Wrestling Match: Dealing With Treatment Decisions for Stage 3 Lung Cancer

Curt Hammock, 67, found out he had stage 3b lung cancer on his birthday, Jan. 10, in 2011. “I just wanted some socks, but I got cancer instead,” he quips.

Hammock had tumors in his neck and one lung. But because treatment for stage 3 lung cancer is the least straightforward of all stages, it was a month or so before he began treatment.

“There were huge discussions about what to do, because I had two tumors at the same time,” remembers Hammock, a retired auto parts distributor.

Hammock’s experience is typical of stage 3 patients, doctors say. Stage 3 lung cancer: It’s complicated.

Most lung cancer patients are diagnosed at advanced stages, about 30 percent of them at stage 3, which can also be described as “locally advanced disease.” Another 40 percent get diagnosed at stage 4, when the cancer has metastasized to other organs.

PHOTO COURTESY OF CURT HAMMOCK

After his diagnosis with stage 3 lung cancer, CURT HAMMOCK waited a month as doctors considered his many possible treatment options. [PHOTO COURTESY OF CURT HAMMOCK]

Lung cancer, including both small cell and non-small cell, is the second most common type of cancer in both men and women. The average age at diagnosis is about 70. The disease accounts for 27 percent of all cancer deaths, more than all breast, prostate and colon cancer deaths combined.

One Size Does Not Fit All

Yet while oncologists are generally united about how to treat early-stage lung cancer (aggressive treatment in hope of a cure) and late-stage lung cancer (palliative care to keep the patient comfortable, but with no hope of cure), there’s less agreement about how to handle stage 3 cases.Doctors wrestle with questions such as: How aggressive should the treatment be? Should these patients be encouraged to try clinical trials, one possibility recommended by the National Cancer Institute, because a relatively small percentage will survive with conventional treatments? If new techniques make surgery an option for stage 3 patients, will that surgery make a difference? In what order should treatments be administered? Which doses of chemotherapy and radiation are most effective? What balance should there be between quality of life and the effectiveness of treatment? “Stage 3 is the most controversial disease we have in lung cancer,” explains Jyoti Patel, a thoracic oncologist at Northwestern University’s Feinberg School of Medicine. “There is wide variation in these patients. Some may only have microscopic lymph involvement. Others may have large nodes that are causing symptoms like shortness of breath. And yet we lump all these patients together. One size definitely does not fit all. Treatment has to be personalized for your stage and your body.”

It’s more common than not for stage 3 patients to receive two or more kinds of treatment, what doctors call “multimodality therapy.” However, since stage 3 patients can vary so widely when it comes to their disease characteristics, it’s been difficult to devise studies that would make general recommendations possible, according to a 2013 review in the journal Chest. The paramount goal in treating stage 3 patients, the review says, is to eradicate the visible disease in the chest and reduce the incidence of metastases elsewhere in the body.

Patel advises patients that the most important thing is to get a biopsy to make absolutely sure that their disease is stage 3, cancer that has spread from the lungs to lymph nodes in the chest. If only lymph nodes on the same side of the chest as the primary cancer are involved, that’s considered stage 3a. If disease has spread to the neck or to lymph nodes on the opposite side, that’s considered stage 3b.

Stage 3 refers to non-small cell lung cancer (NSCLC) cases. Small cell lung cancer, which accounts for 15 percent of cases, is divided into “limited stage” (all within the chest area) and “extensive stage” (spread beyond the chest). Treatments for the two types are similar, involving chemotherapy, sometimes radiation therapy and rarely surgery, but are distinct from treatment strategies for NSCLCs.

Surgical Options

Of those diagnosed at stage 3a, about 27 percent will be alive five years later. Of stage 3b patients, 10 percent will survive to the five-year mark. It’s important to remember, though, that many, many factors play into survival rates: overall health, other health conditions, gender, race, age and how well treatment is tolerated.Surgery is often part of a stage 3 treatment plan. In the past, surgery was only possible for stage 3 patients if their disease had not spread very far. The chest is complex, and tumors are often close to vital organs such as the superior vena cava (the large vein that carries oxygen-depleted blood to the heart), the trachea (windpipe) and the esophagus. The location of stage 3 disease makes it difficult to remove cancers without damaging other organs, and difficult to get disease-free margins in the tissue removed.

Today, advances in imaging (PET scans) and minimally invasive techniques (doing an operation through small incisions rather than opening up the chest) have made it possible to remove some tumors that might have been inoperable a decade ago.

Nevertheless, the effectiveness of surgery for stage 3 patients remains largely unclear.

“We all have ideas, but none of them are proven,” explains Jessica Donington, a thoracic surgeon at New York University Langone Medical Center. “Our understanding is better than it was, but it’s still not good.”

Surgery studies of stage 3 patients have tended to have small sample numbers (making the data less strong), Donington says, and it remains unclear whether it’s better to have surgery before or after other treatments. It’s also unclear whether surgery, before or after chemotherapy and radiation, is better than chemotherapy and radiation alone. And so far, “debulking” (removing a lot of a local tumor, but not all of it) doesn’t seem to have any benefit. The only time stage 3 surgery has shown a clear benefit in the clinic has been when a tumor could be completely eliminated by removing a lobe of the lung.

Experts say it’s best to take into account patient preferences and health situations when deciding whether or not to do surgery. Further, experts advise, these procedures are complex. So if you’re considering surgery, Donington advises, it makes sense to consider traveling to a large hospital that does a lot of lung cancer surgeries.

Chemotherapy and Radiation

“One thing we’ve learned in trials is that expertise matters,” Donington says.The risk of relapse or recurrence remains fairly high for stage 3 patients, so experts say that surgery should never be the only treatment in these cases. Some sort of systemic therapy, like chemotherapy or radiation, also will be part of the plan for most patients, oncologists say. The exact dosing and timing of these treatments can vary widely and, to some extent, depends on what’s done at your cancer center. It is ideal if a multidisciplinary team that includes surgical, medical and radiation oncology expertise can deliberate on a treatment plan in advance. Some of the common treatment plans include:

• Chemotherapy and a targeted monoclonal antibody
• Chemotherapy and radiation
• Chemotherapy, radiation and then surgery
• Surgery before chemotherapy and/or radiation

In order to pack as big a punch as possible, chemotherapy and radiation are often given at the same time to stage 3 patients who generally are self-sufficient, functioning well and haven’t lost too much weight. Side effects from chemotherapy can include nausea and vomiting, hair loss, mouth sores, diarrhea or constipation, and radiation can cause nausea and vomiting, fatigue, and skin changes or hair loss at treated sites. Simultaneous treatment with these methods can be even more harrowing than the systemic treatments given one after the other, the option chosen if a patient is not generally healthy. It’s important to be as healthy as possible going into these regimens, and to have a good support network to help get you through them.

Chemotherapy may be given, along with radiation, to try to shrink a tumor before surgery. This is called “neoadjuvant” therapy, but studies of stage 3 patients have neither shown this to be better nor worse than just radiation. In other cases, it makes sense to do surgery, and sometimes radiation, first. Chemotherapy is administered afterward to try to stamp out any cancer cells that might be left behind. Or, for some stage 3b patients who might not be well enough to tolerate surgery, chemotherapy may be given as the main treatment. Oncologists usually give chemotherapy in cycles, generally of three to four weeks including a treatment period and a break, to allow the body to recover from each infusion of medication. Research has shown that lung cancer tumors respond well to a combination of two drugs, called “doublet therapy,” while adding a third drug doesn’t really help that much, and only makes side effects more severe

Generally, lung cancer patients get a platinum-based chemotherapy drug like cisplatin or carboplatin plus one other drug. In some cases, other combinations may be recommended, such as gemcitabine with vinorelbine or paclitaxel. Since studies haven’t been able to identify an “ideal” combination for stage 3 patients, researchers recommend using what seems to work for the particular patient and, if possible, what causes the fewest side effects.

Usually, a lung cancer chemotherapy regimen lasts for four to six cycles. But some studies have shown that, after this initial treatment, it’s useful to continue taking one chemotherapy medication or targeted therapy after the initial round of chemotherapy. This “maintenance therapy” has been shown to keep the cancer in check and help patients live longer.

A couple of years ago, oncologists tried to push up the radiation doses for stage 3 patients. However, they found that standard doses were more effective and caused less suffering for patients. Both imaging and targeting have improved, making radiation treatment more exact. Three- and four-dimensional techniques and “respiratory gating,” a process of monitoring the movement of tumors during normal breathing, have helped to reduce off-target damage to nearby lung tissue, or to the esophagus or spinal cord. Studies of stage 3 patients show that radiation improves the local control of tumors, but doesn’t seem to improve overall survival.

“I had 37 radiation treatments and eight rounds of chemo,” remembers Hammock, a married father of two. “I couldn’t swallow [because of scarring from radiation] and I was so tired I put my cell phone on my pillow. I didn’t have energy to reach to the night stand to pick it up.”

Hammock, now four years out with no evidence of disease, still has dry mouth and trouble swallowing.

Newer Modalities

“It’s important to consider how patients will do after treatment,” Patel says. “Chemo and radiation often cause scarring in the lungs. After surgery, a patient may have lost one lobe of their lung. We want to treat the disease aggressively, but we also want to remain aware of the collateral damage. Patients want to be able to climb stairs without being oxygen-dependent.”In recent years, there have been exciting advances in targeted lung cancer treatment. Some target specific mechanisms within cells. Others target gene mutations, or processes that feed cancer cells, such as the development of blood vessels.

In order for cancer cells to grow, they need blood vessels to supply them with oxygen and nutrients. Avastin (bevacizumab) targets a growth factor, a protein called vascular endothelial growth factor (VEGF), that helps blood vessels to form. Cyramza (ramucirumab) targets a particular receptor on VEGF, blocking blood vessel growth.

Other drugs — (Tarceva [erlotinib], Gilotrif [afatinib], Iressa [Gefitinib]) — target the epidermal growth factor receptor, or EGFR, a receptor on the surface of cells. Normally, EGFR helps cells to grow and divide. Blocking it slows the growth of cancer cells. These drugs are more effective in cases in which EGFR harbors certain mutations.

Finally, about 5 percent of lung cancer patients, usually non-smokers or light smokers, have a rearrangement in a gene called ALK. New drugs — Xalkori (crizotinib), Zykadia (ceritinib) — block this protein.

Still other new drugs enlist the patient’s own immune system to fight the cancer. The immune system needs to know which cells are “self” and which are “not self” and should be attacked. To do this, it uses checkpoints, markers on the outside of cells that say, “Don’t attack! I’m one of you.” Sometimes, cancer cells adopt these markers to evade the immune system. These new drugs inhibit a marker called PD-1, thus boosting the immune response against cancer cells.

Side effects of targeted drugs, which can vary depending on the class of drug, can include sinus infections, dizziness, nausea, fatigue, diarrhea and rash, and more serious problems, too — blood clots, decreased white blood cells, or lung, kidney, gastrointestinal or skin problems. PD-1 inhibitors come with their own list of potential side effects: rash, colitis, hormonal problems and lung inflammation.

For many patients with stage 3 lung cancer, these drugs may not yet be options. Most of these advances largely have been tested in stage 4 patients, yet some treatments that seem to work in more advanced patients don’t seem to work as well in stage 3 patients. Why that’s so remains unclear. Studies of some of these strategies in stage 3 patients are taking place now, so ask your doctor if one of these newer medications might be appropriate for your case.

C

“Can we successfully integrate immunotherapy into treatment for stage 3 patients?” asks Patel. “Most of the drugs have been tested in stage 4 patients, but we’re doing stage 3 studies now. I’m hopeful.”