	During an OncLive Peer Exchange video roundtable discussion held in the spring of 2013, the following five lung cancer experts discussed recent advances and current issues surrounding the treatment of non-small cell lung cancer (NSCLC): David R. Gandara, MD, director of the Thoracic Oncology Program at University of California Davis Cancer Center; Corey J. Langer, MD, director of Thoracic Oncology at Abramson Cancer Center of the University of Pennsylvania; Alan B. Sandler, MD, principal medical director at Genentech (formerly at Oregon Health & Science University); Mark A. Socinski, MD, director of the Lung Cancer Section at University of Pittsburgh; and Anne S. Tsao, MD, director of the Thoracic Chemo-Radiation Program at The University of Texas MD Anderson Cancer Center. In part one of this series, the faculty discussed several issues surrounding the impact of molecular testing on upfront treatment decisions for patients with advanced NSCLC.

		Professor of Medicine Division of Hematology and Oncology Director, Thoracic Oncology Program, Associate Director, Clinical Research, UC Davis Cancer Center Sacramento, CA

Concurrent or Sequential Molecular Testing?

: Corey, I know you raised the issue about concurrent versus sequential testing. Our thinking is evolving for symptomatic patients with stage IV disease, because if you test first for 

 mutation and then wait for the results, and then have to test for 

, etc, a lot of time can go by. How do you decide on an individual patient basis whether you will test concurrently or sequentially?

: We routinely perform molecular testing concurrently for at least

. The big issue is the timing. We ideally like to get these results within 1 to 2 work weeks. If patients are highly symptomatic and very ill with a declining performance status and the test results are not back yet, I’ll start them on chemotherapy. For these patients, we don’t really have the luxury of waiting.

Stay the Course With Chemotherapy or Switch to 

 The big dilemma, of course, is what to do after these patients have received a cycle or two of chemotherapy and their disease has stabilized or improved, and the test results are positive for 

 mutation. Should we switch to erlotinib at that point or should we see them through the course of chemotherapy and then perhaps use erlotinib as a maintenance approach or even integrate it later on in the second-line setting? I don’t think we have a firm grasp on the optimal approach.

: If patients are doing well on chemotherapy, I will actually maintain them on chemotherapy for 4 to 6 cycles and then go on to maintenance therapy. Depending on the nature of their response, how symptomatic they were at presentation, and how well they’re tolerating the chemotherapy, I will choose either switch maintenance (use of an agent for maintenance that was not used in the first-line setting) or continuation maintenance (use of a component of the first-line agents for maintenance). If they’ve had a tough time with the chemotherapy, I’ll typically go on to erlotinib maintenance. Certainly, the SATURN trial showed a major progression-free survival (PFS) advantage for erlotinib maintenance in patients with 

 That hazard ratio is down around 0.1,2 which is really one of the most striking results I’ve ever seen. Therefore, deciding how to treat patients in this situation is a big dilemma, but it’s a better dilemma to have than we have had in the past (ie, before the advent of erlotinib, bevacizumab, pemetrexed, crizotinib, and afatinib). 

:I would echo that. I am a firm believer that you should complete the chemotherapy evaluation, at least to 2 cycles. The response rate for EGFR inhibition in 

 but if your patient responds, that’s 100% for that patient and, prognostically, patients with EGFR-mutated disease do better with chemotherapy than those with 

-wild-type disease (see NSCLC trials sidebar— IPASS).

 So, I get those 2 cycles in and then if they’re doing well, I continue as I would without knowing their 

 mutation status and then I would make that same assessment you did, Corey, and would probably use erlotinib as maintenance.

			Important NSCLC Trials of EGFR Inhibitors

:A phase III trial that examined the addition of maintenance erlotinib after first-line chemotherapy with a platinum doublet in patients with advanced NSCLC. Median progression-free survival (PFS) was significantly but modestly longer with erlotinib than with placebo (12.3 weeks vs 11.1 weeks; hazard ratio [HR] = 0.71; 

 mutation-positive subgroup, erlotinib had a profound predictive effect on PFS compared with placebo (HR = 0.10; P < .001).

: A phase III trial that compared gefitinib to carboplatin/paclitaxel in previously untreated patients in East Asia with advanced adenocarcinoma. The gefitinib group showed a PFS advantage compared with the chemotherapy group (HR = 0.74; 

 Among the patients with EGFR-mutated disease, PFS was significantly longer for gefitinib compared with chemotherapy (HR = 0.48; 

 Compared with EGFR-wild-type disease, those patients with EGFR-mutated disease had a higher response rate to chemotherapy (47.3% vs 23.5%).

: A phase III trial that compared first-line erlotinib to doublet chemotherapy in patients with advanced 

-mutated (exon 19 or exon 21) NSCLC. Median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the chemotherapy group (HR = 0.37; 

 First-line erlotinib produced a grade 1/2 rash in 67% of patients and grade 3 rash in 13% of patients.

: A phase III trial that compared afatinib with cisplatin/pemetrexed in patients with advanced EGFR-mutated adenocarcinoma. Based on its PFS advantage over cisplatin/pemetrexed (HR = 0.58; 

 afatinib recently earned FDA approval for patients with 

-mutated disease. When only patients with the common exon 19 and 21 mutations were examined, the HR was 0.47.

: It’s intriguing. If you look at survival from the EURTAC trial in the setting of 

 mutation, whether erlotinib was used first- or second-line after chemotherapy failed, the survival was essentially the same (see NSCLC trials sidebar).

 This echos prior data from Rosell et al published in 

, where survival seemed to be identical whether EGFR TKIs were given first- or second-line.

: And I think part of the art of managing advanced NSCLC now is not abandoning prematurely therapies that are working. For a patient with a very nice symptomatic, radiographic response to chemotherapy, I would have no problem continuing that treatment, followed by some form of maintenance. Then, as shown by the EURTAC results,

 you have a very good second-line treatment—erlotinib&mdash;for that particular patient. So, I don’t think getting an 

-positive test result necessarily mandates that you switch to erlotinib. Remember, erlotinib is a convenient drug, but it has its share of toxicities (see NSCLC trials sidebar—EURTAC).

: I agree, it can be quite toxic. I just saw a patient yesterday who had a grade 3 rash. He’s thrilled because his disease is essentially in complete remission, but, to be frank, he’s had a bit more toxicity on erlotinib than he had on prior chemotherapy.

 If I get test results showing the patient has an exon 19 deletion, I am more likely to push to get them onto an EGFR TKI because we know that those patients are probably a little bit more sensitive to the EGFR TKIs.

 mutations, and sometimes those with the more common 

 point mutation, I will let them ride out the chemotherapy for 4 to 6 cycles and then switch them over to maintenance erlotinib. 

: I haven’t really made distinctions based on the nature of the two actionable activating mutations in exon 19 and 21 (

		Specific EGFR Mutations in NSCLC Tumors

:Point mutation in the tyrosine kinase domain, in which threonine is replaced by methionine at codon 790. This mutation is believed to be acquired through selective pressure during treatment with erlotinib.

 Thus, patients can have dual mutations: their endogenous 

 mutation and the acquired T790M mutation.

: In-frame exon 19 deletions that usually include deletions of leucine-747 to glutamic acid-749.

 These mutations account for ~45% of all 

: Point mutation in exon 21, most frequently in which leucine is replaced by arginine at codon 858 (

 Exon 21 mutations account for ~45% of all EGFR mutations.

 Studies have shown that patients with exon 19 mutations have higher response rates,

 and improved OS7,11 compared with patients with exon 21 mutations.

 mutations are missense mutations or in-frame duplications and/or insertions in exon 20.

 In a clinical study of 34 patients with 

 mutations, the 5 patients with exon 20 mutations failed to achieve a response to gefitinib, despite a response rate in the overall population of 55%.

: You know, I might feel exactly the opposite, Anne. If the patient has an exon 19 deletion, which means they are quite sensitive to EGFR inhibition,

 then I might choose to let them ride out the chemotherapy or maintenance therapy, perhaps including bevacizumab, and then I would think about using erlotinib, knowing that they’re going to be quite sensitive. I don’t think we have consensus on this management issue yet.

: This situation perfectly illustrates the value of this educational series—we’re raising a lot of questions today that, in reality, have no right or wrong answers. We have an expert panel and we get to have different opinions.

I’ll throw in my own two cents: Our published data suggests that patients with 

 mutations have very low DNA repair capacity,

 which suggests that they should respond better to platinum-based chemotherapy. Our data mimics the data from Mass General. And, interestingly, it is the exon 19 deletion tumors, which are most sensitive to chemotherapy, that have the lowest 

 So, I actually feel comfortable about finishing up the chemotherapy for those patients with 

-mutated disease, but, again, there’s no right or wrong answer here.

Is EGFR Mutation Testing Prior to Erlotinib Necessary?

: Well, I have a case I’d like to present to Anne, and I think the answer here will be obvious, but it’s a valuable take-home message. I’ll give you the case of a young woman, 39 years old, who’s never smoked, and she has now been diagnosed with stage IV adenocarcinoma of the lung. Would you, in 2013, offer this patient erlotinib without molecular testing?

: Absolutely not. The IPASS data indicate that you can actually cause some harm to an 

-wild-type patient if you treat them with an EGFR inhibitor (see NSCLC trials sidebar).

 So, it’s very critical to test these patients 

: I’m sure a lot of our audience is familiar with the IPASS study by Tony Mok,

 but I just want to emphasize the trial population, because these were all poster children for EGFR TKIs. They were all patients from East Asia. Nearly all had adenocarcinoma. Nearly 80% of the patients were female and 94% of the patients had never smoked.

 So, if you had to pick a population for EGFR inhibition based on the phenotype, this would be it, and yet if they didn’t have that 

 mutation in their cancer, they did much better with standard chemotherapy.

: Approximately 40% of that population did not have the mutation,

 which frankly I was surprised about. I thought it would be a smaller percentage. So, getting the mutation testing, even in a phenotypically favored patient, is absolutely crucial.

: That’s why I think the IPASS trial is a game changer. I think it’s probably the most important trial we’ve seen in lung cancer because it really defined lung cancer as having a genotypic abnormality, and it ushered in this era of molecular genetics. This is critical because you can no longer sit in your office, simply look at your patients, and decide to give them erlotinib. And you wondered why some of these people didn’t do very well on erlotinib and whether they would have done better with other approaches.

: These data also illustrate that not only identifying those patients who should be treated with something, but identifying a population that should 

 be treated with something can be just as important.

: I would also add that I think it’s going to matter, and not just prognostically, what the specific mutation is. For instance, a patient might have a dual mutation, including the 

 mutations sidebar). It’s very rare, but if they have that, they are not going to respond to the EGFR TKIs.

 This example emphasizes that not only do you have to get the biopsy and find out what the mutation is, but you have to know the subtype of the mutation.

: In the IPASS trial, there were approximately 30% of patients with 

-mutated disease receiving gefitinib who didn’t respond,

 so one wonders if that might have been due to this type of dual mutation.

: Yes, I think it’s an important point because, although we speak broadly about 

 mutations, there’s actually a spectrum of the mutations. There are the common ones—exon 19 mutations are prognostically better than exon 21 mutations&mdash; but then there are the uncommon ones, and for many of them, we don’t really understand what role EGFR TKIs play.

: Well, Mark, maybe you could just briefly expand on that topic, because perhaps some of our audience hasn’t yet made that distinction. The two most common EGFR mutations are the exon 19 deletions and the L858R point mutation in exon 21 (see 

 mutations sidebar). What do the studies show?

: About 90% of the patients that have a mutation will have one of these exon 19 or 21 mutations—they’re almost a 50/50 split.9 Between the two, the exon 19 mutations do better with regard to response and PFS (see 

 Anne’s made that point a couple of times, and I agree that you need to think differently about exon 19 and 21 mutations in your clinical decision making, at least to some extent. In my practice, when I get the result back that a patient has an exon 19 mutation, I get a little excited. If it’s an exon 21 mutation, I think, “Hmm, I wish it were 19.” So, you have that distinction between the two most common mutations.

The other 10% of patients have an uncommon mutation, but this is really a spectrum of mutations. These patients tend not to do as well (see 

 I recently had a patient this week who had a 

 mutation that I had never heard of before. I don’t quite know what to make of this yet, but I need to research this and decide if it should influence my decision making. So, for these uncommon mutations, we don’t really quite know yet the optimal role of an EGFR TKI.

: By and large, most of the phase III trials that were mutation-specific really targeted the exon 19 deletion and exon 21 mutations. The one recent exception was LUX-Lung 3, which compared afatinib to chemotherapy (see NSCLC trials sidebar). It actually included some of these less common mutations, which, as you point out, are associated with therapeutic resistance, typically those in exon 20 (see 

 mutations sidebar). I thought that was a fairly gutsy move, actually, in the design of that trial. It could have potentially sabotaged the results, and yet the trial was still quite positive, although it was a bit more positive when you just looked at the exon 19 and 21 populations (see NSCLC trials sidebar).

: True, but going into that trial, it was felt that 90% of the patients were going to have exon 19 or 21 mutations.

: There is a growing body of literature—people are keeping track of these uncommon mutations.

 As we learn more, we do know that some patients with these mutations do get 6 months PFS benefit with an EGFR TKI. So, I think that oncologists have to really become very cognizant of the subtype of mutations for 

To view the videos from this peer exchange, 

	This interchange by the faculty highlights not only the profound implications of molecular testing on the management of patients with advanced NSCLC but also the evolving nature of these approaches. As we gain understanding of the molecular drivers in lung cancer, the management of these patients is sure to evolve as well. In addition to the preceding discussion on the role of molecular testing on first-line treatment decisions, this panel of lung cancer experts also explored other key topics that impact the management of patients with NSCLC. Some of these topics will be presented in future issues of 

			Cappuzzo F, Ciuleanu T, Stelmakh L, et al.; SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. 

			Brugger W, Triller N, Blasinska-Morawiec M, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. 

			Petrelli F, Borgonovo K, Cabiddu M, et al. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials. 

			Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. 

			Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.

			Mitsudomi T, Kosaka T, Endoh H, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small cell lung cancer with postoperative recurrence. 

			Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. 

			Hirsch FR, Franklin WA, McCoy J. Predicting clinical benefit from EGFR TKIs: not all EGFR mutations are equal (abstract). 

			Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. 

			Gandara DR, Grimminger P, Mack PC, et al. Association of epidermal growth factor receptor activating mutations with low ERCC1 gene expression in non-small cell lung cancer. 

			Riely GJ, Pao W, Pham D, et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. 

			Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations.

			Yang JC-H, Schuler MH, Yamamoto N, et al. LUX-Lung 3: a randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations.Presented at the American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, Il. 

			Pao Lab. Vanderbilt University Medical Center. Available at: www.mc .vanderbilt.edu/root/vumc.php?site=paolab&doc=41373. Accessed September 5, 2013.

			Cleveland Clinical Laboratories. Technical Brief: EGFR Mutation Analysis. Available at: www.clevelandcliniclabs.com/Portals/66/PDF/TechBriefs/ EGFRMutationAnalysis.pdf. Accessed September 5, 2013.

Articles

Five lung cancer experts discuss recent advances and current issues surrounding the treatment of non-small cell lung cancer 

Impact of Molecular Testing on First-Line Treatment Decisions in NSCLC

	The recent approval of the second-generation proteasome inhibitor carfilzomib by the FDA comes nine years after the initial approval of bortezomib, the first-in-class drug of its type. Not only does carfilzomib demonstrate activity in a relapsed and refractory setting, it has a superior toxicity profile as well. Multiple new proteasome inhibitors currently in clinical or preclinical development bode well for potential future therapies for multiple myeloma, both in frontline and relapsed or refractory settings.

 The recent significant improvements in overall survival and remission duration in multiple myeloma (MM) are largely due to the advent of novel therapeutic agents, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).

 Proteasomes serve an important cellular function in enabling clearance of abnormal or mutant proteins.2 Tumor cells are more heavily dependent on this clearance mechanism and are sensitive to proteasome inhibition, leading to an antiproliferative and proapoptotic effect mediated via induction of endoplasmic reticulum stress, activation of caspases, and reactive oxygen species.

	For many years, bortezomib (Velcade), an intravenous/subcutaneous dipeptide boronate PI, was the only available agent in its class. Bortezomib is a reversible inhibitor of the chymotrypsin-like catalytic activity of the β5 subunit of the 20S mammalian proteasome. It was initially approved by the FDA in 2003 for refractory MM, and subsequently expanded for use in combination therapy in the first-line setting.

 Bortezomib therapy in MM is limited by development of peripheral neuropathy and eventual drug resistance

 mediated via overexpression of the β5 subunit, mutation of active drug binding sites, or downstream upregulation of survival pathways.

	This mandates development of novel agents that retain activity in a multi-agent refractory setting and are easy to administer (orally vs intravenous) and tolerate. This review will address the current clinical development and results with second-generation PIs including carfilzomib, oprozomib (ONX 0912), ixazomib (MLN9708), marizomib (NPI-0052), and delanzomib (CEP-18770) (

). They have a distinct mechanism of action as well as pharmacokinetic profile compared with bortezomib. Of these, carfilzomib has been recently approved by the FDA, and it and the others are being investigated in clinical trials (

			Table 1.Second-Generation Proteasome Inhibitors

	Carfilzomib (Kyprolis, PR-171), is an intravenous, irreversible tetrapeptide epoxyketone second-generation PI. The irreversible binding and higher affinity for proteasome translates into superior biological activity and cytotoxicity in bortezomibresistant cell lines in vitro and in vivo.15,16 It was approved by the FDA on July 20, 2012, for treatment of patients with MM who have received at least two prior therapies, including bortezomib and a IMiD, and have demonstrated disease progression within 60 days of completion of last therapy.

 The FDA approval was based on a phase II study of 266 patients that demonstrated a response rate of 23.7%, median response duration of 7.8 months, and median overall survival of 15.6 months.

	The current carfilzomib administration schedule consists of intravenous (IV) dosing of 20 mg/m

 for cycle 1 concurrently with IV fluids for hydration and dexamethasone, and subsequent dose escalation to 27 mg/m

 if cycle 1 was well tolerated.18 It is anticipated that the administration will be further simplified, especially in a frontline setting, as well as dose escalation to 36 or 45 mg/m

, with higher doses currently being studied.

	The side effects with single-agent carfilzomib were generally mild, with largely nonhematologic side effects, as well as a clear superiority over bortezomib in terms of peripheral neuropathy. In fact, patients with preexisting neuropathy did not have worsening symptoms with carfilzomib. As with development of bortezomib, carfilzomib is also being tested in combination chemotherapy and in frontline settings (

). Clinical trials evaluating first-line use of carfilzomib may be especially relevant for patients who have significant preexisting peripheral neuropathy, and are therefore not good candidates for bortezomib.

			Table 2. Selected Clinical Trials with Second-Generation Proteasome Inhibitors

						Relapsed MM after at least 1 prior therapy

						Relapsed MM patients who have received 1 to 3 prior therapies

						Relapsed and refractory MM patients who have received 3 or more prior therapies

						MLN9708 + R + d/D vs placebo + R + d/D

Multiple new proteasome inhibitors currently in clinical or preclinical development bode well for potential future therapies for multiple myeloma, both in frontline and relapsed or refractory settings.

Novel Proteasome Inhibitors for Multiple Myeloma

: Despite recommendations for triennial cervical cancer screening for low-risk women aged 30 years and older, annual screening remains common. We studied how often women receiving care from an academically affiliated medical group were screened, and patient and provider factors associated with overuse and underuse. We also explored the impact of changing measurement intervals on computed screening frequency.

: The study included women aged 30 years and older continuously enrolled over a 3-year period and excluded women with history of abnormal screening and conditions of high risk for cervical cancer.

: Administrative and laboratory data were merged to link Papanicolaou (pap) test results with patient and ordering provider characteristics. We used logistic regression to analyze multivariate models for overuse and underuse, and modified measurement intervals to test sensitivity to early and late pap smears.

:The 8018 women had a mean age of 48 years and 95% had an ambulatory physician visit during the observation period. Thirty-four percent of women received guideline-based screening, 45% had overuse, and 21% had underuse. Factors independently associated with overuse included younger age, more medical visits, contraceptive management visits, and gynecology provider specialty. Underuse was associated with older age, fewer medical visits, and increased comorbidity. Overuse was 47% if unsatisfactory paps were not considered and was reduced to 35% if the observation interval was reduced from 36 to 30 months.

: Overuse and underuse of cervical cancer screening are common, and clinician and patient factors are identifiable to target quality improvement interventions. Modifying the measurement interval may improve the measure.

For a decade, US medical professional organizations

 and the US Preventive Services Task Force (USPSTF)

 have suggested that low-risk women (history of multiple normal Papanicolaou [pap] tests, age over 30 years) receive cervical cancer screening every 3 years as part of routine preventive services. Prior to these guidelines, observational and case control studies supported similar clinical outcomes between 1- and 3-year intervals.

 However, surveys showed that most (60-70%) gynecologists and primary care providers continued to perform annual screening, and many were unaware of the new guidelines.

 Recently, the USPSTF solidified its recommendations for the 3-year interval,

 and they and the American College of Obstetricians and Gynecologists suggest a 5-year interval with negative HPV testing.

A 2010 study using the National Ambulatory Medical Care Survey projected that triennial screening would reduce testing by 6.3 million pap tests per year and reduce costs by $403.8 million.

 An earlier study projected that an additional 69,665 pap smears and 3861 colposcopies would need to be performed in women 30 to 44 years of age to avert one case of cervical cancer by screening every year instead of every 3 years. For women 45 to 59 years old, 209,324 pap tests and 11,502 colposcopies would need to be performed.4 Using National Health Interview Survey data, projected compliance with triennial screening would decrease the anannual number of pap smears from 75 million to 34 million.

Since 2009, a pay for performance measure has been applied to managed care plans in California to encourage triennial rather than more frequent screening, but there has been little exploration of cervical cancer screening rates in populations affected by this measure. Furthermore, preventing overuse might encourage underuse, so both should be simultaneously evaluated. To encourage targeted use of screening, understanding physician and patient factors associated with overuse and underuse is needed.

We evaluated usage of cervical cancer screening in one medical group’s patients with the goal of identifying factors amenable to intervention. In addition, we varied the time period of the 3-year measure and accounted for clinically insufficient pap tests to evaluate the proportion of patients that were close to receiving appropriate screening to test the clinical applicability of the measure, which is important in order to promulgate interventions with clinicians.

We evaluated cervical cancer screening provided to female patients in an academic medical center—affiliated group (commercial health maintenance organization [HMO] and Point of Service enrollees). We linked laboratory data for pap smear pathology with patient encounter data and then linked this with patient general claims data and administrative records for physicians in order to link testing patterns to patient and physician characteristics. After categorizing cervical cancer screening patterns, multivariate models were constructed to identify factors independently associated with screening overuse and underuse.

Eligible female patients were women aged 30 years and older continuously enrolled with the practice from January 1, 2007, to December 31, 2009. The study population was refined using the following exclusion criteria: (1) ICD-9 codes for cervical or endometrial cancer or DES exposure, any grade of cervical dysplasia (CIN) or abnormal cervical cytology (ASCUS, ASC-H, LSIL, HSIL, AGC) or HPV infection, and high-risk conditions for cervical cancer (HIV infection, leukemia, neutropenia, history of organ transplantation); and (2) CPT codes for procedures related to abnormal cervical cytology (colposcopy, LEEP, or cryotherapy). These criteria were applied during the study period and the preceding 3 years.

Pathology results were available for every pap smear performed on a patient, which also identified the ordering provider. The text of the cytology result was analyzed to identify and eliminate unsatisfactory pap smears. Characteristics of ordering providers were collected from an online physician database maintained by the health system. The UCLA Institutional Review Board approved the study.

Each patient in the study population was assigned a cervical cancer screening category, based on the total number of satisfactory pap smears performed during the 36-month observation period. Assignment of category accounted for age and whether a woman had a hysterectomy. Pap smears deemed inadequate for histologic evaluation were excluded from analysis. The three cervical cancer screening categories were: (1) Underuse—0 screening episodes for a woman with a uterus (measure not applicable for age greater than 67 years); (2) Guideline-consistent use&mdash;exactly 1 screening episode over the 3-year observation period for a woman with a uterus (0 or 1 acceptable for women over 67 years) or 0 screening episodes for a woman without a uterus; and (3) Overuse&mdash;2 or more screening episodes for a women with a uterus or 1 or more screening episodes for a women without a uterus.

Using billing data, we collected patient age (at study entry), race/ethnicity (Asian/Pacific Islander, Hispanic, non-Hispanic black, non-Hispanic white, and non-Hispanic other), and preferred language (English, Spanish, or other). Age was subdivided into three categories (30-50 years, 51-70 years, 71 years and older). In cases where ethnicity information was missing (5.9%), non-Hispanic was assigned, as this was the modal condition (82%). Using billing and encounter data, we also collected total outpatient visits over the observation period (categorized as 1-10 and greater than 10), presence of comorbidities (diabetes, coronary artery disease, hypertension, cerebrovascular disease, and depression), average total Medicare Risk Adjustment Factor (RAF) score (which reflects patient complexity and illness severity), any visits for contraceptive management over the observation period, and for women over 40 years of age, number of mammograms received during the 3-year interval.

Utilizing the laboratory data link to physician, we derived a variable describing specialty mix of ordering providers for all pap smears performed on each patient (primary care only, gynecology only, primary care and gynecology, neither primary care nor gynecology). We collected information on the gender of provider, years since medical school graduation, and clinical specialty. We also included a variable indicating whether a provider attended a medical group—sponsored CME meeting about cervical cancer screening guidelines.

We described patient characteristics and computed for each patient her cervical cancer screening category. We compared patient characteristics across the three screening categories using Pearson’s χ2 and simple logistic regression, as appropriate. We also examined distribution of screening category by pap smear provider specialty mix. All analyses were performed using SAS version 9.2 (SAS Institute, Cary, North Carolina).

We separately evaluated predictors of overuse compared with guideline use and underuse compared with guideline use, using hierarchical logistic regression. The underuse model contained only patient characteristics because no pap provider existed. These models included the following patient characteristics (described above): age, race/ethnicity, language (English and non-English), greater than 10 outpatient visits over the study period (versus 10 or less), RAF score, comorbid conditions, and whether the patient had a visit for contraception. The overuse model included each of these variables plus provider gender, specialty, attendance at a cervical cancer screening CME lecture, and greater than 8 years in practice. For the overuse model, we carried out a subanalysis for women aged 40 years and older that added mammogram count. This analysis aimed to understand whether adherence to one guideline was associated with adherence to another or whether screening was performed in a regular, non-targeted fashion.

We performed an analysis to understand how sensitive the triennial measure is to pap smears performed at the extremes of or just outside of the measurement period. An additional 6 months of data were collected from January 1, 2010, to June 30, 2010. Alternate observation periods of 30 months (January 2007 to June 2009) and 42 months (January 2007 to June 2010) were used to recompute the cervical cancer screening category for each patient. In order to evaluate the effect of a pap smear being performed late and just outside the 3-year interval, we compared underuse rates in the 42- and 36-month study intervals. In order to evaluate the effect of a pap smear being performed early and just inside the 3-year interval, we compared overuse rates in the 30- and 36-month study intervals. In order to evaluate the secular trend, we compared overuse and underuse in the original 36-month window (January 1, 2007, to December 31, 2009) with the 36-month window of July 1, 2007, to June 30, 2010. The multivariate analysis was repeated to examine the effect of changing observation period on the multivariate results.

There were 10,111 women continuously enrolled with the medical group from January 1, 2007, to December 31, 2009. After exclusions were applied, 8018 women remained in the sample. Laboratory data from the study period showed that 10,998 pap smears were performed on this group of 8018 women. A total of 450 unsatisfactory test results were removed from the analysis. The final laboratory sample had 10,548 unique pap smear results. These tests were performed by 166 providers (see 

Fifty-four percent of the 8018 women were 50 years or younger (mean, 48 years; standard deviation [SD]=10.5; range, 30-91 years). Over half were white non-Hispanic ethnicity and 16.5% were Asian/Pacific Islander. Nearly all women were Englishspeaking. Ninety-five percent had at least one outpatient clinic visit, with an average of 16 visits over the 3-year study period (SD=15; range, 1-186 visits). Most visits were to primary care providers.

		Table 1. Demographic and Clinical Characteristics of Study Patients, Overall and by Cervical Cancer Screening Category

For a decade, US medical professional organizations and the US Preventive Services Task Force have suggested that low-risk women (history of multiple normal Papanicolaou [pap] tests, age over 30 years) receive cervical cancer screening every 3 years as part of routine preventive services. 

Summer 2013 | Contemporary Oncology®

Impact of Molecular Testing on First-Line Treatment Decisions in NSCLC

Novel Proteasome Inhibitors for Multiple Myeloma

Cervical Cancer Screening Overuse and Underuse: Patient and Physician Factors