 is difficult enough without having to cope with the effects of treatments intended to save your life. While most of those effects are temporary, menopause caused by medical or surgical treatments is a permanent reality.

, defined as the permanent end of menstruation (and fertility) not caused by any medical intervention. Natural menopause usually occurs at about age 51, and after a gradual transition that can last for years. During this transition, called 

, the ovaries’ production of hormones—including estrogen, progesterone, and androgen&mdash;gradually declines, often causing symptoms such as erratic periods, hot flashes, vaginal dryness, difficulty sleeping, and mood swings.

	Menopause caused by a medical treatment or surgery is called 

. This can occur at any age prior to natural menopause, and can be the result of surgical removal of both ovaries (called 

) or treatments that damage both ovaries, such as certain types of chemotherapy or pelvic radiation used to treat certain cancers. (Note: Hysterectomy does 

 cause menopause unless both ovaries and the uterus are removed.)

	When caused by surgery, menopause occurs immediately, and the abrupt loss of hormones can cause symptoms that are more severe than those experienced with natural menopause. When menopause is caused by medical treatments, there may be a short transition while the ovaries gradually cease production of hormones.

	Whether brought about by surgery or medical treatments, induced menopause forces women to deal with a number of emotional, physical, and practical issues—all in addition to the original diagnosis. The following tips will help you to prepare for and cope with induced menopause in the most effective way possible.

 Before having surgery or beginning any cancer treatment, ask your physician if that treatment will cause menopause. The unknown can be frightening, and knowing what to expect often makes it easier to cope with events when they occur. Furthermore, having this information ahead of time will help you to prepare, both physically and emotionally, while giving you the information you need to make some important life decisions. If, for example, you had hoped to begin or add to your family when you were diagnosed with cancer, referral to a fertility specialist may be appropriate. Depending upon your situation, you may be a candidate for a procedure such as egg harvesting, which can be done before your treatment.

 Everyone’s menopause experience is different, and some women still have misconceptions about what menopause is and isn’t. While family and friends can often provide emotional support, it’s best to get your medical information from the experts, especially since expert opinions on menopause and midlife women’s health tend to change rapidly as research findings are reported. When in doubt, ask your physician. When you feel the need for additional information, be sure to get it from a trusted source. One such source is The North American Menopause Society (NAMS, 

), a world leader in menopause information and education that offers a wide range of resources, including patient-friendly online information and publications such as the 

. Various cancer-related websites, such as those sponsored by the American Cancer Society (

) or groups associated with your specific type of cancer, may also offer information about induced menopause.

After menopause, whether natural or induced, women no longer have the protective effects of ovarian hormones such as estrogen, the loss of which places them at increased risk for certain conditions such as the bone-thinning disease osteoporosis and osteoporotic fractures. Women who experience induced menopause at a young age live without this protection for more years, and are therefore at greater risk for certain diseases. A number of treatments and lifestyle choices can help to prevent many of these diseases, making regular visits to your physicians, including your gynecologist, more important than ever. Be sure to choose physicians who understand the complexities of your cancer diagnosis and are well versed in menopauserelated issues.

 Menopause-related symptoms can range from annoying to severe. Women who experience symptoms, such as hot flashes and vaginal dryness, sometimes view them as inevitable, not realizing that, in many cases, they can be effectively managed with medications, supplements, dietary and other lifestyle choices, or a combination of all of these. Women who experience induced menopause tend to require treatment for menopauserelated symptoms more often than those who reach menopause spontaneously, and sometimes for longer periods and at higher doses—not only to control symptoms but also to reduce the risk of menopauseassociated diseases later in life. Keep in mind that many nonhormonal medications are available for relieving menopause symptoms and for disease prevention/ treatment for those women unable or unwilling to use hormonal therapies. Choose physicians very familiar with the symptoms of menopause, as well as your type of cancer and your treatments.

 While many women who experience natural menopause come to accept it as a new phase of life, and even describe a sense of relief from the worries about periods and pregnancy, the emotional consequences of earlier or premature menopause (before age 40) can be very different. Even when not related to cancer, younger women who experience menopause may feel as if they’ve become old before their time or have lost their femininity. For some of these women the reality of being unable to bear children can be devastating. Fortunately, the days when talking about menopause was considered taboo are long gone. Support groups offer the opportunity to share with other women coping with similar situations. Such groups can be found by asking a hospital social worker or searching online. When doing so, look for groups for women of your own age since older women tend to view menopause very differently. When appropriate, involve your spouse or partner.

 People with cancer are often described as strong or even heroic, sometimes making them feel the need to put on a brave face to live up to others’ expectations. Be sure to give yourself permission to feel what you feel, and to grieve, cry, and even fall apart. Finally, keep in mind that asking for help is, indeed, a sign of strength rather than weakness.

Articles

Whether brought about by surgery or medical treatments, induced menopause forces women to deal with a number of emotional, physical, and practical issues-all in addition to the original diagnosis. 

When Cancer Treatment Causes Menopause: Tips for Preparing and Coping

 To determine actual first-line treatment patterns for metastatic triple-negative breast cancer (mTNBC) in the United States by analyzing records of patients treated in community practices.

 We derived our data from the Georgia Cancer Specialist Database (GCSD) (2003-2008) and the International Oncology Network’s (ION) Treatment and Outcomes Database (2003-2008). In both data sets, patients with stage IV TNBC were selected and followed for up to 1 year after the initial mTNBC diagnosis. Chemotherapy was deemed first-line if initiated within 120 days of mTNBC diagnosis.

 The study included 30 and 29 mTNBC patients from GCSD and ION, respectively. In the GCSD sample, 16 patients (53%) were treated with monotherapy, namely capecitabine and the taxanes (44% each of the monotherapy recipients). Fourteen patients received combination therapy, with the taxanes and cyclophosphamide/doxorubicin the most frequently used agents (79% and 36%, respectively). The ION data analysis showed that 38% of patients received monotherapy, most commonly with the taxanes (64% of monotherapy recipients); 62% received combination therapy, with cyclophosphamide/doxorubicin and bevacizumab/paclitaxel being the most frequent concurrent agents (33% for each). We determined ION mTNBC patients had higher treatment costs, due at least in part to the greater use of bevacizumab.

 First-line treatment patterns for mTNBC were diverse, reflecting a lack of consensus and an unmet need for standardized therapy. These results will need to be confirmed with data derived from other community settings.

		Triple-negative breast cancer (TNBC) is characterized by aggressive tumors whose cells lack estrogen receptors (ERs) and progesterone receptors (PRs), and do not overexpress HER2.

 Approximately 10%-17% of all breast cancers in the United States are triple negative.

 Compared with women diagnosed with other subtypes of breast cancers (non-TNBC) in the United States, patients diagnosed with TNBC are more likely to be younger (<35 y) and African-American.

 Patients diagnosed with TNBC also have a higher rate of mortality (42.2% vs 28.0%; 

 < .0001) and distant recurrence within the first 5 years of diagnosis when compared with non-TNBC patients.

 TNBC is further associated with higher tumor grade, increased risk for visceral or cerebral metastasis, and poor survival after recurrence.

		Early-stage TNBC is treated with a combination of surgery, radiation, and neoadjuvant/adjuvant chemotherapy, which can often lead to a good prognosis. However, compared with other breast cancers, TNBC patients experience a higher proportion of distant recurrence (33.9% vs 20.4%; 

 < .0001).1 Furthermore, prognosis is poor in advanced disease, with a median overall survival of only 13.3 months following diagnosis of metastatic TNBC (mTNBC).

		Despite the reported benefits from treatment with chemotherapy, prognosis remains poor for TNBC patients. Furthermore, the shorter survival times may also be affected by the decreased treatment options currently available compared with options for other forms of metastatic breast cancer (mBC).

 Standardized therapies such as trastuzumab and lapatinib are available for HER2-expressing breast cancer in the metastatic and adjuvant settings.

 Cancers that are ER-positive and/or PR-positive can also be treated with endocrine therapies.

 However, lack of hormone-receptor expression and HER2 overexpression render TNBC resistant to treatment with these agents.

 Consequently, standard cytotoxic chemotherapy remains the preferred treatment for TNBC.

			Table 1. Approach to Selecting First-Line Therapy for Metastatic Breast Cancer

Bevacizumab used in combination with paclitaxel for HER2-negative breast cancer.

Trastuzumab used in combination with single-agent or combination chemotherapy (except with doxorubicin/cyclophosphamide), or can be considered for monotherapy, in the treatment of HER2-positive breast cancer.

		Sequential single-agent chemotherapy is often preferred to combination chemotherapy in the treatment of patients with mBC because of its similar antitumor efficacy and decreased toxicity.

 However, for rapidly progressive visceral disease, improved response rates and time to progression can justify use of a combination strategy, despite greater toxicity.

 In HER2-negative mBC, conventional chemotherapy and biologic therapy (

) with the vascular endothelial growth factor (VEGF) ligand inhibitor bevacizumab are potential first-line treatment choices that are often used for mTNBC. When combined with taxane therapy, bevacizumab significantly improved the objective response rate (36.9% vs 21.2%; 

 < .001) and prolonged median progression-free survival (PFS) (11.8 mo vs 5.9 mo; hazard ratio [HR] = 0.60; 

 < .001) in first-line treatment of mBC patients, compared with taxane alone.

 Furthermore, taxane/bevacizumab combination therapy displayed greater efficacy than single-agent taxanes in a broad range of breast cancer patient subgroups.

 Bevacizumab in combination with capecitabine, nab-paclitaxel, docetaxel, or anthracycline compared with the chemotherapy agent alone resulted in an increase in median PFS for each combination in a first-line setting in the RIBBON-1 trial.

 There were, however, no significant differences in overall survival. The HR for triple-negative status was 0.78 (95% CI, 0.53-1.15); the HR for non—triple-negative status was 0.61 (95% CI, 0.48-0.77); and the HR for unknown status was 0.52 (95% CI, 0.15-1.78). In the second-line setting, bevacizumab in combination with chemotherapy again resulted in an increase in median PFS from 5.1 to 7.2 months, but there was no significant difference in overall survival.

 In an analysis of the 159 patients in this trial with triple-negative cancer, the median PFS was 6.0 months with bevacizumab/chemotherapy compared with 2.7 months with chemotherapy alone.

 However as the subsequent studies failed to confirm the same degree of benefit observed in the initial trial, the indication of bevacizumab for mBC has been withdrawn by the FDA.

		The debate continues over the merits of sequential monotherapy versus combination therapy, especially given the emergence of innovative, less-toxic formulations. In a nonrandomized study following 631 mBC patients pretreated with at least 2 chemotherapeutic regimens, the antimetabolite capecitabine achieved an overall response rate of 34.7% (N = 345 evaluable patients), with a median time to progression of 6.6 months and median overall survival of 10.0 months.

 A more recent study conducted in mBC patients who received prior adjuvant anthracycline-based chemotherapy (including doxorubicin itself) showed that pegylated liposomal doxorubicin plus cyclophosphamide achieved an overall clinical benefit rate (complete response plus partial response plus stable disease for >6 months) of 71%. Unlike standard doxorubicin, the liposomal formulation appeared to confer no significant cardiotoxicity.

 In a randomized phase II study, gemcitabine in combination with vinorelbine versus sequential monotherapy showed no significant benefit in median overall survival (10.6 mo vs 8.9 mo; 

 Similarly, previous work demonstrated that combination chemotherapy achieved higher response rates and longer times to progression, but with greater toxicity and no prolongation of survival, compared with single-agent therapy.

		Several combination therapies have proven to be effective in the first-line treatment of mTNBC. For example, the nontaxane microtubule inhibitor ixabepilone combined with capecitabine yields a higher mTNBC response rate than capecitabine alone. In phase III trials, the combination achieved a 31% overall response rate compared with 15% for capecitabine monotherapy. It also resulted in increased median PFS (4.2 mo vs 1.7 mo, respectively; HR = 0.63).

 These trials took place in a taxane-experienced mBC population. In a partially taxane-naïve population, another metabolite inhibitor, gemcitabine, was added to paclitaxel therapy, resulting in a 35.7% response rate in 14 mTNBC patients with a 6-month median time to progression.

 Nanoparticle albumin-bound paclitaxel administered in combination with bevacizumab and gemcitabine resulted in an overall clinical benefit rate (overall response rate plus stable disease) of 84.6% (11/13 patients with mTNBC) with an 18-month overall survival rate of 82.5% and minimal toxicity.

		In a retrospective review of phase II and III studies in first-line therapy of mBC, carboplatin/docetaxel and carboplatin/paclitaxel combination therapies attained response rates of 53%-62%.

 When administered as first-line treatment in phase II trials, carboplatin with docetaxel resulted in an overall response rate of approximately 60% and a median time to progression of 6.5-9.6 months.

 On the other hand, a randomized phase III trial in mBC showed no significant differences in the overall response rates between carboplatin/paclitaxel and single-agent paclitaxel (38% vs 49%; 

		Evidence suggests that platinum-based combination therapy with cisplatin or carboplatin may enhance response rates in TNBC to a greater extent than in other breast cancer types, though results are inconsistent for metastatic disease.

 A small, retrospective study found that mTNBC patients taking cisplatin plus gemcitabine had improved median PFS compared with the patients with other types of mBC (5.3 mo vs 1.7 mo; 

		Several novel treatments are currently under investigation for the treatment of mTNBC. These include inhibitors of PARP1, a cellular enzyme that plays a central role in repairing single-strand DNA breaks.

 Other agents under investigation for TNBC have biologic targets that include VEGF, mammalian target of rapamycin (mTOR), and epidermal growth factor receptor (EGFR).

		Despite the lack of approved, standardized TNBC-specific therapy, the above discussion identifies some of the chemotherapeutic options available for mTNBC. An evaluation of actual first-line treatment patterns for mTNBC would provide insights into how patients with this clinically aggressive breast cancer type are treated in current practice.

		In this study, we sought to identify current patterns of first-line mTNBC chemotherapy by analyzing data from community practices in the United States. We further compared the costs of anticancer drugs administered as first-line therapy between mTNBC and other mBC (metastatic non-TNBC) patients during the first year following diagnosis of stage IV TNBC.

		We analyzed de-identified records for patients with breast cancer stored in the Georgia Cancer Specialist Database (GCSD) from 2003-2008 and the International Oncology Network’s Treatment and Outcomes Database (ION) from 2003-2008.

		Georgia Cancer Specialists is one of the largest private oncology practices in the United States. It records 160,000 cancer patient visits annually at its offices in north and central Georgia, southeast Tennessee, and southwest North Carolina. The GCSD includes patient demographics (eg, age, sex, race, smoking status); disease diagnosis; staging at diagnosis; chemotherapy protocols including protocol name, line of therapy, and start and end dates of the protocol; longitudinal records of infusion drugs (chemotherapy and nonchemotherapy); outpatient services; outpatient prescriptions; laboratory results; insurance information; and survival status.

		ION’s Treatment and Outcomes Database houses longitudinal information on more than 105,000 unique oncology patients from 2003 to 2008. It represents more than 100 private practice oncologists across the United States (Alabama, California, Georgia, Nebraska, North Carolina, Ohio, Texas, Virginia, and Wisconsin). The available data include demographics, diagnoses, staging, death, visit information, treatment plans, medication administered (eg, date of infusion or prescription, drug dosage), and laboratory results. Since these were de-identified patient databases, the study was exempt from institutional board review.

		In both data sets, patients with stage IV mTNBC or metastatic non-TNBC were selected and followed for up to 1 year after initial diagnosis. We identified patients as having breast cancer based on the presence of a 174.

 International Classification of Diseases, Ninth Revision

 diagnostic code in their records. The selected patients had complete records on their ER, PR, and HER2 status. Those with negative values for all ER, PR, and HER2 statuses were categorized as having mTNBC, while others with at least 1 positive ER, PR, or HER2 were classified as having metastatic non-TNBC. We excluded patients with other primary tumor types prior to the initial stage IV breast cancer date.

First-line treatment patterns for metastatic triple-negative breast cancer are diverse, reflecting a lack of consensus and an unmet need for standardized therapy. 

Treatment Patterns of Metastatic Triple-Negative Breast Cancer in US Community Practice Settings

		John Theurer Cancer Center at Hackensack University Medical Center

 includes a focus on 2 challenging situations: management of metastatic triple negative breast cancer (TNBC) and of advanced stage non—small–cell lung cancer (NSCLC).

	Christiansen and colleagues report on actual first-line treatment patterns for the management of metastatic TNBC in community practice settings in the United States. TNBC is characterized by aggressive tumors with cells that lack estrogen receptors (ERs) and progesterone receptors (PRs), and do not overexpress HER2. The study looked at patients with stage IV metastatic TNBC in 2 databases (Georgia Cancer Specialists Database and International Oncology Network’s Treatment and Outcomes Database). Though the number of patients evaluated was relatively small, the patterns seen confirmed previous observations.That is, the analysis found that there was no general consensus in current treatment for stage IV TNBC. The basis of therapy remains the use of conventional cytotoxics from single agent chemotherapy (capecitabine, taxanes) or combinations regimens (cyclophosphamide, doxorubicin with and without bevacizumab), with corresponding significant differences in costs.

	Although the metastatic potential in TNBC is similar to that of other breast cancer subtypes, these tumors are associated with a shorter median time to relapse, a greater chance of visceral- and organ-based metastatic disease, and overall worse outcomes and survival. Unfortunately, there are no reliable prognostic factors in TNBC, and molecular studies have shown this is a very heterogeneous disease.

	Although TNBC is often referred to as surrogate for basal-like breast cancer, there is clearly a need for further subclassification. One of the main issues, as seen in these results, is the lack of clear guidelines in TNBC. Ongoing studies (more than 60 currently) looking at new combinations—including new targeted therapies focusing on EGFR, CHK-1, PARP-1, PI3K/mTOR inhibitor, and TKI (dasatinib), among others&mdash;may shed some light on the management of this disease. Recent work (Lehmann, BD et al. 

. 2011;121:2750-2767.) identified 6 molecular subtypes of TNBC. Using representative TNBC cell lines of the 6 distinct subtypes, investigators showed that the various subtypes had different sensitivities to targeted therapies currently under laboratory and clinical investigation, providing a rationale for future studies.

	Meanwhile, the treatment of NSCLC has seen a paradigm shift over the last decade, with the integration of novel therapies based on a better understanding of some of the driving mutations. In this issue, the article by Steven A. Sandler, MD, reviews these advances.

	NSCLC, which accounts for approximately 85% of all lung cancers, is divided further into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma histologies. Lung cancer is the leading cause of cancer-related mortality in men and women, both in the United States and worldwide. In 2006, lung cancer resulted in 158,000 deaths in the United States alone—more than colorectal, breast, and prostate cancer combined.

	Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis. Only a third of patients with NSCLC present at diagnosis with disease that is sufficiently localized to attempt curative surgical resection (stages IA and IB, IIA and IIB, and IIIA). Radiation is a reasonable option for lung cancer treatment for those who are not candidates for surgery. However, approximately half of patients who undergo an attempt at curative local therapy experience local or systemic relapse. As a result, about 80% of all patients with NSCLC receive chemotherapy at some point during the course of their disease. NSCLC is only moderately sensitive to chemotherapy, with single-agent response rates in the range of 15% or better. Newer agents (eg, gemcitabine, pemetrexed, docetaxel, vinorelbine) have shown promising single-agent activity, with response rates from 20% to 25% (although there has been no clear benefit demonstrated with triple agents combinations).

	The most impressive changes seen in NSCLC relate to the benefit of targeted therapies. These changes have been so dramatic that screening for “driver mutations” in NSCLC is now part of routine management and National Comprehensive Cancer Network guidelines. One driver mutation—overexpression of epidermal growth factor receptor (EGFR), which is common in NSCLC&mdash;correlates with increased resistance to therapy, metastatic potential, and poorer outcome. Gefitinib and erlotinib, both EGFR tyrosine kinase inhibitors (TKIs), have shown dramatic benefit in NSCLC, particularly in subsets of patients carrying a mutation for EGFR. (In one study, patients with mutated EGFR had significantly longer PFS in the gefitinib group, for example, compared with carboplatin-paclitaxel). These favorable mutations for EGFR were more common in women, non-smokers, and patients of Asian origin. On the other hand, patients with EGFR expression and absence of KRAS mutations (similar to what has been seen in colon cancer) may be considered for the addition of cetuximab to first-line chemotherapy.

	Another remarkable example of the benefit of targeted therapies is crizotinib (Xalkori), which was approved by the FDA in August 2011, for the treatment of locally advanced or metastatic NSCLC that is anaplastic lymphoma kinase, ALK-positive as detected by the Vysis ALK Break Apart FISH Probe test. Other directed therapies, such as the anti- VEGF monoclonal antibody (bevacizumab), have already been approved for clinical use, while a number of others are in clinical testing (eg, targeting MET, VEGFR, HER2, PIK3CA, and IGF-1). Finally, ongoing efforts to identify additional targetable driver mutations will help dissect further the heterogeneity of NSCLC to the benefit of our patients.

	The paradigm shift in lung cancer offers great hope for future endeavors, including in TNBC, but also represent a true illustration of the ongoing shift toward personalized medicine across the board in oncology.

This issue of Contemporary Oncology includes a focus on 2 challenging situations: management of metastatic TNBC and of advanced stage NSCLC.

Personalized Medicine: A Promising Future in Oncology Practice

	For years, the progress in treating non—small-cell lung cancer (NSCLC) had reached a plateau. In the last decade, primarily because of molecular oncology, translational research has emerged as the foundation for new therapies for this resistant disease. Recently, we have seen a paradigm shift in our approach to NSCLC. New and relevant studies are examining the role of histology, biomarkers, and growth factor receptor inhibitors in the treatment of NSCLC. The expanding role of identifying “driver mutations” will lead to more effective therapies. This review explores some of the emerging options for the treatment of NSCLC.

	The National Cancer Institute estimated that 222,520 individuals (116,750 men and 105,770 women) were diagnosed with and 157,300 individuals (86,200 men and 71,000 women) died of cancer of the lung and bronchus in 2010.

 The cure rate for this disease is estimated to be only 15%.

	Results of 2 major trials should help us to better define our screening strategies. Previous lung cancer screening trials showed that screening did not decrease mortality. However, several shortcomings in these trials may have failed to detect a small screening benefit.

	The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial began in November 1993 and ended in July 2001. This was a randomized controlled study that included 154,901 participants aged 55-74 years and was initiated specifically to determine whether screening would reduce mortality rates from PLCO cancers. Participants received a baseline chest radiograph (CXR), followed by 3 annual single-view CXRs at the 10 US screening centers versus a usual-care control group. The results showed that lung cancer mortality was not reduced when annual CXR screening was compared with usual care in high-risk individuals.

	From August 2002 through April 2004, the National Lung Screening Trial enrolled 53,454 persons at high risk for lung cancer at 33 medical centers in the United States.

 Eligible participants were between 55 and 74 years of age at the time of randomization, had a history of cigarette smoking of at least 30 pack years, and, if former smokers, had quit within the previous 15 years. Persons who had previously received a diagnosis of lung cancer, had undergone chest computed tomography (CT) within 18 months before enrollment, had hemoptysis, or had an unexplained weight loss of more than 6.8 kg (15 lb) in the preceding year were excluded. Participants were randomly assigned to undergo 3 annual screenings with either low-dose CT or single-view postero/anterior chest radiography. The study demonstrated a 20% reduction in lung cancer deaths with low-dose helical CT screening in high-risk patients compared with a conventional CXR.

	Surgery is the primary treatment modality for patients with early-stage operable NSCLC. Approximately half of these patients eventually experience relapse after resection, with a much higher proportion of distant metastases than local recurrences. The 5-year survival rates for NSCLC range from 45% to 50% in stage I, 30% to 35% in stage II, 15% in stage IIIA, 5% in stage IIIB, and only 1% in stage IV.

	The International Adjuvant Lung Cancer Trial, the largest cisplatin-based adjuvant study, showed positive results after a median follow-up of 56 months, but the significant effect was no longer present after a median follow-up of 90 months.

 The lack of long-term survival may be because of the toxicity of chemotherapy or other comorbidities. In the recently updated Medical Research Council meta-analysis and in the Lung Adjuvant Cisplatin Evaluation, the 5-year absolute benefit of chemotherapy compared with placebo ranged from 4% to 5.3% (

 The most common chemotherapy regimen in the trials and the most robust data for adjuvant chemotherapy outside the United States are with the use of vinorelbine (Navelbine) and cisplatin. This regimen does not enjoy such popularity in the United States.

	A subgroup analysis of the JBR10 National Cancer Institute—Canada adjuvant study and Adjuvant Navelbine International Trialist Association trials showed no benefit for stage IB disease.

 The Cancer and Leukemia Group B (CALGB 9633) trial is the only randomized study to look at the role of adjuvant chemotherapy exclusively in stage IB disease.

 The study compared carboplatin and paclitaxel with observation in 344 patients. The trial was closed early at 4 years when the first interim analysis showed a survival advantage of 12% (hazard ratio [HR] = 0.62). A subgroup analysis of CALGB 9633 showed a benefit for patients with tumors ≥4 cm in diameter (

 = .043). Unfortunately, the benefit disappeared at 5 years. A meta-analysis consisting of 2353 patients with stage IB disease reported that adjuvant chemotherapy is effective for this subgroup.

 Most clinicians use a cutoff of ≥4 cm to justify adjuvant chemotherapy in stage IB patients. A current study, Eastern Cooperative Oncology Group (ECOG) 1505, is randomizing completely resected stage IB (≥4 cm)—stage IIIA NSCLC patients to a cisplatin-containing doublet with or without bevacizumab.

 Postoperative adjuvant cisplatin-based chemotherapy is now the standard treatment for patients with resectable NSCLC ≥4 cm in size.

	The standard of care for stage IV NSCLC is to give 4-6 cycles of chemotherapy.

 In advanced disease, there does not appear to be any advantage when cisplatin is combined with gemcitabine, docetaxel, or paclitaxel, or for the regimen of carboplatin and paclitaxel. The overall response rates are approximately 19%, and the median survival is 7.9 months. Histology matters, and patients with adenocarcinoma survive longer than those with squamous cell NSCLC. This difference is reflected in the induction chemotherapy regimen selected.

 Socinski et al reported a randomized trial comparing nab-paclitaxel and carboplatin with Cremophor-based paclitaxel and carboplatin as first-line therapy in advanced NSCLC.

 The response rate was 41% for the patients with squamous cell histology and 26% for the patients with nonsquamous cell histology. The reason for this difference is not entirely clear; however, it is known that albumin binds to the endothelial receptor gp60. By a process called endocytosis, the albumin-bound paclitaxel is bound with the protein caveolin 1 and forms calveolae, which facilitates the transport of the agent across the cell membrane to the tumor environment. Caveolin 1 is overexpressed in squamous cell tumors. In the peritumoral milieu, secreted protein acidic and rich in cysteine (SPARC) is present, which binds to albumin and is important for cell growth and proliferation. This protein is inhibited by nab-paclitaxel, allowing more drug to reach the tumor, which may explain the differential benefit of this agent in squamous cell tumors.

	In stable or responding patients, there has been a great deal of interest in extending the disease-free survival (DFS) and hopefully the overall survival (OS). The 2 common paradigms are called either “continuation maintenance,” in which 1 or more of the induction drugs are continued after the initial 4-6 cycles, or “switch maintenance,” in which different agents are begun after induction.

	Five phase III randomized trials are investigating the role of continuation maintenance chemotherapy in advanced NSCLC patients who have responded or remained stable after 4 cycles of a platinum-containing regimen. While most have shown an improvement in progression-free survival (PFS), none of the trials has shown a benefit in OS.

 This is also true for the recent PARAMOUNT trial.

 The trial investigated whether pemetrexed continuation maintenance therapy improved PFS after pemetrexed-cisplatin induction therapy in patients with advanced nonsquamous NSCLC. Pemetrexed continuation maintenance resulted in a 36% reduction in the risk of progression. The median independently reviewed PFS was 3.9 months (95% CI, 3.0-4.3) in the pemetrexed maintenance arm and 2.6 months (95% CI, 2.2-2.9) in the control arm. No OS has been reported.

	Three phase III studies examined the role of switch maintenance. In the study by Depierre et al, participants with stage IV disease received 4 cycles of induction chemotherapy with mitomycin-ifosfamide-cisplatin, and participants with stage IIIB disease received 2 cycles of the identical chemotherapy followed by the addition of 60 Gy of radiotherapy.

 Responders were randomly assigned to vinorelbine or observation. A total of 6 months of vinorelbine was given if a response was maintained. Only 23% of the patients completed the 6 months of vinorelbine. There was no difference in PFS or OS. In fact, maintenance vinorelbine was associated with additional toxicity. A trial conducted by Fidias et al began with the induction regimen of 4 cycles of gemcitabine and carboplatin.

 Stable or responding patients went on to receive immediate or delayed docetaxel at progression. Because of intervening factors, 40% of the patients were never able to receive delayed docetaxel. There was significant PFS in the group that received immediate docetaxel versus the delayed group, but no difference in OS was seen. The third study was conducted by Ciuleanu et al.

 The JMEN study began with an induction platinum-containing regimen for 4 cycles. Pemetrexed or bevacizumab could not be included in the induction regimen. Patients whose disease did not progress were randomized to pemetrexed versus best supportive care versus placebo plus best supportive care for NSCLC. A majority of the patients in both arms went on to receive additional chemotherapy. There was evidence of improved PFS (2.6 mo) and OS (5.2 mo) in the patients with nonsquamous cell histology, but no difference in PFS or OS was observed in the patients with squamous cell histology.

	Platinum-containing regimens in combination with bevacizumab or cetuximab, followed by continuation maintenance of the targeted agent, have been shown to result in an improvement in OS.

 ECOG study E4599 was the first randomized study to show a survival benefit from the addition of bevacizumab.

 The patients had to have an ECOG performance score of 0 or 1. The study included patients with stage IIIB or IV disease. Patients in the bevacizumab arm received the drug during induction, which consisted of up to 6 cycles of paclitaxel and carboplatin. Those in the bevacizumab arm who responded or remained stable received bevacizumab maintenance until progression. The control group, who received paclitaxel and carboplatin, never received any bevacizumab or maintenance therapy. The OS was extended by 2 months in the group that received bevacizumab. The study highlighted the controversy regarding the value of bevacizumab in patients with NSCLC. In the FLEX trial, patients with stage IIIB or IV disease received induction chemotherapy with up to 6 cycles of vinorelbine and cisplatin.

 Patients who did not progress were randomized to cetuximab or placebo until progression or unacceptable toxicity. There was a 1.2 month improvement in OS. This study highlighted the controversy regarding the need for bevacizumab in induction and/or maintenance therapy in patients with advanced NSCLC. In contrast, the AVAIL study failed to show a survival benefit when cisplatin was combined with gemcitabine and bevacizumab,

 and the BMS-099 study also showed no benefit when cetuximab was added to carboplatin and paclitaxel.

	The PointBreak study is a phase III trial comparing the phase II study of 4 cycles of pemetrexed, carboplatin, and bevacizumab followed by maintenance pemetrexed and bevacizumab with the superior arm of the E4599 trial consisting of up to 6 cycles of paclitaxel, carboplatin, and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous NSCLC.

 Accrual has been met and the results are awaited. The study has 2 variables and may be difficult to interpret. Accurate evaluation of the advantage of maintenance antibodies would require a phase III randomized study comparing bevacizumab, cetuximab, and placebo. EGOG study 5508 is planning to answer the question of the optimal maintenance regimen in advanced NSCLC.

 All patients receive 4 cycles of induction chemotherapy with carboplatin, paclitaxel, and bevacizumab. The patients are then randomized to either pemetrexed, bevacizumab, or the combination. There is no placebo arm, however.

	The epidermal growth factor receptor (EGFR) is a cell surface protein. When activated, it has an important role in cell proliferation, adhesion, migration, angiogenesis, apoptosis, and cell survival. Approximately 10% of North Americans and up to 40% of persons of Asian descent harbor activating mutations in the EGFR. This condition leads to up-regulation of the EGFR protein and uncontrolled proliferation of the tumor.

	Gefitinib and erlotinib are 2 oral, reversible tyrosine kinase inhibitors that block the binding of adenosine triphosphate to its binding pocket in the EGFR moiety. They then inhibit autophosphorylation and block downstream signaling primarily through the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. These agents interrupt the activating mutations of the EGFR, primarily by binding to deletions in exon 19 and the L858R point mutation in exon 21 of the EGFR. Gefitinib and erlotinib have shown remarkable activity in patients with stage IV NSCLC who harbor these mutations.

 The usual doses of gefitinib and erlotinib are 250 mg/day and 150 mg/day, respectively. The major side effects are rash, diarrhea, and fatigue.

	Gefitinib and erlotinib have been studied in many different settings. In 2004, it was discovered that activating mutations in the EGFR correlate with the response to gefitinib.

 The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) BR.19 trial randomized 503 patients with resected stage IB-IIIA NSCLC from September 2002 until April 2005.

 The trial was closed prematurely. The study showed that adjuvant gefitinib after complete resection of early-stage NSCLC did not confer DFS or OS advantage in the overall population. In a subset analysis, there was no advantage in the patients with 

 mutations. A retrospective study done at Memorial Sloan-Kettering Cancer Center in patients with completely resected stage I-III lung adenocarcinoma who received adjuvant gefitinib or erlotinib showed a DFS benefit for patients with the EGFR-activating mutations in exon 19 or 21.

 RADIANT is a study to evaluate the effectiveness of erlotinib versus placebo following complete surgical removal of the tumor with or without chemotherapy after surgery in stage IB-IIIA NSCLC patients with 

 mutations. The study is ongoing, but is no longer recruiting participants.

	The INTACT I and 2 and the TRIBUTE 1 and 2 studies looked at combination platinum-containing doublets with or without gefitinib and erlotinib, respectively.

 There was no difference in response rate, PFS, or OS in any of the arms. Gefitinib and erlotinib have been compared with placebo in patients with NSCLC who have failed chemotherapy. In the Iressa Survival Evaluation in Lung Cancer trial, gefitinib showed a small but significant 0.4-month benefit over placebo in time to treatment failure, but no significant benefit in OS.

 The NCIC CTG BR.21 researchers studied erlotinib. The results showed both a statistically significant PFS of 0.4 month and a statistically significant increase in OS with erlotinib compared with placebo, after first-line or second-line chemotherapy (6.7 mo vs 4.7 mo).

 Because of these results, the FDA issued a New Labeling and Distribution Program for gefitinib. Gefitinib would still be available to a specific subset of patients who: (1) were receiving and continuing to benefit from the drug; (2) had previously received and benefited from the drug in the past; or (3) were now receiving the drug as newly enrolled patients in a clinical trial.

	Gefitinib is still widely used in Europe and Asia. Subgroup analysis showed that patients of Asian descent, women, and patients with no history of smoking have a better response to gefitinib or erlotinib.

	The EGFR tyrosine kinase inhibitors have been studied in maintenance therapy. Gefitinib has been compared with docetaxel after failure of first-line chemotherapy in NSCLC. In a noninferiority trial, the Iressa NSCLC Trial Evaluating Response and Survival versus Taxotere (INTEREST) demonstrated that gefitinib was noninferior to docetaxel after frontline chemotherapy.

	The Sequential Tarceva in Unresectable NSCLC (SATURN) trial randomized 889 patients with nonprogressing stage IV NSCLC after a platinum-based doublet to either erlotinib or placebo.

 In the randomized patients, the median PFS and OS was 4 weeks and both were statistically significant. In an interesting subset analysis, patients with the EGFR mutation had significantly longer PFS (HR = 0.10) but not OS, probably due to crossover. The patients with adenocarcinoma had longer PFS and OS; however, the patients with squamous cell histology had longer PFS but not OS. This study led to the approval of erlotinib as maintenance therapy in patients who do not experience progression after 4 cycles of a platinum induction regimen. In the ATLAS trial, 1160 patients with advanced NSCLC were treated with a platinum doublet and bevacizumab. After 4 cycles, the patients were continued on bevacizumab and randomized to erlotinib or placebo.

 The trial stopped early because the primary endpoint of PFS was reached; however, the total predetermined accrual goal was still met. No OS benefit was demonstrated on further follow-up. The BeTa trial studied the role of erlotinib with or without bevacizumab after failure of standard first-line chemotherapy in advanced NSCLC.

 The primary endpoint of improved OS was not met; however, there was a benefit in PFS of 1.7 months.

	A study from Japan examined the role of switch maintenance gefitinib versus continuation of chemotherapy after 2-6 cycles of a platinum-containing doublet.

 There was a PFS advantage of gefitinib over the chemotherapy, but the endpoint of improved OS was not met.

	The Iressa Pan-Asia Study (IPASS) was a landmark study conducted in Asia. Patients with adenocarcinoma of the lung (nonsmokers or former light smokers) who had not received chemotherapy for advanced disease were randomized to gefitinib or chemotherapy with carboplatin and paclitaxel.

 The PFS at 1 year was significantly better in the gefitinib group (24.9% vs 6.7%). The OS, however, was the same and was thought to be secondary to the high degree of crossover to gefitinib in the patients failing the chemotherapy. Among the IPASS patients, 60% had the EGFR mutation.

	Three studies from Japan examined the role of frontline gefitinib versus frontline chemotherapy in patients with the 

 These studies showed an improvement in PFS but not in OS. The OPTIMAL study from China randomized patients with stage IIIB or IV NSCLC with the EGFR-activating mutations (exon 19 deletion or the L858R point mutation) to erlotinib or placebo until disease progression or unacceptable toxic effects, or up to 4 cycles of gemcitabine plus carboplatin.

 mutation type, histology (adenocarcinoma vs nonadenocarcinoma), and smoking status. The endpoint of median PFS was reached (13.1 mo with erlotinib vs 4.6 mo with chemotherapy; 

	The European Randomized Trial of Tarceva vs Chemotherapy (EURTAC) trial randomized stage IIIB or IV NSCLC Caucasian patients with exon 19 deletions or exon 21 L858R point mutations to erlotinib or 4 cycles of a platinum doublet.

 The objective response rate was 60% for the erlotinib patients and 15% for the chemotherapy group. The endpoint of PFS was 9.4 months in the erlotinib group and 5.2 months in the chemotherapy group. Erlotinib resulted in a significant 63% reduction in the risk of progression compared with the platinum-containing chemotherapy group. The response rate in the chemotherapy group was lower than what is traditionally reported with standard platinum doublets.

	In summary, the gefitinib and erlotinib versus chemotherapy studies in first-line patients with

 mutations have shown a PFS but not an OS benefit. This result is explained by the substantial crossover at disease progression. These studies should not dissuade physicians from using EGFR inhibitors as first-line therapy in patients with 

 mutations. A historical study from Japan found that the survival of patients with 

 mutations after gefitinib approval was 27.2 months; the survival was 13.6 months for patients before gefitinib approval.

 mutation status is unknown, it is reasonable to begin with chemotherapy and switch to an EGFR inhibitor if the patient is found or suspected to have an 

	Identification of the novel transforming gene 

 The authors were able to show that a small inversion within chromosome 2p resulted in the fusion gene containing portions of echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase gene in NSCLC. This fusion transcript occurred in 6.7% of their patients.

 rearrangements are more common in patients who have never smoked or have a smoking history of fewer than 10 pack-years. In this enriched population, the incidence of patients who are 

-positive increases to 15%. Patients with the 

 rearrangement are younger than those without the rearrangement, and the median age is about 50 years. 

 rearrangement is associated with adenocarcinoma. The 

, leads to dependency of the tumor on the activated kinase. This created the environment for the development of an inhibitor of ALK, crizotinib, a oral, small-molecule inhibitor of the ALK tyrosine kinase.

 This targeted agent and the EGFR inhibitors are less toxic and more effective than standard chemotherapy agents.

	The reported response rate for crizotinib is 57% at a median of 6.4 months. There was 1 complete response, and 33% of patients had stable disease. The probability of a 6-month PFS was 72%. The relatively mild side effects included nausea, emesis, diarrhea, edema, constipation, and visual changes.

	New Agents for First-line and Resistant Patients With 

	BIBW 2992 (afatinib, Tomtovok) is an irreversible inhibitor of EGFR/HER1 and HER2, which is active in EGFR-mutated advanced NSLC. The LUX-1 lung trial compared BIBW 2992 plus best supportive care with placebo plus best supportive care in patients with NSCLC failing first- and second-line chemotherapy and erlotinib or gefitinib (LUX-Lung 1).

 There was an improvement (4.4 mo vs 1 mo for placebo) in PFS, but not in OS.

	The LUX-2 Lung trial was a phase II single-arm study of BIBW 2992 in NSCLC patients who failed 1 line of chemotherapy or who were chemotherapy-naïve, and who had an EGFR-activating mutation. This trial showed that the use of afatinib led to a high rate of tumor size reduction (objective response rate of 61%) and a long delay in the progression of cancer by over 1 year (PFS of 14 mo). The OS was superior to what has been reported with erlotinib.

	BIBF 1120 (Vargatef) is a triple angiokinase inhibitor that acts on 3 growth factors simultaneously: vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and fibroblast growth factor receptor. The LUME-1 lung cancer trial is evaluating whether docetaxel plus BIBF 1120 is more effective that placebo plus docetaxel in stage IIIB, stage IV, and recurrent NSCLC.

	The mechanism of resistance to the EGFR tyrosine kinase inhibitors is of much interest. A mutation in a domain on exon 20 of the EGFR receptor called T790M interferes with binding of the EGFR tyrosine kinase inhibitor to the inhibitory docking site.

 Some patients have the T790M mutation at diagnosis, and others acquire the mutation. There is also overexpression of c-MET in about 20% of patients who acquire resistance to the EGFR tyrosine kinase inhibitors. ARQ197 (Tivantinib), a selective inhibitor of the c-MET receptor tyrosine kinase, has been evaluated in this setting. The combination of an EGFR/MET receptor inhibitor is logical in this setting. In a randomized study by Schiller et al, patients receiving second- or third-line therapy and who were erlotinib-naïve were randomized to erlotinib and ARQ 197 or erlotinib and placebo.

 Among the intent-to-treat group, the median PFS was 16.1 weeks for the combination group versus 9.7 weeks in the placebo group (HR = 0.81; 95% CI, 0.57, 1.15; 

 = .23). The treatment was well tolerated.

	A recent study examined the activity and tolerability of afatinib in combination with cetuximab in patients with NSCLC who have an acquired resistance to erlotinib or gefitinib.

 A second mutation in the EGFR molecule at the exon site 20 EGFR T790M is seen in up to 50% of these cases. The combination of afatinib and cetuximab is the first combination to show activity in this setting. A 29% PR was reported in patients who were resistant to gefitinib or erlotinib and expressed the T790M mutation.

	The first Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial was done in patients with stage IIIB, stage IV, or advanced incurable NSCLC who had progressed on at least 1 prior chemotherapy regimen.

 The study required another biopsy before selection of the patient’s next line of therapy. A randomization technique called Bayesian adaptive randomization was used. The purpose of Bayesian adaptive randomization was to identify promising benefits of certain drugs with certain molecular markers as the study proceeds. Patients were selected for 1 of 4 therapies depending on the molecular characteristics of the lung cancer. The options included erlotinib, sorafenib, vandetanib, or erlotinib and bexarotene. BATTLE’s endpoint was disease control at 8 weeks, which recent research has found is a good indicator of OS. A novel phase II clinical trial program, BATTLE showed that patients whose treatment was determined by their tumor biomarkers had better disease control than patients treated nonselectively with the other 3 drugs. The study found, for example, that 61% of patients with a 

 mutation in their tumors who took sorafenib had disease control at 8 weeks, compared with 32% for the other 3 drugs. Erlotinib did best against 

 mutations, vandetanib against high VEGFR-2 expression, and the erlotinib-bexarotene combination fared best with Cyclin D1 defects or amplified numbers of the 

	The overall results showed that 46% of patients in the trial had disease control at 8 weeks, compared with a historical experience of around 30% for advanced-stage NSCLC. Median OS was 9 months, and the 1-year survival was 38%, with only 6.5% of patients experiencing a significant side effect.

	Finally, the National Cancer Institute’s Lung Cancer Mutation Consortium is looking at stage IV adenocarcinoma lung cancer patients to determine whether there is a “driver mutation.” They were able to find to find such a mutation in 54% of the patients. The most common mutations were 

. These findings hopefully will help researchers to develop more targeted therapies.

	These studies are defining a new era in “personalized medicine” for the treatment of lung cancer.

	Steven A. Sandler, MD, is in the section of hematology and oncology at Skokie Hospital in Skokie, Illinois.

	Dr Sandler reports no financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

	Steven A. Sandler, MD, Section of Hematology and Oncology, Skokie Hospital, 9669 N Kenton Ave, Ste 510, Skokie, IL 60076. E-mail: 

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New and relevant studies are examining the role of histology, biomarkers, and growth factor receptor inhibitors in the treatment of NSCLC.

Spring 2012 | Contemporary Oncology®

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