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February 2011 VOL 2, NO 1

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Review

Maintenance Therapy For Non–Small Cell Lung Cancer

Improving outcomes for patients with non– small cell lung cancer (NSCLC) is particularly relevant because NSCLC accounts for 85% of all cases of lung cancer.1 In the appropriate patients with advanced NSCLC, maintenance therapy may help control the disease and extend patients’ lives. Maintenance therapy is relatively new in NSCLC treatment, representing a change from the past approach of retreatment upon disease progression.2 Two chemotherapy agents previously approved by the US Food and Drug Administration (FDA) for the treatment of advanced NSCLC—pemetrexed and erlotinib—recently received FDA ap proval for a new indication for maintenance therapy of advanced NSCLC.

Pemetrexed, a folate analog metabolic inhibitor, was granted FDA approval for maintenance therapy of advanced or metastatic lung cancer in July 2009.3 This new indication for pemetrexed is specifically for patients with nonsquamous NSCLC that has not progressed after 4 cycles of platinum-based first-line chemotherapy.4 Pem - etrex ed is also indicated as initial treatment in pa - tients with locally advanced or meta static nonsquamous NSCLC, in combination with cisplatin, and after prior chemotherapy as a single agent.4 Erlotinib, an endothelial growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), received FDA approval in April 2010 for an expanded indication as a maintenance treatment in patients with locally advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy.5,6 Erlotinib is also indicated to treat locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen.6

Identifying the appropriate patients as characterized by histology (nonsquamous) or molecular (EGFR mutation) profile is an important consideration when selecting the appropriate maintenance therapy.7 Using predictive biomarkers to target specific agents for maintenance therapy may help improve benefits and reduce risks by tailoring a specific treatment to the appropriate patient.7 For example, pemetrexed is an option for maintenance therapy in patients with nonsquamous histology.1,4

In addition, a molecularbased strategy may be useful in selecting the appropriate patients best suited for maintenance therapy with erlotinib.7 Progression-free survival (PFS) was significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib as maintenance therapy compared with EGFR-positive patients who received placebo, based on a randomized, placebo- controlled study.8 In addition to histology and genetic markers, maintenance therapy decisions involve a number of other important considerations, including the latest clinical data, evidence-based clinical practice guidelines, and the patient’s performance status and personal preferences. Although maintenance therapy may slow the growth of disease and extend life, the benefits of treatment must be weighed against the potential toxicities and other side effects associated with extended treatment. Costs and resource utilization associated with maintenance therapy must also be considered.

NSCLC: BURDEN AND ECONOMIC IMPACT

Lung cancer claims the lives of more Americans than any other type of cancer.1 Moreover, lung cancer imposes a substantial economic burden on our healthcare system. The estimated annual costs to the American public as well as lost productivity costs associated with lung cancer were previously outlined in the first part of this article.9

Treatment costs associated with lung cancer, as well as treatment failure costs, are also substantial. A retrospective, case-control cohort study that followed patients for 2 years from the first diagnosis of lung cancer showed that the monthly cost per patient was $11,496 for initial treatment, $3733 per month for secondary treatment, and $9399 for terminal care treatment.10 Failure of initial treatment was associated with increased costs: patients who experienced treatment failure incurred an additional $10,370/month in initial treatment phase costs and $8779/month after starting the secondary and/or terminal care phase of treatment.10 Moreover, treatment failure was associated with incremental costs of $19,149/ month and $74,697 across the study period.10 The study authors concluded that improvements in prevention or treatment of lung cancer, including new therapies or adjuvant chemotherapy, might reduce healthcare resource utilization and costs, and that strategies aimed at reducing hospitalizations and preventing or delaying treatment failure may offset the associated cost burden.10

More than 68% of all patients diagnosed with lung cancer are 65 years of age or older.11 The burden and cost of NSCLC may continue to grow as the baby boom generation (people born between 1946 and 1964) reaches the age of 65 years and older over the next 20 years.12

MAINTENANCE THERAPY AGENTS FOR THE TREATMENT OF ADVANCED NSCLC

Maintenance therapy, sometimes also referred to as consolidation therapy or early second-line therapy, 7 is a relatively new approach to improving outcomes in patients whose disease either responded to initial chemotherapy or was stable following that, and is intended to improve survival without adversely affecting quality of life.13 Aside from improving outcomes, the optimal maintenance treatment should be well-tolerated by patients and associated with few or no cumulative toxicities.7

The National Comprehensive Cancer Network (NCCN) has established specific recommendations for the use of pemetrexed in maintenance therapy, as well as for the use of erlotinib.1 These guidelines also include recommendations for several other agents, including docetaxel, bevacizu - mab, and cetuximab.1

Pemetrexed

Based on phase 3 study results, patients who received maintenance therapy with pemetrexed showed a significantly greater PFS (1.7 months longer), compared with the placebo group, and a significantly greater overall survival (OS) duration (2.8 months longer), compared with the placebo group.14 Specific findings from the study were previously highlighted in Part I of this article. 9 Moreover, in patients with nonsquamous histology treated with pemetrexed, the OS was 5.2 months longer than in the placebo arm.14

The most common any-grade ad verse reactions associated with pemetrexed included nausea (19%) and anorexia (19%).14 The pemetrexed group had a greater frequency of grade 3 or higher adverse events than the placebo group, including fatigue (5%) and neutropenia (3%).14

Another study that compared the combination of cisplatin plus pemetrexed with cisplatin plus gemcitabine in chemotherapy-naïve patients with advanced NSCLC demonstrated superior efficacy and reduced toxicity in the group receiving cisplatin plus pemetrexed.15

Erlotinib

Based on a phase 3 study, patients who received maintenance therapy with erlotinib showed a greater PFS (0.8 weeks longer) and an improved OS (1 month longer), compared with the placebo group.6,8 In patients with EGFR-positive immunohistochemistry treated with erlotinib, compared with EGFR-positive patients receiving placebo, PFS was significantly greater (1.2 months longer) in the erlotinib group, compared with the placebo group, in patients with EGFR-positive immunohistochemistry treated with erlotinib.8 Specific study results were previously highlighted.9

The most common any-grade ad verse reactions associated with erlotinib were rash (49.2%) and diarrhea (20.3%).6 The most common serious adverse event was pneumonia (2%), and the most common grade 3 or higher adverse events included rash (6%) and diarrhea (2%).8

OTHER AGENTS INCLUDED IN CLINICAL PRACTICE GUIDELINES

Docetaxel

Although docetaxel, a microtubule inhibitor, does not have a specific FDA approval for maintenance therapy in NSCLC, this agent is indicated as a single agent for locally advanced or metastatic NSCLC after failure on platinum therapy; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC.16 Based on a phase 3 randomized study that assessed the efficacy and safety of docetaxel administered either immediately after gemcitabine or at disease progression, immediate docetaxel was associated with a significantly greater PFS (5.7 months) compared with delayed docetaxel (2.7 months), and immediate docetaxel was associated with a greater median OS (12.3 months) compared with delayed docetaxel (9.7 months).17 However, the difference in median OS was not statistically significant (P = .0853). There was no significant difference in quality of life between the immediate and delayed docetaxel groups.17

Based on studies of docetaxel as monotherapy for NSCLC patients previously treated with platinum- based chemotherapy (n = 176), the most common grade 3/4 adverse reactions included neutropenia (65%), leuko penia (49%), and pulmonary effects (21%).16 The most common anygrade adverse reactions include neutropenia (84%); leukopenia (84%); anemia (91%); asthenia (53%); pulmonary effects (41%); infection (34%); nausea (34%); fluid retention (34%); neurosensory effects (34%); stomatitis (26%); diarrhea (23%); and vomiting (22%).16

In chemotherapy-naïve advanced NSCLC patients receiving docetaxel in combination with cisplatin (n = 406), the most common grade 3/4 adverse reaction was neutropenia (74%).16 The most common any-grade adverse reactions included neutropenia (91%); anemia (89%); alopecia (75%); asthenia (74%); nausea (72%); vomiting (55%); fluid retention (54%); diarrhea (47%); neurosensory effects (47%); anorexia (42%); infection (35%); peripheral edema (34%); and fever (33%).16

Bevacizumab

Bevacizumab, a monoclonal antibody that inhibits vascular endothelial growth factor, is indicated for the treatment of nonsquamous NSCLC, with paclitaxel and carboplatin for the first-line treatment of unresectable, locally advanced, recurrent, or metastatic disease.18 According to the NCCN clinical practice guidelines, the criteria for bevacizumab therapy include a performance status of 0-1, nonsquamous histology, and no history of hemoptysis.1

Adding bevacizumab to chemo therapy with paclitaxel plus carboplatin has shown a significant im provement in median OS (12.3 months), compared with chemotherapy alone (10.3 months), based on a randomized 3-year study of patients with recurrent or advanced NSCLC (N = 878) conducted by the Eastern Cooperative Oncology Group.19 An increased risk of treatment- related deaths were ob served in the group treated with bevacizumab plus paclitaxel and carboplatin, and the rate of clinically significant bleeding was 4.4% in this arm.19 Other adverse events included grade 4 neutropenia (24%), grade 3/4 hemorrhage (4.5%), hemoptysis (1.9%), and hypertension (6%).1 According to the NCCN guidelines, caution is advised when chemotherapy regimens with a high risk for thrombocytopenia and/or possible bleeding are combined with bevacizumab.1

Further studies are needed to determine whether bevacizumab maintenance is associated with a survival benefit compared with the combination of chemotherapy and bevacizumab without maintenance bevacizumab.20

Cetuximab

Cetuximab, a monoclonal antibody that targets EGFR, is indicated for the treatment of specific head and neck cancers and colorectal cancers; however, this agent does not have an indication for the treatment of NSCLC.21 Cetuximab use is not recommended for patients with colorectal cancer whose tumors have KRAS mutations in codon 12 or 13.21

According to a study of patients (N = 1125) with advanced NSCLC (stage IIIB or IV; majority were stage IV), patients treated with cetuximab in combination with vinorelbine and cisplatin showed no difference in PFS and a significantly improved OS (11.3 months) compared with patients receiving vinorelbine and cisplatin alone (10.1 months).1,22 Treatment-related deaths were similar in both groups.22 Patients receiving cetuximab had increased grade 3/4 febrile neutropenia (22%) and grade 3 acne-like rash (10%).1,22

EVIDENCE-BASED PRACTICE GUIDELINES

For the NCCN NSCLC clinical practice guidelines (updated in March 2010), a new section with maintenance therapy recommendations was added.1 These recommendations categorized maintenance therapy into 2 types: continuation maintenance therapy and switch maintenance therapy. Con tinuation maintenance therapy refers to the use of at least 1 of the agents administered as first-line therapy.1 Switch maintenance therapy refers to the initiation of an agent that was not included as part of the first-line treatment regimen.1 Based on 2 recent studies demonstrating a benefit in PFS and OS, the guidelines now recommend initiation with pemetrexed or erlotinib for switch maintenance therapy in patients without disease progression (Category 2B recommendation).1

Highlights of the NCCN guideline recommendations for continuation maintenance therapy and switch maintenance therapy were outlined previously in the first part of this article.9 Information about the American Society of Clinical Oncology (ASCO) guideline update, as well as recent guidance from the National Institute for Health and Clinical Excellence are also highlighted in that article.

THE ROLE OF HISTOLOGY AND MOLECULAR BIOMARKERS IN MAINTENANCE THERAPY

It is important to identify the histologic subtype of NSCLC (ie, squamous cell vs nonsquamous cell) when selecting maintenance therapy.23 Histologic information may be particularly useful when augmented by molecular testing.23 Detecting the bronchoalveolar subtype of NSCLC adenocarcinoma may suggest a specific treatment approach, particularly if it is associated with specific mutations in the EGFR tyrosine kinase domain, which indicates it may respond to treatment with an EGFR TKI.23 However, it is important to point out within this NSCLC subtype, there are also variabilities in histology and molecular information.23

Several predictive molecular biomarkers play a key role in NSCLC treatment,1 and these biomarkers and associated characteristics were summarized in Part I.9 Initial retrospective studies suggest that approximately 90% of patients with a tumor response to erlotinib and gefitinib (both EGFR TKI agents) had EGFR mutations E19 deletion and L858R mutation, whereas patients without a response to these 2 agents did not carry these mutations.1 The NCCN guidelines recommend that pathological evaluation be performed to classify the lung cancer, determine its extent of invasion, determine the status of surgical margins, and identify molecular abnormalities that may predict the treatment response, or resistance to, EGFR TKI therapy.1

OTHER MAINTENANCE THERAPY CONSIDERATIONS

The potential benefits of maintenance therapy— preventing cancer recurrence, slowing disease growth, and prolonging life—must be weighed against the potential risks—increased side effects and potential for toxicities, drug resistance, and more frequent doctor visits. Another consideration is that maintenance therapy does not provide the patient with a chemotherapy break, also referred to as a wait-and-see period.7 Data on the quality of life associated with maintenance therapy are limited, including data on cumulative toxicity associated with extended chemotherapy.7 Although maintenance therapy increases chemotherapy costs and may increase overall costs, it may conversely decrease costs associated with palliative radiotherapy and hospital admissions resulting from performance stat us deterioration.20

The value of maintenance therapy is the subject of ongoing discussion among clinicians, particularly in light of its cost and potential toxicity.24 Pemetrexed administered in 6 cycles at the average wholesale price of $3000 per cycle would total $18,000.24 The wholesale acquisition cost for erlotinib maintenance treatment would be $4000 per month ¥ a mean PFS of 3 months, for a total treatment cost of $12,000.24

Some of the challenges surrounding cost of added survival were presented at the 2010 ASCO meeting by Scott Ramsey, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle.24,25 Ramsey asserted that maintenance therapy was unlikely to be cost-effective, based on a ratio that considers both the price over standard care and the months of OS benefit. However, he acknowledged that pharmacogenomic strategies may improve the costeffectiveness of therapy and that the cost of testing will be a factor. Ramsey claimed that many new oncology agents do not meet the criteria for cost-effectiveness and that many economic analyses do not meet the guidelines for economic evaluation.24,25 Guideline-driven pharmacoeconomic studies may shed light on whether maintenance therapy is the most cost-effective.

The rationale in favor of maintenance therapy was presented at the 2010 ASCO meeting by Tracey Evans, MD, of the Abramson Cancer Center, University of Pennsylvania, in Philadelphia.26 According to Evans, “maintenance therapy for advanced NSCLC is absolutely a standard of care” that should be considered for all patients, particularly based on clinical data showing prolonged survival and tolerability.26 An opposing point of view was presented by Tom Stinchcombe, MD, of the Lineberger Comprehensive Cancer Center, at the University of North Carolina at Chapel Hill.27 According to Stinchcombe, maintenance therapy is not necessarily a standard of care for every patient but rather an option to be considered, which depends on toxicities as well as the patient’s disease burden, extent of symptoms, performance status, and preferences.27 He maintained that a treatment-free interval is still an option in this incurable disease setting.27

CONCLUSION

Maintenance therapy, a relatively new approach in the treatment of patients with advanced NSCLC, has the potential to extend survival and improve outcomes. Key considerations for tailoring treatment for the appropriate patients include the histology of the carcinoma, genetic biomarkers, the extent of disease invasion, and the patient’s performance status and preferences. The benefits of maintenance therapy must be weighed against the potential toxicities and other side effects associated with extended treatment. Selecting the appropriate therapy for the appropriate patients and involving patients in the decision process are important aspects of the treatment plan. Strategies for managing side effects warrant careful consideration. Optimally, the agent selected for maintenance therapy should be well-tolerated by the patient, demonstrate improved patient outcomes, and have minimal side effects/cumulative toxicities.7

Recent clinical data and evidence-based guidelines are valuable decision-making tools for clinicians. However, data assessing quality of life, costeffectiveness, and cumulative toxicity of maintenance therapy are lacking. Costs and resource utilization associated with maintenance therapy must be balanced against the risks and costs of not treating or of deteriorating performance status. A delay strategy may be associated with a shorter survival time and a faster disease progression than immediate additional therapy.28,29 In any case, the prospect of extended survival of several months, or even weeks, particularly if treatment is well-tolerated, represents an important milestone for patients with advanced NSCLC.

References

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Non-small cell lung cancer, V.2.2010. March 5, 2010. www.nccn.org/professionals/ physician_gls/PDF/nscl.pdf. Accessed September 15, 2010.

  2. Peck P. Maintenance pemetrexed extends NSCLC survival by 3 months. Medpage Today. May 30, 2009. www.medpagetoday. com/tbprint.cfm?tbid=14437. Accessed September 22, 2010.

  3. Riley K. FDA approves first maintenance drug therapy for advanced lung cancer [press release]. July 6, 2009. US Food and Drug Administration. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm170515.htm. Accessed Sep - tember 22, 2010.

  4. Alimta (pemetrexed disodium) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2010.

  5. Waknine Y. FDA approves use of erlotinib as maintenance therapy for advanced non-small cell lung cancer [press release]. April 20, 2010. www.medscape.com/viewarticle/ 720446. Accessed September 22, 2010.

  6. Tarceva (erlotinib) [package insert]. Melville, NY: OSI Pharmaceuticals Inc; and South San Francisco, CA: Genentech; 2010.

  7. Owonikoko TK, Ramalingam SS, Belani CP. Maintenance therapy for advanced non-small cell lung cancer: current status, controversies, and emerging consensus. Clin Cancer Res. 2010;16:2496-2504.

  8. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomized, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521-529. Epub May 20, 2010.

  9. Maintenance therapy for non-small-cell lung cancer: a valuebased approach to improve patient care and outcomes, part I of II. Value-Based Cancer Care. 2010;1:24-26.

  10. Kutikova L, Bowman L, Change S, et al. The economic burden of lung cancer and the associated costs of treatment failure in the United States. Lung Cancer. 2005;50:143-154. Epub August 19, 2005.

  11. National Cancer Institute, US National Institutes of Health. Surveillance, Epidemiology, and End Results. SEER stat fact sheets: lung and bronchus. http://seer.cancer. gov/statfacts/html/lungb.html. Accessed September 20, 2010.

  12. Vincent GK, Velkoff VA. The Next Four Decades, the Older Population in the United States: 2010 to 2050. Current Population Reports, P25-1138. Washington, DC: US Census Bureau; May 2010.

  13. American Society of Clinical Oncology. Explaining maintenance therapy. Cancer.net. Updated February 22, 2010. www.cancer.net/patient/All+About+Cancer/Cancer.Net+ Feature+Articles/Treatments%2C+Tests%2C+and+Proced ures/Explaining+Maintenance+Therapy. Accessed September 20, 2010.

  14. 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;374: 1432-1440. Epub September 18, 2009.

  15. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage NSCLC. J Clin Oncol. 2008;26:3543-3551.

  16. Taxotere (docetaxel) [package insert]. Bridgewater, NJ: sanofi-aventis US, LLC; 2010.

  17. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after frontline therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:591-598. Epub December 15, 2008.

  18. Avastin (bevacizumab) [package insert]. South San Francisco, CA: Genentech, Inc; 2009.

  19. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.

  20. Eaton KD. Maintenance chemotherapy in non-small cell lung cancer. J Natl Compr Canc Netw. 2010;8:815-821.

  21. Erbitux (cetuximab) [package insert]. Branchburg, NJ: ImClone Systems Inc; 2010; and Princeton, NJ: Bristol- Myers Squibb Company; 2010.

  22. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemo therapy in patients with advanced non–small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009;373:1525-1531.

  23. Neal JW. Histology matters: individualizing treatment in non-small cell lung cancer [editorial]. Oncologist. 2010;15: 3-5. Epub January 19, 2010.

  24. Hayes E. Will maintenance sell in NSCLC? Experts weigh costs against benefits. Pharmaceutical Ap provals Monthly. August/September 2010.

  25. Ramsey S. Cost effectiveness in lung cancer trials and treatment. Presented at the 2010 American Society of Clinical Oncology Meeting—Education Session. June 4-8, 2010; Chicago, IL.

  26. Evans TL. Maintenance therapy for advanced NSCLC is standard of care. Presented at the 2010 American Society of Clinical Oncology Meeting—Education Session. June 4-8, 2010; Chicago, IL.

  27. Stinchcombe T. Maintenance therapy for advanced NSCLC is not standard of care. Presented at the 2010 American Society of Clinical Oncology Meeting— Education Session. June 4-8, 2010; Chicago, IL.

  28. Belani CP, Liao J. Maintenance therapy for non-small cell lung cancer [comment]. Lancet. 2010;375:281-282; comment on Stinchcombe T, West H comment in: Lancet. 2009;374:1398-1400.

  29. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:3277-3283. Epub May 26, 2009.

 

Nursing and Patient Management Considerations for Maintenance Therapy in Non–Small Cell Lung Cancer

By Beth Eaby-Sandy, CRNP

Outpatient Thoracic Oncology Nurse Practitioner, University of Pennsylvania Health System, Philadelphia

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.

Nursing Considerations

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.

Managing Toxicities

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.

References

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

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