How patients with operable non-small cell lung cancer are faring after tumor resection.
DINA LEONARD, non-small cell lung cancer, recalls her experience with adjuvant chemotherapy. - PHOTO BY: TRACEY SPERO
When Dina Leonard had her first surgery for non-small cell lung cancer (NSCLC) in 2007, advice was still mixed as to whether post-surgery adjuvant therapy — be it chemotherapy alone or followed by radiation — would help reduce the risk of recurrence. Adjuvant therapy is a term used for treatments intended to address residual microscopic tumor cells that could later spread, and that therefore, if successful, lower the risk of recurrence and death from cancer. In Leonard’s case, her tumor was isolated and smaller than 3 centimeters, so her surgeon and oncologist agreed that adjuvant chemotherapy wasn’t necessary. At age 41, Leonard, of Long Island, New York, was anxious to have the tumor removed, so she could get back to work as a graphic designer and to caring for her daughter, then three years old.
“The tumor was in the lower lobe of the right lung,” Leonard recalls. “They could take out a slice and it would be gone and we would be back to normal.”
When doctors removed another small, isolated tumor in 2009, they again agreed that adjuvant chemotherapy and radiation were unnecessary. Leonard — who had never smoked — enjoyed several years with no evidence of disease. But when the cancer came back in 2012, the rules had changed. Oncologists were beginning to understand then, as they know now, that adjuvant chemotherapy after tumor removal (resection) increases survival rates in operable NSCLC. Adjuvant platinum-based chemotherapy after resection is now standard procedure at certain stages. Meanwhile, ongoing studies aim to uncover additional therapies as well as ways to help identify the best candidates for each option.
“We need to find a better way to relay the benefit of perioperative chemotherapy to our patients,” says Jamie Chaft, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center (MSK) in New York City. “Supportive care for chemo-therapy side effects has gotten much better, and people aren’t getting nearly as sick as they did when [adjuvant chemotherapy methods] were [first] studied 20 years ago. So even a small reduction in the risk of recurrence may warrant treatment. We hope that with lung cancer screening and better drugs and drug delivery, with adjuvant chemotherapy now or immuno-therapy in the future, we can save more lives.”
ADJUVANT THERAPY AND WHO COULD BENEFIT
Five-year survival rates for operable NSCLC with surgery alone depend on cancer stage and the person’s overall health. For stages 1 and 2, for example, when the tumor is completely removed, five-year survival rates range from 60 to 80 percent. Postoperative, or adjuvant, chemotherapy in operable NSCLC increases those five-year survival chances by about 5 percent.
In the biggest clinical trials that demonstrated the benefits of postoperative chemotherapy, most patients received cis-platin plus vinorelbine, and so, many doctors select that co-bination. But other drugs combined with cisplatin, such as Alimta (pemetrexed), the taxanes paclitaxel and docetaxel, and some vinca alkaloids, perform just as well.
“It’s not that the vinorelbine combination is the best; it’s just the one that was most rigorously tested,” says Taofeek Owonikoko, M.D., Ph.D., a medical oncologist at Emory Winship Cancer Institute in Atlanta.
Studies show that postoperative platinum-based chemotherapy brings the greatest benefits to patients with resected stages 2 and 3A NSCLC. The therapy doesn’t seem to impact significantly on long-term prognosis for patients with earlier stages of the disease, which for them is already quite good.
When Leonard had a recurrence in early 2012, she was stage 3A-N2, which means the cancer had spread to nearby lymph nodes. In this situation, patients might benefit from adjuvant chemotherapy followed by radiation of the lymph nodes after surgery.
That was the opinion Leonard chose.
“Involvement of the lymph nodes around the root of the lungs and the center of the chest means there’s a higher risk that the cancer will come back. Giving radiation following surgery and chemotherapy when there is involvement of central lymph nodes seems to further reduce the chance of cancer coming back and ultimately improves survival,” Owonikoko says.
Leonard had her right lung removed and then received four rounds of cisplatin plus docetaxel, a platinum-based chemo-therapy combination, followed by a 20-day course of radiation.
Limited evidence suggests that postoperative chemotherapy might also offer benefits to some patients at stage 1B, but results are mixed. Patients at stage 1B whose tumors are larger than 4 centimeters seem to be the best candidates, according 31to Owonikoko. With lower stages, the very small improvements in recurrence rates have to be balanced against the side effects — it is hard to draw a precise, firm line to decide who should, and who should not, get adjuvant chemotherapy.
Of course, disease stage alone doesn’t determine whether adjuvant therapy is the right choice. A patient must be healthy and strong enough after lung surgery to withstand chemotherapy, which can have harsh side effects such as anemia, fatigue, vomiting, nausea and hair loss. Traditionally, doctors recommended that therapy start within six to nine weeks of surgery. However, a later start, for patients who are not well enough in six weeks, fortunately doesn’t have a negative effect on prognosis, according to a recent study in JAMA Oncology.
“There was a common perception that chemotherapy given outside of that window was not as likely to work, and that’s a problem because a fair number of patients recover slowly from lung cancer surgery,” says Daniel Boffa, M.D., a thoracic surgeon at Yale School of Medicine’s Smilow Cancer Hospital in New Haven, Connecticut, and senior author of the study. “Often, patients and their oncologists are put in a situation where they struggle to balance recovery from an operation with the urgency to get chemotherapy.”
The study, which Boffa co-authored with Yale visiting research scientist Michelle Salazar, M.D., found that adjuvant, multiagent (more than one drug) chemotherapy was just as beneficial to eligible candidates who started it 18 weeks after surgery as it was to those who started seven weeks post resection. Patients who started on the later end of the spectrum still had better overall survival rates than patients who had surgery alone.
“We’re not saying that it doesn’t matter when you give chemotherapy, because our study could miss a subtle benefit to giving chemotherapy earlier. We’re saying it’s OK to give chemotherapy later if for some reason you weren’t able to get it during that traditional window,” Boffa says.
“It is difficult to gauge how many patients could benefit from this flexibility in chemotherapy timing,” adds Boffa. “Whether it is 50 or 5,000, I have little doubt there will be people who will live longer because of this observation, which should be credited to the American College of Surgeons and the American Cancer Society. They co-sponsor the National Cancer Database, which made the study possible.”
Adjuvant chemotherapy can benefit women and men of any age who are healthy enough and at the appropriate stage. Older age should not deter an adequately strong person from adjuvant therapy.
Doctors hope one day to have a test to determine the odds that a patient would benefit from a given treatment before it is offered. For instance, patients with tumors that express a protein called ERCC1 might not benefit from chemotherapy. However, tests for the protein are not extremely reliable as they frequently yield both false positives and negatives. Researchers continue to search for other biomarkers that might aid in treatment decisions.
WEIGHING THE RISKS AGAINST THE BENEFITS
The benefits of adjuvant chemotherapy in NSCLC come with risks of unpleasant side effects and toxicity. Leonard admits that the four cycles of cisplatin plus docetaxel made her pretty sick. “The side effects were as expected,” she recalls. “Extreme fatigue, nausea, loss of appetite and hair loss.”
Leonard and her husband, Tom, a tireless member of her care team, learned to anticipate and plan for her best and worst days. “She’d have a week of feeling bad,” he says. “Then a week of feeling better, then a week of feeling well.”
“But by the end of 2012,” she notes, “I had gotten most of my strength and stamina back and just resumed periodic CT scans.”
Neutropenia (low white blood cell count) is the most common side effect of adjuvant chemotherapy. When accompanied by fever, the condition is called febrile neutropenia. Besides these, the symptoms Leonard experienced — nausea, vomiting, extreme fatigue or weakness — are among the most common side effects. The treatment might also cause constipation and neuropathy (painful, numbing nerve damage). A rare side effect is loss of platelets, known as thrombo-cytopenia, which can cause bruising and slow the blood-clotting process.
In most cases, within about nine months, patients feel like they did before they started chemotherapy, a pattern Leonard followed. Nerve pain, however, can linger.
In rare cases, about one percent of the time or less, a complication during chemotherapy can result in death. “Patients at greatest risk for toxicity and death are those with significant other illnesses,” says Owonikoko. “That’s why you want to care-fully screen patients to make sure they are able to withstand the potential side effects of treatment.”
ON THE HORIZON
Because adjuvant chemotherapy for NSCLC isn’t perfect and doesn’t guarantee a cure, researchers continue to explore treatments that might work better, with fewer side effects, and to probe into better ways to predict who will respond well to which treatment.
Immunotherapy, medication that helps the immune system fight disease, has brought benefits to patients with many different types and stages of cancer. Researchers are beginning to explore the potential benefits of four such drugs — Opdivo (nivolumab), Keytruda (pembrolizumab), Tecentriq (atezolizumab) and durvalumab — as adjuvant therapy in operable NSCLC. Each of these drugs is a type of PD-1/PD-L1 check-point inhibitor, which means they release the brakes on the immune system so it can mount an attack against the cancer. Initially, the adjuvant studies will examine the effects of these drugs in addition to chemotherapy, not in lieu of it.
“While these studies are underway and actively enrolling patients around the world, the nature of adjuvant investigation is that it requires recurrences to define success or failure, so the results aren’t anticipated for many years,” says Chaft.
Each of these drugs is also currently under investigation as a treatment option for advanced, inoperable lung cancers.
Targeted therapies, medications that disable a specific genetic mutation in the tumor that helps it grow, might also be a viable adjuvant therapy in operable NSCLC. Different tumors express different cancer-promoting mutations; therefore, researchers are testing medications aimed at various targets.
In the currently recruiting ALCHEMIST trial, for example, researchers test lung tumors after removal for expression of epidermal growth factor receptor (EGFR). Those whose tumors test positive receive an EGFR-blocking drug, Tarceva (erlotinib). If study participants have a gene mutation called an ALK rearrangement, which also promotes cancer growth, they receive a drug that targets that: Xalkori (crizotinib). Among the people who have neither one of those tar-gets, half will receive immunotherapy in the form of a PD-L1 inhibitor and half will not. All tumors will be examined for additional mutations that could be future drug targets.
“It’s a great study that combines both what we know about genetic abnormalities and their role in personalized adjuvant therapy, as well as a learning phase to identify future targets for treatment by genetically profiling surgically managed tumors,” Boffa says.
Leonard’s tumors express a cancer-promoting element most often seen in breast cancer called HER2. Ten years after her initial diagnosis, she is not disease-free, but the cancer now seems to be well controlled with the HER2-targeted drug Kadcyla (adotrastuzumab emtansine) that she receives through a clinical trial at MSK.
Since she began receiving infusions of the drug, periodic CT scans have shown significant shrinkage of the cancer lesions. She manages the fatigue that the medication causes and presses on.
“I’m tired, but I have a 13-year-old daughter,” says Leonard. “I have places to take her and things to do. I want to enjoy my husband and daughter as much as I can. They get me through it, no question.”