Advancing Cancer Care Through Key Clinical Trials and Translational Research

Since its founding, Fox Chase has played a critical role in the development of therapeutics and treatment approaches in medical, radiation, and surgical oncology

When discussing research at Fox Chase Cancer Center, it is common to hear about the groundbreaking laboratory science that has been conducted. What is often overlooked is that from its very beginning, Fox Chase has played a critical role in the development of therapeutics and treatment approaches in medical, radiation, and surgical oncology, advances that have improved the daily lives of patients around the world.

When looking back, it is important to note that many of the advances of today were being discussed at Fox Chase decades ago. In the first Fox Chase Scientific Report in 1975, a year after the center’s founding, immunologic approaches to cancer focusing on melanoma are prominently mentioned. But Fox Chase’s impact is far greater than even the partial list of substantial contributions noted here.

From at least the 1960s, it has been recognized that collaborative, multi-institutional, multidisciplinary research is necessary for the advancement of clinical care in oncology. Fox Chase investigators collaborating with their peers in academic institutions, government, and industry have consistently been at the forefront of this rapidly evolving area. Much of the early research at Fox Chase is what would now be categorized as “translational” in that it clearly had the objective of developing testable clinical hypotheses or evaluated biological correlates of novel therapies. 

Fox Chase clinical investigators have been leaders in advancing cancer care through clinical trials and translational research for 50 years. That work continues. (For more examples of this groundbreaking research, see “Fox Chase Cancer Center’s 20 Most Influential Studies”.)

The words of Robert Comis, MD, then Vice President of Medical Science, in the 1985-1986 Scientific Report are as true today as they were almost 40 years ago: “We now have a complement of investigators in the medical sciences who appreciate the value of fundamental biologic research and are involved in the required gamut of research activities ranging from the most basic to the most highly applied. All of our departments and programs are now led by leaders in their respective fields. Now the hard part begins.”

Breast Cancer

Fox Chase researchers in breast cancer, the most common malignancy in women, were among the first to evaluate a variety of regimens. Beginning in the 1970s, Richard Creech, MD, Paul Engstrom, MD, and Michael Mastrangelo, MD, and others reported on several innovative regimens and drugs. The breast cancer program was nationally recognized primarily due to the work of Lori Goldstein, MD, FASCO. Goldstein’s work on drug resistance and her ECOG studies were well received nationally, and she also led a multidisciplinary team that was among the first to evaluate the influence of hormone replacement therapy on breast cancer outcomes.

Gary Freedman, MD, was the principal investigator on a study testing moderately hypofractionated intensity-modulated radiation therapy instead of conventionally fractionated conventional radiation therapy after surgery for women treated with breast-conserving therapy. It was the first of its kind in the United States for a therapy that is now the standard of care for all women treated with breast-conserving therapy.

Genitourinary Cancers

Fox Chase has a long history of prominent contributions in all modalities in genitourinary malignancies. Gary Hudes, MD, led the trial that established temsirolimus as a front-line therapy for advanced renal cell carcinoma before the widespread use of tyrosine kinase inhibitors or immunotherapy (Top 20 Study, #4). He was also the senior author for a paper by Elizabeth Plimack, MD, FASCO, which established accelerated MVAC, a chemotherapy combination, as the standard regimen for the neoadjuvant treatment of transitional cell carcinoma of the bladder. In the modern immunotherapy era, demonstration of the efficacy and the long-term outcomes of immunotherapy (PD-1 antagonists) in bladder and renal cancers were led by Plimack (Top 20 Study, #6).

Investigators in the Department of Urology have made significant strides in advancing kidney cancer care. Notably, the development of the R.E.N.A.L. Nephrometry Scoring System has been a groundbreaking achievement. The first of its kind, this system objectifies decision-making and report of anatomic complexity of renal masses, affecting clinical practice and patient outcomes on a global scale (Top 20 Study, #14). Key trials in renal carcinoma evaluated the role of adjuvant therapy in patients who underwent surgery to remove renal masses. Other research has underscored the importance of knowing when not to treat. Investigation of active surveillance protocols for small renal masses has allowed for more personalized and less invasive management of patients, leading to improved outcomes and quality of life. 

Radiation is an important modality for the treatment of prostate cancer, the most common malignancy in men. Alan Pollack, MD, conducted a trial that established that moderately hypofractionated intensity-modulated radiation therapy was equivalent to conventionally fractionated intensity-modulated radiation therapy for men with non-metastatic prostate cancer. It was the first trial of its kind in the United States and led to this approach becoming the standard of care.

Gastrointestinal Cancers

In the 1980s, Fox Chase established a multidisciplinary clinic for evaluation of gastrointestinal, pancreatic, and biliary cancers. Louis Weiner, MD, was among the first translational scientists to develop mouse models of antibody therapy, work that led to new clinical trials. In another key area, accurate staging of disease, Elin Sigurdson, MD, PhD, made a fundamental contribution with her analysis of a trial that demonstrated that colon cancer survival is associated with the increasing number of lymph nodes analyzed, which became a quality measure for the American College of Surgeons. Steven Cohen, MD, led a study evaluating the use of circulating tumor cells as a prognostic and predictive marker for treatment in advanced colorectal cancer. 

In the past decade, the gastrointestinal cancer program has continued to focus on new therapeutics and explored approaches to the treatment of elderly patients and the importance of nutritional assessment and chemotherapy toxicity. Work on the development of new drugs is also advancing, including a trial led by Igor Astsaturov, MD, PhD, exploring stromal modification in pancreatic cancer.

Head and Neck Cancer

The Head and Neck Cancer Program has been very productive and contributions by Fox Chase investigators have been recognized by professional societies and the clinical trials establishment. Sometimes this influence comes not so much from individual studies but from leadership that can change the mindset of a field. John A. “Drew” Ridge, MD, PhD, FACS, was a long-time leader in the field and his presidential address to the American Head and Neck Society is credited with engaging the head and neck surgery community in the conduct of trials. Ridge, along with colleagues from other institutions, was instrumental in harnessing clinical trials planning meetings to break the logjam in protocol advancement that ensued after cooperative groups were harmonized.

Fox Chase researchers led numerous trials in this area, which, typical of the era, were negative, but still important, including one which concluded that a potential drug did not warrant additional development for head and neck cancer. On a more positive note, Fox Chase investigators developed institutional studies that combined chemotherapy and radiation, which led to the definitive multicenter cooperative group studies establishing these therapies.

Retrospective studies and analysis of big data by Fox Chase head and neck investigators led to prospective trials and altered approaches to management of disease. The center has been instrumental in analyzing large amounts of information from the National Cancer Data Base and others to evaluate issues such as time to treatment initiation from diagnosis and outcome (longer is worse), duration of radiation therapy (longer is worse) and the importance of multidisciplinary care and outcomes.

Lung Cancer

Research in lung cancer, the most common cause of cancer mortality, has been part of the clinical research program at Fox Chase since its inception. Studies in both small cell and non-small cell lung cancer are featured in the very first scientific report from the center. Investigation of paclitaxel in multiple disease sites, including lung cancer, was very active in the early 1990s. This is now an “old” drug, but at the time, it was the first of a new group of active agents that created optimism in the field and paved the way for the dramatic progress seen in the last decade. 

Investigators led by Corey Langer, MD, reported on the then-novel carboplatin/paclitaxel regimen in advanced non-small cell lung cancer, research that established this regimen as a standard for the treatment of the disease. It remains a core regimen, with the addition of immunotherapy, for the management of non-small cell lung cancer to this day.

Research on immunotherapy, which harnesses the body’s immune system to fight cancer, has been done at Fox Chase since the field emerged. Earlier tools were insufficient, but innovative approaches to immunotherapy have vastly changed the landscape. Hossein Borghaei, DO, led one of the first studies to demonstrate the potential of immunotherapy in treating non-small cell lung cancer (Top 20 Study, #1). He has continued this work, leading trials to evaluate approaches to enhance immunotherapy activity by modulating the tumor microenvironment, which consists of noncancerous cells, molecules, and other components that surround tumor cells.

Rare Tumors: Sarcoma, Melanoma, and Others 

Imatinib was the first truly targeted therapy in cancer. Its specific target was the Philadelphia Chromosome, which was co-discovered by a Fox Chase researcher, and it was initially developed to treat chronic myelogenous leukemia. Margaret von Mehren, MD, was a leader of the paradigm-shifting trial that led to the approval of imatinib for the treatment of advanced GIST — gastrointestinal stromal tumors (Top 20 Study, #3). This study was then followed by the evaluation of imatinib as preoperative therapy for GIST, which led to its use in that setting. Trabectedin, a drug derived from the Caribbean sea squirt, has been found to be highly active for the treatment of malignancies, particularly sarcomas, and von Mehren played a key role in its development. 

Early Developmental Therapeutics

Early phase research, including first-in-man trials, has been a characteristic of clinical research at Fox Chase since its formation. An early area of interest was biological response modifiers and immunotherapy. Robert Krigel, MD, Robert Comis, MD, and Paul Engstrom, MD, and others performed numerous early studies with agents such as interferon alpha, interleukin 2, and others that paved the way for the modern immunotherapy revolution.

The evaluation of drug activity through sequential analysis of tumor specimens in solid tumors has only come into widespread use at academic centers in the last decade or so. But studies by early phase investigators at Fox Chase employed biochemical analysis of sequential biopsies as early as 1990.

The list of experimental agents evaluated with Fox Chase clinicians as primary investigators is long, and these efforts continue today with a robust program led by Anthony Olszanski, MD, RPh. A recent example of an early phase trial is one that evaluated nivolumab with interferon gamma, which was led by Matthew Zibelman, MD.

Prevention and Survivorship

There are numerous issues that impact a cancer patient in addition to the actual drugs administered. Fox Chase investigators have been actively investigating these areas for many years, with some recent research focusing on factors that delay onset of treatment.

An increasingly important aspect of the management of many malignancies is the consequences of treatment in long-term survivors. Though this issue may at first seem new, it has long been a topic for research and intervention at Fox Chase. For example, Crystal Denlinger, MD, now CEO of the National Comprehensive Cancer Network, created survivorship care plans for patients cured of disease. 

Corey Langer, MD, was among the first to specifically address the issue of treatment of elderly patients and those with compromised performance status, and several other Fox Chase investigators have developed studies focused on how to best adapt treatments for patients who are elderly, frail, or have comorbidities that may increase the toxicity of currently available regimens. 

Researchers are also exploring a vaccine to prevent colorectal cancer. Fox Chase is one of four sites evaluating this approach under the leadership of Michael Hall, MD.