administration.

To better characterize the potential delivery, toxicity, and efficacy of these high specific activity RNL, intracranial application by convection enhanced delivery (CED) in a U87 glioma rat model was investigated. RNL remained confined to the site of injection over 96 hours, and doses of up to 1850 Gy were administered without evidence of toxicity. Animals treated with RNL had a median survival of 126 days (95% CI, 78.4-173 days) compared to 49 days (95% CI, 44-53 days) in controls. Log rank analysis between these two groups was highly significant (

 = .0013), and was even higher when 100 Gy was used as a cutoff (

<.0001). MRI and luciferase imaging showed significant difference in tumor size 

, with many tumors completely ablated. Duplication of tumor volume differences and survival benefit was possible in a more invasive U251 orthotopic model with median survival in treated animals not reached at 120 days due to lack of mortality, and log rank analysis of survival highly significant (

= .0057). Analysis of tumors by histology revealed minimal areas of necrosis and gliosis.

Good Laboratory Practice (GLP) toxicology studies in beagles have shown that intracranial administration of RNL up to 360 Gy produced no significant test article related pathologic changes in the brains of dogs at 24 hours or 14 Days, supporting the study of RNL in humans. I am currently leading a phase I clinical trial of RNL in patients with glioblastoma supported by NanoTx Therapeutics at the CTRC in San Antonio, Texas.

		ï¿¼ï¿¼ï¿¼ï¿¼Ostrom QT, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. 

		Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. 

		Chang JE, et al. Radiotherapy and radiosensitizers in the treatment of glioblastoma multiforme. 

		Werner-Wasik M, et al. Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas. Radiation Therapy Oncology Group Study 83-02. 

		Bao A, et al. A novel liposome radiolabeling method using 99mTc- ”SNS/S” complexes: in vitro and in vivo evaluation. 

		French JT, et al. Interventional therapy of head and neck cancer with lipid nanoparticle-carried rhenium 186 radionuclide. 

		Wang SX, et al. Intraoperative 186Re-liposome radionuclide therapy in a head and neck squamous cell carcinoma xenograft positive surgical margin model. 

		Wang SX, et al. Intraoperative therapy with liposomal drug delivery: retention and distribution in human head and neck squamous cell carcinoma xenograft model. 

Andrew Brenner, MD, PhD, discusses how liposomal encapsulation of radiotherapeutics holds significant promise as a treatment of glioblastoma.

Liposomal Encapsulation of Radiotherapeutics Holds Promise in Treating Glioblastoma

Director, Experimental Therapeutics and Melanoma Service

	New York-Presbyterian Hospital/ Columbia University Medical Center

At a recent patient symposium, I had the opportunity to speak with a number of individuals affected by uveal melanoma, a rare and aggressive form of the disease that is clinically and molecularly distinct from its more common cutaneous counterpart. Unlike for advanced cutaneous melanoma, a disease for which there have been dramatic advances in treatment options, there is no FDA approved effective treatment option for metastatic uveal melanoma. Without the time pressures and relative formality associated with clinic, the discussions I had with the attendees focused less on clinical management options, and rather on the experience of being a patient with uveal melanoma or the challenges of caring for an individual with this disease. Fear and a sense of isolation are common themes raised by those affected by cancer; however, these emotions seemed amplified and were echoed repeatedly by those present at the symposium.

Although these emotions were partially allayed by the presentations by the researchers who discussed recent advances in our understanding and treatment of uveal melanoma, as well as by the nurses and social workers who spoke about managing the impact of this disease upon the patient and family, it was the opportunity for patients and family members to share their own experiences with the other symposium participants that was most effective in alleviating the fear and feeling of isolation. It was the knowledge that others were going through similar challenges to what they themselves were facing and the sense of community that rapidly developed over that weekend that the participants most appreciated.

The acknowledgment of the importance of community by those affected by rare cancers is reflected in the number of patient-established rare cancer support groups. For uveal melanoma, there is the Melanoma Research Foundation CURE OM (Community United for Research and Education of Ocular Melanoma) initiative, the Ocular Melanoma Foundation, OcuMelUK, the Eye Cancer Network, and others. For gastrointestinal stromal tumors, there is the Life Raft Group, the GIST Cancer Awareness Foundation, GIST Support UK, and GIST Support International. For neuroendocrine tumors, there is the NET Patient Foundation, the Carcinoid Cancer Foundation, and the Caring for Carcinoid Foundation.

The groups listed here are just examples of some of the many support groups available for patients and family members facing these and other rare tumors. These groups allow individuals to learn from one another, help each other navigate the complexities of our health system, identify potential treatment options, and provide emotional support. While similar organizations exist for those affected by more common cancers, the importance of these groups for those with rare cancers is augmented by the limited awareness by others regarding their diseases, the frequently more limited treatment options, and their own knowledge of the relatively limited funding and focus by the research community on finding a cure for their diseases.

The creation of rare cancer consortiums within the medical community to foster research in and enhance awareness of these malignancies, in many cases, has lagged behind the development of these patient and caretaker communities. While groups such as SARC, the CanLiv International Hepatobiliary Cancers Research Consortium, and the Lustgarten Foundation Pancreatic Cancer Research Consortium have successfully led significant research efforts in the fields of sarcoma, hepatobiliary malignancies, and pancreatic cancer, respectively, similar efforts either do not exist or are in their infancy for other rare cancers, such as adrenocortical cancer, small bowel cancers, thymomas, and many others.

Over the past several years, the uveal melanoma research community has been brought together due to the efforts of groups such as CURE OM and the International Rare Cancer Initiative (IRCI). CURE OM is the Melanoma Research Foundation’s initiative to increase awareness, education, treatment and research funding for uveal melanoma, and aims to meet these goals by providing grants, sponsoring biannual international scientific meetings, and forging partnerships with leading academic and industry organizations. Thus far, CURE OM has provided over $800,000 in grants specifically for uveal melanoma research.

IRCI is a joint initiative between the National Institute for Health Research (NIHR) Cancer Research Network (NCRN) and Cancer Research UK (CR-UK) in the United Kingdom, the National Cancer Institute (NCI) in the United States, and European Organisation for Research and Treatment of Cancer (EORTC), and the Institut National Du Cancer (INCA) in France. The aim of this initiative is to facilitate the development of international clinical trials for patients with rare cancers in order to boost the progress of new treatments for these patients. Uveal melanoma is one of the nine cancers initially targeted for the IRCI efforts, and the IRCI uveal melanoma committee meets twice yearly to coordinate international research efforts in this disease.

As defined by the National Institutes of Health (NIH), each rare cancer affects fewer than 200,000 individuals in the United States at any one time; however, approximately half of all individuals diagnosed with malignancy are diagnosed with a rare cancer. Outcomes for patients with these rare cancers are generally inferior to those diagnosed with more common cancers. Thus, it is critical that research aimed specifically at understanding and improving outcomes for patients affected by each rare cancer is supported and promoted. It is equally critical that those of us whose research focuses on rare cancers learn from our patients who have long recognized the importance of community.

It is only through the development of effective collaborations between clinicians and researchers focused on rare cancers within the United States and internationally, industrial partners, and those affected by rare cancers that the progress toward our goal of cure for these diseases will be most rapidly achieved.

Richard D. Carvajal, MD discusses the significance of researching, understanding, and improving outcomes for patients with rare cancers. 

April 2015 | Oncology & Biotech News

A Community in Unity

"The Emperor of All Maladies"-The Amazing Biography of Cancer...Can We Do Even Better?

Liposomal Encapsulation of Radiotherapeutics Holds Promise in Treating Glioblastoma

Community and the Care of Patients With Rare Cancers