From OncoLog, April 2008, Vol. 53, No. 4

Cancer as a Chronic Disease

by Dianne C. Witter and John LeBas

When Max Watson was diagnosed with multiple myeloma more than 6 years ago, he faced a generally incurable malignancy with a 5-year overall survival rate of about 35%. Given this outlook, Mr. Watson knew he might die of his cancer.

But what he didn’t expect was that cancer would become a way of life, rather than solely a threat to it.

“I was inevitably surprised at the cyclical nature of the situation,” said Mr. Watson, describing the long line of stem cell transplantations, radiation, and drug therapies he has received at The University of Texas M. D. Anderson Cancer Center. When one therapy failed, another would become available, enabling a long-term management of his disease that Mr. Watson and his doctors didn’t initially think was possible. “Eventually I realized that this was something I would be dealing with for a long time.”

During this up-and-down cycle of treatment, Mr. Watson joined a growing subset of patients—those who are living with cancer as a chronic disease. These patients have metastatic disease that cannot be cured but can be controlled over the long term. And they are living months or years longer than did patients with the same types of advanced cancers less than a generation ago.

A changing landscape

In fact, many cancers, while still very serious, could become largely manageable chronic diseases with ongoing surveillance and/or treatment—similar to the way heart disease, diabetes, and HIV infection are managed today. While this vision has yet to become a reality for most forms of cancer, the past 10–20 years have seen a marked acceleration in advances toward this goal.

The reasons for this shifting paradigm are as varied and complex as cancer itself, but a few big factors are at play. Improved symptom control along with less toxic and “targeted” therapies have enabled patients to better tolerate systemic treatment. Furthermore, more clinical trials of experimental agents are available today than ever before, offering patients with metastatic cancer more chances at disease control after standard options have been exhausted. Successful trials have, in turn, broadened the field of effective agents available to the wider patient population.

Many cancers for which only a single therapy was available just a few years ago now have second- or even third-line therapies available today. Thus, patients are living longer by using one therapy until its effectiveness wanes, then moving to the next option, and then to the next. Michael Fisch, M.D., an associate professor of gastrointestinal medical oncology and director of M. D. Anderson’s General Oncology Program, describes this as the “hitchhiker model”—buying time for the patient by going from point A to point B, from point B to point C, and so on. The longer a patient lives, the greater the chances are that another effective therapy will be approved, a promising clinical trial will become available, or—perhaps—a cure will be found.

“Cancer treatment today is less likely to follow the traditional model of offering one or two lines of systemic cancer treatments and then focusing on end-of-life care, but physicians and patients often still think of it that way,” Dr. Fisch said. “The goal of therapy is often turning out to be one of maximizing the area under the quality of life-over-time curve—that is, extending life and maintaining and improving quality of life as long as possible and by whatever means are available in patients who cannot be cured.”

‘Hitchhiker model’ in practice

The concept and practice of longterm cancer management are not new; many low-grade lymphomas and chronic leukemias, for example, have been controllable for years with a combination of watchful waiting and conventional chemotherapies. But the tantalizing idea that this could become the rule for other cancers is gaining momentum, as disease types historically considered among the deadliest join the ranks of manageable cancers.

Multiple myeloma is a prime example, with Mr. Watson among the beneficiaries. Over the past 6 years, his doctors have sought a lasting abatement of his disease using the hitchhiker model of therapy. When an autologous stem cell transplant was not effective, he underwent a second transplant, this time with cells from a matched donor. The procedure put him into temporary remission, but it also led to both acute and chronic graft-versus-host disease. This complication has had ongoing effects, some of them serious, such as pulmonary problems that cost him the use of one of his lungs.

When Mr. Watson’s disease eventually relapsed, his doctor gave him bortezomib, a proteasome inhibitor approved by the U.S. Food and Drug Administration in 2003; this brought about a partial remission. He also received radiation in an attempt to further reduce the number of cancer cells. Most recently, he was having some success with the thalidomide analogue lenalidomide, which studies have shown delays disease progression, until complications leading to a broken clavicle made it necessary to discontinue the therapy. Currently, he and his doctor are reviewing the next options.

The promise of targeted therapies

Agents such as the ones that have helped keep Mr. Watson’s disease in check have resulted directly from our rapidly expanding knowledge of cancer’s molecular roots. For example, researchers are identifying abnormal proteins that promote cancer proliferation and developing agents that block those proteins or induce their normal expression. These agents are known as targeted therapies because they interfere with specific molecular pathways to cancer, in contrast to older, broadly cytotoxic chemotherapies. Since they are generally less harmful to the patient and can be administered for greater lengths of time than traditional chemotherapies, targeted therapies are emerging as a crucial component of cancer management, particularly for widespread disease.

One of the first agents developed to target a specific molecular pathway—the tyrosine kinase inhibitor imatinib—has dramatically reduced disease-progression rates for patients with chronic myelogenous leukemia (CML) since clinical trials began in the 1990s. Although imatinib resistance sometimes develops, those patients can now turn to next-line targeted therapies for CML (specifically, dasatinib and nilotinib) that didn’t exist a decade ago.

Exciting results from targeted therapies are also being seen in solid tumors, such as conventional-type (formerly known as clear-cell) renal cell carcinoma. From the early 1980s to 2005, the only agents available for metastatic conventional-type renal cell carcinoma were the cytokines interferon and interleukin-2. About 5% of patients could be 2 and only 1%–2% with interferon; additionally, these therapies are generally toxic and suitable only for young patients with good performance status and no brain metastasis. The median overall survival after metastasis was about 1 year.

Finally, after years of negligible progress against the disease, three new agents were approved from 2005 to 2007: sorafenib, sunitinib, and temsirolimus. In one large phase III trial at M. D. Anderson and other institutions, temsirolimus was associated with an increase in median overall survival of roughly 50% for patients with advanced renal cell cancer, said Nizar Tannir, an associate professor in the Department of Genitourinary Medical Oncology. Sorafenib and sunitinib have been associated with improved progression-free survival. “We’re not curing these patients, but they are living longer,” Dr. Tannir said, explaining that many patients today are expected to survive about 2 years after the discovery of metastatic renal cell cancer. “I think it’s fair to say that these drugs have changed the paradigm, changed the landscape of renal cell cancer. Renal cancer has pulled away from the pack of those dreaded cancers where, for metastatic disease, there has not been any meaningfully effective therapy.”

Moreover, the newer therapies are appropriate for a wider spectrum of renal cell cancer patients, including those who are older and have a poorer performance status. Also, in addition to these recently approved agents, two or three other agents are expected to gain approval within the next year, giving oncologists the opportunity to offer multiple lines of therapy. “We now have first-, second-, and third-line therapies, and this is why people are living longer,” Dr. Tannir said.

Successes in breast cancer

Some types of metastatic breast cancer have also become manageable over the long term, perhaps most famously with tamoxifen, which can slow or stop malignant cell growth in many women with estrogen-dependent cancer by blocking hormone receptor sites on tumor cells. And in the past decade, researchers have developed a new class of aromatase inhibitors that target estrogen production, with initial results of clinical trials showing them to provide better results than tamoxifen.

Another important advance has been made in the HER2-positive subtype of metastatic breast cancer, which used to be associated with an overall survival of 1–2 years. But thanks to trastuzumab, a monoclonal antibody that targets the overexpressed HER2 protein in this cancer, many patients with metastatic HER2-positive breast cancer are surpassing the 5-year survival mark.

Francisco J. Esteva, M.D., an associate professor in the Department of Breast Medical Oncology, has seen multiple successes attributable to trastuzumab since its approval more than a decade ago. One patient, for example, was diagnosed with stage II breast cancer in 1995. She underwent a mastectomy to remove the primary tumor and received tamoxifen for 5 years, but pulmonary metastases were discovered in 2000. The patient was then treated with aromatase inhibitors until she developed progressive disease. Because the cancer was HER2-positive, doctors began treating it with trastuzumab as a single-agent therapy—and with very positive results. “The trastuzumab therapy was able to stabilize her metastases for years, and that’s something we had not seen before,” Dr. Esteva said. The patient, who participated in several clinical trials of novel therapeutics at M. D. Anderson, is currently receiving a standard therapy combination of trastuzumab with nanoparticle albumin-bound paclitaxel and is enjoying a relatively normal quality of life.

Future implications

Dr. Esteva sees the unfolding of a watershed period, one that will lead to widespread, effective cancer management as more is learned about the genetic profiles of specific disease types. “I think that what the HER2 story has taught us is that if you find a critical pathway that cancer cells need to survive and if you can target that pathway by blocking even a single protein like HER2, you can make a significant impact on outcome for that patient,” he said. “One of the hopes in the next 10 years is that we will understand the genetic makeup of each tumor, find the pathway driving that tumor, and treat the patient accordingly.”

As genetic profiling improves, clinicians might be able to identify those who could benefit from experimental therapeutics before they undergo cytotoxic chemotherapy, which often makes patients ineligible for trials of new agents. The more patients in clinical trials, the faster the development of next-generation therapeutics can proceed.

While a cure remains the ultimate goal, even for patients with metastatic disease, the chances for long-term cancer control have never been so great.

For more information, call Dr. Fisch at 713-563-9905, Dr. Tannir at 713-563-7265, or Dr. Esteva at 713-792-2817, or visit www.mdanderson.org.

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