Significant ad van ces in treat ing non–small cell lung cancer (NSCLC) have been made over the past 10 years; nevertheless, survival im provement in this disease pales compared with many other solid tumors. Because maintenance chemo - therapy offers improved survival in NSCLC, patients and doctors are justifiably excited.
In my dealings with patients, there seem to be 2 distinct responses to maintenance treatment. On the one hand, patients are very happy that they can continue receiving some sort of therapy, because they feel that they are continuing the fight. Before the data supporting maintenance chemo therapy for NSCLC, we would stop therapy after 4 to 6 cycles and give a treatment break, and many patients were worried that they weren’t doing anything to treat their disease during this time. Conversely, I have also encountered many patients who are yearning for a break in therapy. Suggesting maintenance chemotherapy, which promises more toxicity similar to what the patient is already experiencing, leaves them bewildered. But because the treatment offers a survival advantage, patients usually will continue with it because they want to live longer. However, they frequently ask when there will be a break, and this often gives them the realization that they will be receiving this treatment for the rest of their lives.
It is important for oncology treatment providers to have a detailed discussion with patients about the pros and cons of maintenance therapy for NSCLC. These patients have a terminal illness with average survival of around a year. Doctors and nurses must allow pa tients the autonomy to make decisions about receiving maintenance therapy, along with possible breaks to have a vacation or spend time with family. Maintenance therapy can continue indefinitely, which can leave a patient feeling that his/her life is a constant schedule of treatments and can cause tremendous emotional stress.
As maintenance therapy becomes a more widely used treatment option for patients with NSCLC, it is important to weigh its toxicities. Pemetrexed, which is US Food and Drug Administration (FDA)-approved in the maintenance setting, and docetaxel, which has a recommendation (although not an FDA approval) for maintenance therapy, are both cytotoxic chemo therapy agents and pose concerns different from other approved maintenance therapies. Common side effects of chemotherapeutic agents, including risk for myelosuppression, fatigue, and nausea, are a concern for patients receiving maintenance therapy, especially be cause there is no defined end date to it unless there is disease progression or unacceptable toxicity. So patients may end up taking these drugs without a break for up to a year or more.
In the pemetrexed maintenance study, anemia occurred in 15% of patients in the pemetrexed maintenance arm versus 6% in the placebo arm.1 Patients receiving pemetrexed may therefore require more frequent blood transfusions and possibly colony-stimulating factors such as darbepoe - tin or erythropoietin. Managing fatigue can become difficult for these patients, and considering that they are dealing with a terminal illness, fatigue must be taken into serious account in terms of its effect on the patient’s quality of life. Nausea was also reported in 19% of patients in the pemetrexed arm versus 6% in the placebo arm.1
The targeted therapies erlotinib (in the switch maintenance setting) and bevacizumab and cetuximab (in the continuation maintenance setting) do not typically induce the same side effects as chemotherapy but rather carry their own set of unique toxicities. The toxicities from these agents can also interfere with a patient’s quality of life and must be considered and addressed before embarking on maintenance therapy.
Rash was the most common side effect in patients receiving erlotinib in the maintenance trial. Grade 3/4 rash, causing interference with activities of daily living, was 6%.2 Because good randomized data on treating this rash have not emerged, management strategies have focused on best-practice recommendations. Depending on severity, papulopustular rash can be treated with topical steroids or antibiotics, oral antibiotics, and even oral steroids in severe cases.3 These medications can be used in combination or separately depending on the grade of rash. Although it is rarely life-threatening, rash can be uncomfortable and disfiguring at times. In the cetuximab continuation trial, rash was present in approximately 70% (382/548) of patients, with 10% experiencing grade 3/4 rash.
Rates of grade 3/4 diarrhea in both the cetuximab and erlotinib maintenance trials were 4% and 2%, respectively.2,4 It is usually easily controlled with loperamide and sometimes re quires a prescription-strength anti diarrheal. Concern for dehydration may be an issue given that this patient population is often elderly, so prompt assessment and ensuring fluid intake are important.
Bevacizumab is only approved for the use of nonsquamous NSCLC because of bleeding risk. The most common side effects of bevacizumab include hypertension and proteinuria,5 and assessing for these on each visit is recommended. Standard antihypertensives will usually control bevacizumab-associated hypertension; pro tein - uria often improves on holding the bevacizumab dose. In rare NSCLC cases, bevacizumab has the potential to cause fatal pulmonary hemorrhage, so it is essential that practitioners assess for hemoptysis and permanently discontinue bevacizumab if hemoptysis occurs.
In summary, the improvement in survival for metastatic NSCLC by continuing a maintenance therapy after first-line treatment is modest, but it is certainly an advance. Conversations with patients about the schedule, toxicities, and benefits of therapy must be unbiased and thorough. Patients need to be able to voice their concerns and have ample opportunity to shape their treatment regimen because of their limited prognosis and possible effect of maintenance treatment on quality of life.
- Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet. 2009; 74:1432-1440.
- Cappuzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multi-center, randomized, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521-529.
- Lynch T, Kim E, Eaby B, et al. Epidermal growth factor receptor (EGFR) inhibitor-associated rash: an evol ving paradigm in clinical management. Oncologist. 2007;12:610- 621.
- Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009;373:1525-1531.
- Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2007;355:2542-2550.