Treating and Managing Metastatic Disease

Not too many years ago, when a patient received a diagnosis of cancer that had spread beyond the primary site, doctors had little to offer. Now, they have an increasing number of therapies, emotional and financial support and an improved quality of life. Years of research are yielding dividends in the form of more active drugs and more effective treatments to deal with metastatic disease. Many metastatic cancers are moving toward becoming manageable chronic diseases, and for a few types of cancer, cures are even possible.

At age 30 and having never smoked, Anne Marie Cerato received a diagnosis of stage 3 lung cancer in April 2009. The Toronto resident underwent chemotherapy and radiation together, followed by surgery, but the cancer came back in May 2011. Cancer cells had also spread to her other lung. Radiation and surgery were no longer options—doctors told her to wait until she was symptomatic, at which point they would treat her with chemotherapy.

But for Cerato, “going home and sitting and waiting and watching was not good enough,” she says. She began investigating her options and found a clinical trial for an investigational drug, now known as Xalkori (crizotinib). She spoke with her oncologist, who referred her to a nearby center participating in the trial. Analysis of her tumor cells revealed that they carried an uncommon mutation in the ALK gene, which produces a protein leading to growth and spreading of cancer cells that is blocked by Xalkori. She enrolled in a phase 3 trial where she received the experimental treatment. Cerato has been taking the drug for a year. “My scans are clear, everything is stable, and so far there is no evidence of disease in my lungs, which is great,” she says.

Cerato says that while receiving a diagnosis of metastatic (stage 4) disease was devastating, in some ways it was also liberating.

“It gave me permission to realize that my life would never really be normal,” Cerato says, “and allowed me to choose to live my life for myself and not for anyone else.”

One action she found therapeutic was getting tattoos, which was “a way of exerting control over my own body,” she says. While Cerato says she knows Xalkori isn’t a cure, “It has given me a completely clean slate and lots and lots of hope because I’m responding so positively and others are too.”

[My diagnosis] gave me permission to realize that my life would never really be normal and allowed me to choose to live my life for myself and not for anyone else.

The goal of treatment for late-stage cancer varies, depending on the type of cancer. In some cases, a cure may be possible with current therapies, even when the cancer has spread beyond the primary site. In other cases, although a cure may not be attainable, newer and better therapies are extending the time patients can live with their disease while maintaining a good quality of life. A few cancers are even becoming chronic diseases that can be stabilized and managed with a succession of different treatments.

[Read "The Molecular Revolution"]

Testicular cancer is a model of success, with one of the highest cure rates of any solid tumor. Over the past four decades, the cure rate has risen from 25 percent to about 80 percent for patients with metastatic disease. This dramatic improvement was the result of discovering that testicular cancers were particularly sensitive to the chemotherapy drug cisplatin, and regimens containing this drug have become a mainstay of treatment. For patients who relapse, a cure may still be possible with other therapies.

Some forms of lymphoma may be curable at advanced stages, too. Overall, Hodgkin lymphoma has an 80 percent cure rate, while approximately two-thirds of patients with diffuse large B-cell lymphoma can currently be cured. For patients with lymphoma whose disease returns after a remission, one potential option is more aggressive treatment with highdose chemotherapy followed by a stem cell transplantation to replenish essential blood cells that are wiped out during the treatment. However, it has risks of its own and is only appropriate for patients in good overall health, but may be curative for relapsed lymphoma, as well as certain other blood cancers. New drugs are also being investigated for resistant lymphomas, and the FDA recently approved the anti-CD30 antibody drug conjugate Adcetris (brentuximab vedotin) for relapsed Hodgkin lymphoma.

Follicular lymphoma (FL) is a good example of a cancer that cannot be cured with current drugs, but because of its slow disease course and the effectiveness of available treatments, such as chemotherapy plus the anti-CD20 antibody Rituxan (rituximab), it can be managed for long periods of time. In fact, the median survival time is 14 years, with some patients living even longer. Since many patients are older and will likely die of other causes before succumbing to their cancer, the primary goal of treatment in many cases has shifted to maintaining quality of life and managing symptoms while living with FL.

Prostate cancer is similar in some ways to FL. Often, advanced disease can be controlled for years with currently available hormone therapies. The primary concern is managing disease symptoms as well as side effects of therapy. For patients whose disease has developed resistance after treatment with either hormone therapies or standard chemotherapy, a number of drugs have recently been shown to further extend survival, including Provenge (sipuleucel-T), an active cellular vaccine that takes immune cells from the patient and teaches them to recognize and destroy the cancer cells; Zytiga (abiraterone), a drug that blocks the production of androgens, the hormones that fuel prostate cancer cells; and Jevtana (cabazitaxel), a new taxane chemotherapy. Finally, another new drug that inhibits androgen receptor signaling in the cancer cells, Xtandi (enzalutamide), improved survival in men with castration-resistant prostate cancer and was approved by the FDA in late August.

Stage 4 breast cancer is another increasingly manageable cancer (see sidebar, page 19). For patients with estrogen receptor-positive cancer, there are a variety of hormone therapies that can be used, and patients often cycle through several of these before starting more toxic chemotherapy regimens. New targeted agents continue to be tested in combination with hormone therapies to to be tested in combination with hormone therapies to overcome tumor resistance. This approach has recently proven successful. Adding Afinitor (everolimus), a drug that inhibits mTOR (a protein that helps regulate cell growth) to exemestane (an aromatase inhibitor) more than doubled the time until their disease progressed. This combination was approved by the FDA in July.

For women whose breast cancers overexpress the HER2 receptor or exhibit HER2 gene amplification, the introduction of Herceptin (trastuzumab) marked a turning point in treatment and led to an explosion of research into additional HER2-targeted therapies. Perjeta (pertuzumab), an antibody that targets the HER2 receptor in a slightly different way than Herceptin, was recently added to the arsenal for metastatic HER2- positive breast cancer. Another new therapy, T-DM1, uses the Herceptin antibody to deliver a potent chemotherapy drug (emtansine) directly to tumor cells. This drug also extends the progression-free survival, as well as overall survival, and is currently being reviewed by the FDA.

Although colorectal cancer has traditionally had a poor outlook, advances in surgical techniques and systemic therapies have actually made it possible to cure some patients with metastatic disease, particularly if it has only spread to the liver. The use of chemotherapy before surgery may be able to shrink some tumors and make them operable, further expanding the subset of patients who can be treated with curative intent. For patients with more widespread metastases, the outlook has also improved significantly in the last decade. The introduction of targeted agents, such as Avastin (bevacizumab), Erbitux (cetuximab) and Vectibix (panitumumab), as well as refinements in standard chemotherapy regimens, led to an increase in median survival, from eight months to more than two years. More new therapies are poised to enter the clinic, including two new drugs that, like Avastin, block the formation of blood vessels in tumors. Zaltrap (ziv-aflibercept) was approved by the FDA in August, while Stivarga (regorafenib) was approved in September.

Years of patience and basic research is finally beginning to pay off even for those cancers that have traditionally been associated with a very poor prognosis and lack of treatment options. For example, the discovery that lung cancers with mutations in the epidermal growth factor receptor were more sensitive to drugs targeting this receptor triggered the start of individualized, molecularly targeted therapy for non-small cell lung cancer. More recently, about 2 to 7 percent of lung cancers were found to contain a rearrangement of the ALK (anaplastic lymphoma kinase) gene, leading to the rapid testing and approval of Xalkori (crizotinib), an ALKtargeted drug, as mentioned above in Cerato’s story.

David Gandara, MD, director of the thoracic oncology program at the University of California—Davis Comprehensive Cancer Center in Sacramento, Calif., says the biggest change has been the recognition that lung cancer is not just one disease, but multiple subtypes that originated in the lung. “To a certain extent, each patient represents their own subset,” Gandara says, “and we know that because we can distinguish the molecular biology of that cancer—it’s like a fingerprint, and that molecular fingerprint is almost different for every single patient. That’s what has changed therapy, thinking of the patients as individuals.

“I think what patients can look forward to in the future is coming into their oncologist’s office with their own genetic resume—here’s my molecular fingerprint— and working with their physician as a partner to decide what forks down the road they should take,” Gandara says.

There are collaborative efforts under way to study the genome of the two most common subtypes of lung cancer (adenocarcinoma and squamous cell carcinoma).

Some cancers, such as ovarian, are just beginning to enter the era of molecularly targeted therapy. There has been little progress in improving survival outcomes for patients with stage 4 ovarian cancer since the introduction of platinum-based therapy more than 30 years ago, but research efforts are now focusing on targeting therapies toward selected subsets of cancers. For example, inhibitors of PARP (poly [ADP-ribose] polymerase), an enzyme involved in DNA damage repair, are being investigated for patients with ovarian, breast and other cancers that are driven by inherited mutations in the BRCA1 or BRCA2 DNA repair genes. In a randomized phase 2, the PARP inhibitor olaparib extended the remission of ovarian cancer after platinum-based chemotherapy.

Niki Quasney of Munster, Ind., received a diagnosis of stage 4 ovarian cancer when she was 33 years old. The diagnosis didn’t come as a shock—when an older sister developed breast cancer at a young age, Quasney was tested for the BRCA mutations. After she had discovered she was positive for a mutation that increases the risk for breast and ovarian cancers she underwent a prophylactic mastectomy but delayed having her ovaries removed. She had always been told by her doctors that she could wait until she was 35 to 40 years old to remove her ovaries, and she thought she had time. But then a biannual blood test indicated increased levels of CA-125, a biomarker that is elevated in ovarian cancer as well as other conditions. Additional tests revealed ovarian cancer that had spread throughout her abdomen. The hardest part of the diagnosis was telling her family, particularly because her father was in the last stages of pancreatic cancer.

Quasney underwent surgery and intensive chemotherapy, and her cancer went into remission for two years before she experienced a relapse. After surgery and another round of chemotherapy put her cancer back into remission, Quasney enrolled in a clinical trial designed to test whether another investigational PARP inhibitor, veliparib, could help to maintain her remission. So far, it appears to be working, although there are not enough data on this drug yet to know whether it will extend her remission.

Despite the uncertainty, Quasney is putting this remission to good use and living life to the fullest—raising her daughter with her partner, biking and participating in sprint triathlons, fundraising for ovarian cancer research and pursuing social justice issues about which she is passionate. She gets a CA-125 test every three weeks to monitor for signs of the cancer’s return. Quasney compares getting good results to American Idol, “I feel like I’m safe for another three weeks. I haven’t been voted off yet.” If the cancer does return, Quasney says, “I don’t know what the next step is, but I know there are a lot of other drugs out there.”

It's very encouraging to know that these people [researchers] are devoting their jobs and their lives to finding cures for ovarian cancer and new drugs.”

Another cancer that has been traditionally hard to treat is pancreatic cancer, but even there, new treatments are finally beginning to show promising results. A new combination of chemotherapy drugs, FOLFIRINOX (5-FU [fluorouracil], leucovorin, irinotecan and oxaliplatin), was recently shown to improve overall survival in a phase 3 trial.

“Median survival is now over 10 months, close to a year, which is very encouraging, and we’re starting to see patients survive for two years, which we never saw before,” says Ramesh Ramanathan, MD, clinical professor at the Translational Genomics Research Institute and medical director of the clinical trials program at the Virginia G. Piper Cancer Center in Scottsdale, Ariz. Researchers are also investigating targeted agents, searching for biomarkers to identify patients who can benefit most from the already-approved Tarceva (erlotinib), a drug that targets EGFR (epidermal growth factor receptor), and evaluating new therapies that target overexpressed or mutated genes, such as the PI3 kinase inhibitors, c-Met inhibitors, IGF-1R inhibitors and agents targeting the stroma, the supporting nonmalignant tissue that tumor cells op-opt (or recruit) to help support them.

“I think in pancreatic cancer we are moving from standard cytotoxics [chemotherapy] to looking at the molecular profiles of patients,” Ramanathan says. “I think that’s a big advance for pancreatic cancer.”

Ramanathan encourages patients to ask about new approaches and clinical trials related to their individual care.

Cerato says if her cancer stops responding to Xalkori, she is open to trying one of the many new treatments currently under investigation.

“It is interesting what is coming down the line, and it is an exciting time,” she says.

“Clinical trials are where they are going to find things that are going to make a difference,” Quasney says. “It’s very encouraging to know that these people [researchers] are devoting their jobs and their lives to finding cures for ovarian cancer and new drugs.”