Introduction to Adjuvant Therapy: Why More than Just Surgery?

For patients with early-stage non-small-cell lung cancer (NSCLC) (stages I, II and some III), surgical resection (removal by surgery) is the standard treatment. Unfortunately, the rates of recurrence (cancer returning) after resection can be high, and additional therapy (chemotherapy) can improve the odds that the cancer won't return for some patients. This article goes through the data we have that demonstrate the benefit of chemotherapy after surgery for early stage lung cancer, information about chemotherapy before surgery, new treatments being studied for lung cancer patients after surgery and ongoing studies to help better determine which patients might benefit the most from particular treatments. We have learned about the importance of chemotherapy and other treatment after surgery from patients who were willing to go on clinical trials. Patients on the trials either received new treatments or were randomized (assigned by chance) to either get chemotherapy or not after surgery. The information below comes from the analyses that have been done of the patients who were willing to participate in clinical trials.

Patients with stage I NSCLC (lung cancer that has not spread to any lymph nodes or anywhere else in the body) have about a 60-80% chance of being cured with surgery alone. The size of the tumor is important in determining whether or not the cancer may come back, and other factors matter as well. The clinical trials that included patients with stage I lung cancer have not given us a definite answer about whether or not chemotherapy helps this group of patients. The studies have been clear that chemotherapy for patients with small tumors (< 3 centimeters) does not help reduce the risk of the cancer coming back. However, for patients with larger tumors, there does seem to be benefit. In two of the larger trials, patients who had tumors that were at least 4 centimeters in size did seem to have improved survival after receiving 3 months of chemotherapy. The improved survival rate was about 5% at the 5-year mark. That means that if 200 people had surgery for stage I lung cancer that was at least 4 centimeters in size, and they were divided into 2 groups of 100 and 1 group had chemotherapy, in 5 years there would be about 5 more people alive in the group that got the chemotherapy.

Patients with stage II NSCLC (lung cancer that has only spread to lymph nodes in the lung) have about a 50-60% chance of being cured with surgery alone. The larger clinical trials that included stage II patients have mostly shown that chemotherapy can improve the cure rates by 5-10%. All of the most recent trials that have included stage II patients have had similar results, so most physicians are in agreement about recommending chemotherapy for patients with resected stage II lung cancer. Exceptions to this would be people who are felt to be at high risk from chemotherapy either because they haven't recovered well from surgery, or have other health problems.

Age is also a factor. Some of the studies have specifically looked at older patients (> 70 years old) and have shown that they do as well as other patients, assuming they are otherwise healthy. However, as people get to be over 80 years old, the risks of chemotherapy increase. Patients over 80 will have to very carefully weigh the risks and benefits of chemotherapy with their oncologist. It is certainly worth meeting with an oncologist to review the information for nearly all patients with stage II NSCLC though.

Many patients with stage III lung cancer (cancer that has spread to lymph nodes in the mediastinum or center part of the chest) will receive therapy with chemotherapy and or radiation before surgery or will receive chemotherapy and radiation without surgery. For those patients who do have surgery first, the data to support the use of chemotherapy after surgery is very similar to the stage II data. Unfortunately, the risk of the cancer coming back for stage III patients is higher.

Chemotherapy Specifics:

Chemotherapy after surgery seems to work best when started 4-8 weeks after surgery. Some patients will have recovered enough to receive treatment earlier than 4 weeks, but that is unusual. There is some data to support chemotherapy as far as 12 weeks after surgery, but if a patient has still not recovered enough for chemotherapy by 12 weeks after surgery, it is unclear that chemotherapy given later than this will be of any benefit. Traditional chemotherapy is medications given by vein (infusion) that work to poison cancer cells. Most of them work by poisoning cells trying to divide to make new cells. They do this by changing the ability of the cell to make new DNA. Most of them have some factor that makes them more effective against cancer than other types of cells, but they do have side effects.

The chemotherapy given after surgery for early stage NSCLC is usually given over a 3-month period of time. A "cycle" of chemotherapy usually lasts 3 weeks and can included chemotherapy only given every 21 days, or more frequently depending on the specific drug. In general, 4 "cycles" of chemotherapy are given. So 4 cycles, each lasting 3 weeks, is 12 weeks of total chemotherapy time for most patients.

Most of the studies have used chemotherapy combinations with cisplatin as one of the drugs and Navelbine (vinorelbine) as one of the other drugs. The cisplatin can be given once every 3 weeks (with lots of intravenous fluids and anti-nausea medications), though there are other ways to give the drug (weekly for 2 weeks or every 4 weeks). Some patients are not able to tolerate cisplatin, and for those patients a related chemotherapy drug called carboplatin can be used. The carboplatin is generally felt to be slightly less effective than the cisplatin, but has fewer of certain side effects.

Navelbine is given weekly for 2 weeks in a row with 1 week off, or other strategies are possible. Though many of the studies have used vinorelbine, we know that in patients with metastatic (more advanced) lung cancer, other drugs can work as well as or perhaps better than Navelbine, and these drugs are often substituted. The other drugs that are typically used are Taxotere (docetaxel), Gemzar (gemcitabine), Alimta (pemetrexed), and sometimes others. These choices need to be discussed between each patient and physician to decide which chemotherapy drugs are the right ones for a particular person.

Most chemotherapy can cause low blood counts (low white blood cells increase the risk of infection, low red blood cells cause anemia and low energy, with increasing fatigue during treatment; low platelets can increase the risk of bleeding);patients may also experience nausea and vomiting (better controlled with newer drugs), hair loss with some regimens, and/or a rash; kidney function will need to be watched closely; many other side effects are possible. The specific chemotherapy drug and other factors determine how severe the side effects are for a particular patient. It is important to bear in mind, however, that even though the potential negative effects of post-operative chemotherapy are real, this can translate into meaningful improvements in survival from early stage lung cancer.

More Specifics:

The information from the largest trials of chemotherapy given after surgery was pooled together into a meta-analysis (a way of combining data from multiple studies). The LACE meta-analysis included follow-up to up to 5 years and included information on 4584 studies. All the trials included cisplatin chemotherapy as discussed above, and the results showed a 5% 5-year overall survival benefit. As discussed above, the benefit was higher for patients with stage II and III disease versus stage I.

Long-term Data

With longer-term follow-up, at least one of the large trials showed a decrease in benefit over time. In the IALT trial, which included almost 2000 patients, the difference in survival between the groups of patients who either did or did not get chemotherapy diminished over time. At 5 years there was a significant improvement in survival between the group that received chemotherapy and the group that didn't (4.5% improved survival), however by nearly 8 years of follow-up the difference wasn't significant (still in favor of chemotherapy, but not statistically significant). This led people to wonder if the chemotherapy caused some long-term harm to patients. However, other trials that have followed patients for even longer have not seen a decrease in overall survival benefit, so this remains an area of controversy (for instance the JRB.10 study had data for over 9 years of follow-up and saw no decrease in benefit from the chemotherapy over time and no increase in other causes of death in the group who received chemotherapy).

Neo-Adjuvant (pre-surgery) chemotherapy

Another area of controversy is the use of chemotherapy before instead of after surgery. Neoadjuvant (pre-surgery) chemotherapy has also been examined in early-stage NSCLC as an approach to improve survival outcomes (example studies on this topic here and here). Unlike the information looking at chemotherapy after surgery (adjuvant), we don't have large trials in which hundreds of patients either did or did not receive chemotherapy before surgery (neo-adjuvant). We therefore don't know as much about using chemotherapy before surgery. However, a meta-analysis (combination of data from many studies) of the neo-adjuvant trials that have been done, and comparisons of adjuvant to neo-adjuvant studies have all shown that chemotherapy is probably just as effective if it is given before or after surgery.

People have tried to do studies that look at chemotherapy given before or after surgery, but most of those studies have been closed before a definite answer could be reached. One recent study from Spain did look at patients with early stage lung cancer who had it removed with surgery and either had no chemotherapy or chemotherapy before or after surgery. The study, known as NATCH, included many patients with stage I NSCLC, and used carboplatin based chemotherapy. Unfortunately, no differences were seen among the three groups of patients (no chemotherapy, or chemotherapy before or after surgery), likely because so many patients were stage I, a setting for which we haven't seen as convincing a survival benefit. So we will probably never have a clear answer about whether chemotherapy should be given before or after surgery.

Analysis of Biomarkers Predictive of Benefit from Adjuvant Chemotherapy

More important than figuring out whether the chemotherapy should be given before or after surgery, is trying to figure out ways of "individualizing" chemotherapy. We know that not everyone needs chemotherapy, and that not everyone who receives chemotherapy gets benefit (the improvement in survival is only 5-10% and over half of stage I/II patients are cured with surgery alone). There is a lot of research being done to try to figure out tests that can be done on patients or the tumor tissue to figure out who may benefit more from certain treatments.

Some of the data is from looking for particular proteins that are in a tumor. In the IALT trial (a trial looking at chemotherapy or not after removal of lung cancer in nearly 20000 patients), the investigators have looked at multiple proteins in the removed tissue of patients. These studies were done "retrospectively", meaning after the trial was done, so the information from them is not as strong as information looked at "prospectively", meaning planned ahead of time. In the retrospective analyses of the IALT trial, several proteins important for repairing DNA have been found to predict for whether or not a patient may benefit from cisplatin chemotherapy. The one that has gotten the most interest is a DNA repair protein called ERCC1. Adjuvant chemotherapy significantly improved survival compared to not receiving chemotherapy in patients with ERCC1-negative tumors, but not in those with ERCC1-positive tumors, even when patients were followed for nearly 8 years. While this analysis indicates that maybe patients with ERCC1 positive tumors should not get chemotherapy, this needs to be proven in other trials. Very similar results were found with MSH2, another DNA repair enzyme. Patients with high levels of MSH2 may also not be helped with chemotherapy after surgery. There are many other proteins that have also been looked at as predictors of benefit from adjuvant chemotherapy, but still no tests that are considered "standard".

To prove whether or not ERCC1, MSH2 and some other proteins (RRM1, BRCA1/RAP80 and others) are truly valuable predictors that should be used routinely, they are being tested in ongoing trials in the United States and Europe. In these studies, patients have their tumors tested for the proteins of interest, 1 group of patients gets "standard" chemotherapy (4 cycles of cisplatin based chemotherapy as discussed above) and another group gets "experimental" therapy which is based on the results of the tests (ie. if a patients has high ERCC1, they don't get cisplatin chemotherapy if they are on the experimental arm). At least one of these ongoing trials also looks at the epidermal growth factor receptor (EGFR) and othert mutations. Patients who have EGFR activating mutations on that trial receive an EGFR targeted drug instead of chemotherapy. Genomic analyses of tumors, instead of protein analyses, are also being investigated in similar types of trials. So far, the gene signatures from tumors have only been shown to predict which patients will either do well or not well, but not who might benefit from chemotherapy and from certain drugs. Ongoing research will hopefully help with this.

Future Directions

Other research is looking at whether drugs besides chemotherapy can help cure patients with early stage lung cancer. There are many studies like this, but the four largest will be discussed here. Two studies have looked at drugs called epidermal growth factor receptor (EGFR) inhibitors (oral medications) after lung cancer surgery. One study that looked at Iressa (gefitinib) was completed several years ago, and the results will be presented at ASCO 2010. Another study with Tarceva (erlotinib), called RADIANT, has finished taking in new patients, but won't have any results for several years.

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Another study is looking at a drug, Avastin (bevacizumab) that blocks blood vessel formation. This drug is given with chemotherapy and is known to improve the survival for patients who already have metastatic (advanced) NSCLC. An ongoing study for patients with early stage lung cancer includes patients after surgery and assigns them to receive the standard 4 cycles of chemotherapy or the same chemotherapy plus the Avastin (given by vein as well). The Avastin is then continued for up to 1 year because of the theory that the highest risk of tumor regrowth (and need for blood vessel formation) is during that first year. The study, which is known as E1505, is still taking in new patients.

Another large randomized (meaning patients are randomly assigned to 1 treatment group or another) study, known as MAGRIT, is looking at a vaccine to a protein, called MAGE-A3, found on some cancer cells. Patients who have tumors that have this protein can enter the study and have a 50/50 chance of either receiving two years of the vaccine or two years of a placebo (not active) injection. Patients are allowed to have chemotherapy before they start on the study.

Conclusions

Adjuvant chemotherapy with a cisplatin-based combination of drugs has become the standard of care for patients with resected stage II-IIIA. Many patients with larger stage I tumors benefit from chemotherapy after surgery as well. The benefit is in the range of a 5-10% improvement in survival at 5 years, but patients who significant other health problems are less likely to have a benefit and may be harmed by treatment. It is appropriate for almost all patients with early stage NSCLC that has been removed by surgery to meet with an oncologist to review the pros and cons of chemotherapy.

The role of neoadjuvant (pre-surgery) chemotherapy is not as established because of fewer studies, but is likely as effective as adjuvant (post-surgery) chemotherapy. Our hope is that in the future we will be able to do tests on resected (removed) tumor tissue to determine exactly which drugs, whether they are chemotherapy or newer "targeted" drugs like erlotinib or bevacizumab or a vaccine, are the best choice for each individual patient.

This entry, part of the Lung Cancer Reference Library, is made possible by an educational grant from Pfizer, who had no input in its content.