Patient Description

Mr. B is a 62-year-old Caucasian male who has been a two-pack-a-day smoker for 40 years. His wife just underwent a lobectomy for a stage IA lung cancer, which was detected at the time of a workup for acute cholecystitis. Mr. B has had no pulmonary symptoms, and has been in good health except for hypertension controlled with a beta blocker. There is no family history of malignancy. Mr. B's wife insists that he see their primary care physician to inquire about enrolling in a program that screens for lung cancer using low-dose helical computerized tomography (LDHCT).

Clinical Decision Point 1: Role of Lung Cancer Screening

Question 1: Is there a proven role for lung cancer screening?

1. Yes
2. No
3. Controversial

Discussion

(c) The role of lung cancer screening is one of the most controversial issues in any discussion of the management of lung cancer. There is a polarization of opinions depending upon such issues as: (1) Does lung cancer screening increase the survival of patients detected with the disease? (2) Does lung cancer screening decrease the mortality of lung cancer? (3) Does lung cancer screening preferentially detect tumors that are slow growing and indolent, a cohort that many would classify as "overdiagnosis" cases, not likely to result in the death of the individual? (4) Does lung cancer screening subject enrollees to unnecessary biopsy procedures, which are the result of false-positive CT scans? (5) Does lung cancer screening subject the enrollee to lung cancer surgery with undue risk? (6) Does lung cancer screening really have cost-effective potential?

Any discussion of lung cancer screening must start with the individual's risk for lung cancer, and whether an individual is really a candidate for such programs. In essence, a screening program should only involve asymptomatic individuals who are thought to be at a higher risk than the general population for developing lung cancer. The risk of dying from lung cancer depends on the age of the individual, the duration of tobacco exposure, and the dose of the tobacco exposure.¹ Cigarette smoking is the single most important risk factor for lung cancer, with 85% of lung cancer deaths caused by smoking. Risk increases in rough proportion to the number of cigarettes smoked per day. Duration-specific risks increase steadily, but are most significant beyond 20 years of smoking duration. Cancer risk remains elevated in former cigarette smokers, declining significantly beyond 5 years from cessation, but never reaching the level of the never smoker. The relative risk of lung cancer is also influenced by other host factors, including gender, ethnicity, socioeconomic status, occupational exposures, and the presence of airflow obstruction. In general, most screening programs enroll individuals who have a tobacco consumption of at least 20 pack years, and who are older than 50 years of age. Exceptions are made based on an occupational exposure to asbestos, where the screening age may be relaxed to 45 years of age, or if there is a family history of lung cancer. Lung cancer prevalence is particularly high in individuals smoking 30 to 40 pack years or more with airflow obstruction, defined by forced expiratory volume (FEV)1/forced vital capacity (FVC) less than 70% and an FEV1 less than 70% predicted; and airflow obstruction is associated with a four- to five-fold increase in lung cancer when all other risk factors are controlled.² Individuals with emphysema who are being evaluated for lung volume reduction surgery have a 5% prevalence of asymptomatic lung cancers.³

In 2006 and 2007, landmark articles were published regarding the use of CT screening for lung cancer. Henschke and the International Early Lung Cancer Action Project (ELCAP) published the results of screening 31,567 asymptomatic people from 1994 through 2005. ⁴ At baseline, the researchers defined a positive result as the identification of:

• ≥1 solid or partly solid noncalcified pulmonary nodule ≥5 mm in diameter
• ≥1 nonsolid noncalcified pulmonary nodule ≥8 mm in diameter
or
• a solid endobronchial nodule

Patients underwent repeat CT 12 months later if the noncalcified nodules identified did not fulfill the criteria for a positive result or if the test was negative. The researchers defined the diameter of the nodule as the average of the width and length of the cross-sectional area of the largest nodule visualized on CT. If none of the parenchyma was obscured it was described as nonsolid; however, if the nodule obscured the entire or part of the underlying lung parenchyma, consistency was defined as solid and partly solid, respectively. When a positive result was found, the type of workup depended on the diameter of the largest nodule.⁴ The preferred option for nodules 5 to 14 mm in diameter was another CT at 3 months. However, if the images showed growth, then biopsy—ideally by fine-needle aspiration—was performed. If there was no growth, the workup was discontinued. Alternatively, positron-emission tomography (PET) was performed. If the results were positive, biopsy was performed; otherwise, CT was repeated at 3 months. For nodules 15 mm in diameter or larger, irrespective of consistency, immediate biopsy was available in addition to the options already specified for smaller nodules. In the presence of suspected infection, a 2-week course of antibiotics followed 1 month later by CT was an alternative to all the options mentioned. If there was no resolution or growth, biopsy was performed; otherwise, the workup was discontinued. For all subjects in whom the workup was discontinued or for whom the biopsy did not lead to a diagnosis of lung cancer, CT was repeated 12 months after the baseline scan.⁴

Follow-up Screenings

Repeat screenings (27,456 annual/interval) were performed 7 to 18 months after the previous screening.⁴ A positive result was defined as any newly identified noncalcified nodule, regardless of size. CT was repeated 12 months later if no new nodule was seen. When one or more new nodules were visualized, further workup depended on the width of the largest nodule. If all nodules were less than 3.0 mm in diameter, or if the largest nodule was more than 3.0 mm but less than 5.0 mm, CT was performed 6 or 3 months later, respectively. If there was no growth in any of the nodules, the workup was discontinued. If at least one of the noncalcified nodules was 5.0 mm or larger in diameter, then a 2-week course of antibiotics was administered, followed by CT 1 month later.⁴ Biopsy was performed if the nodules showed growth or no resolution. If PET was performed instead of immediate biopsy and the result was positive, biopsy followed. If the PET result was indeterminate or negative, CT was performed 3 months later, and if the scans showed growth, biopsy followed. Otherwise, the workup was discontinued. CT was repeated 12 months after the previous annual CT for all subjects in whom the workup was discontinued or when biopsy did not result in a diagnosis of lung cancer.⁴

Biopsy Results

Based on the criteria described above, 535 biopsies were performed; of these, 43 were nonmalignant (8% of total biopsied, 0.1% of all participants).⁴ Most patients found to have lung cancer were 60 to 79 years of age and screening resulted in a diagnosis of lung cancer in 484 subjects (1.3% of all participants on baseline screening and 0.3% on annual screening). Five of the 484 subjects developed symptoms within 12 months of baseline screening. Median follow-up was 40 months from the time of diagnosis of lung cancer. Of the patients diagnosed with lung cancer, 412 (85%) had clinical stage I lung cancer, and the estimated 10-year survival rate was 88% in this group (95% confidence interval [CI], 84–91). Figure 1 shows the diagnoses of lung cancer resulting from baseline screening and annual CT.⁴ Among the 302 participants with clinical stage I cancer who underwent surgical resection within 1 month after diagnosis, the survival rate was 92% (95% CI, 88–95) (See Fig. 2).⁴ Surgical mortality was 0.5%. Only 21 of the detected lung cancers were noninvasive bronchoalveolar lung cancer (4%), which potentially could have been considered as "overdiagnosis." Moreover, the eight participants with clinical stage I cancer who did not receive treatment died within 5 years after diagnosis.⁴

Audio Commentary by Dr. Langer 

Figure 1. Diagnoses of lung cancer resulting from baseline screening and annual CT.⁴

Figure 2. Kaplan–Meier survival curves for 484 participants with lung cancer and 302 participants with clinical Stage I cancer resected within 1 month after diagnosis. ⁴

Table 1. Distribution of lung cancer diagnoses on baseline and annual CT screening, according to age and median pack-years of cigarette smoking.⁴

*Includes 5 participants with interim diagnoses

A contrary opinion regarding the efficacy of lung cancer screening hinges on historic work performed nearly three decades ago, and on the inability of lung cancer screening with chest x-rays (CXRs) in randomized trials of the 1970s to yield a reduction in mortality despite the fact that more lung cancers were actually detected. This is the primary argument for the NCI-sponsored National Lung Screening Trial (NLST) in which approximately 50,000 individuals were entered over a period of 20 months to be randomized between LDHCT and CXR, with action to be taken on all lesions larger than 1 cm.^5,6

The mortality argument has also led Bach et al to analyze the results of 3246 current or former smokers enrolled in one of three studies conducted at the Istituto Tumori in Milan, Italy, the Mayo Clinic in Rochester, Minnesota, and the Moffitt Cancer Center in Tampa, Florida.⁷ Individuals in all three studies were diagnosed with lung cancer in far greater numbers than would have occurred in the absence of screening. However, there was no evidence that CT screening reduced the risk of death due to lung cancer in any of the studies individually or combined. The mortality from lung cancer was only considered after the first year of the study start and not at its commencement because only one death from lung cancer occurred in the first year compared with 9.5 deaths anticipated if screening was not performed. The authors suggest that this large reduction in the first year may have been due to the requirement that all patients be asymptomatic at the time of enrollment and not because CT screening reduced deaths immediately. Thus, they concluded this represented a healthy volunteer bias and decided to analyze data after the first year. As in other studies of CT screening, the preponderance of lung cancers (96 of 144 [67%]) were early stage (ie, stage I or II), and the outcomes for these individuals were quite good—only 12 (13%) of the individuals with early-stage non–small-cell lung cancer died from lung cancer during the study. These three studies, based on Bach's observations, resulted in a significant portion of late-stage disease by screening, which raises a "red flag," cautioning readers as to whether all of the individuals in the study were indeed asymptomatic at the time of registration, even though the entry criteria specified no prior history of symptoms suggestive of lung cancer. The authors also hypothesize that the reason a larger number of cancers were detected without impacting mortality was that the cancers detected in the main were unlikely to ultimately affect patients' survival (ie, overdiagnosis). In their paper, Bach et al acknowledge the limitations of such modeling. A larger sample size may have allowed the authors to detect a benefit for screening; indeed there were only 144 lung cancers in this small analysis. In fact, the 95% CIs actually allowed for a reduction in lung cancer mortality as large as 30%, which, the authors admit, would "constitute a potentially important public health benefit." The authors also admit that their follow-up time for the study was 3.9 years, and only 33% had been followed after 4 years. A longer period of follow-up, or a longer period of screening, may have allowed the authors to detect a benefit for screening because individuals with a negative initial scan may have developed a new lung cancer on follow-up. These new lung cancers on repeat screening are well known to be more aggressive than those found on prevalence screening. Finally, Bach et al quote a risk of 5% mortality for lung cancer operations in the United States (population-based data), which is certainly contrary to the 1.4% rate in the literature (clinical trial data),^7,8 and, as such, should not be a reason to dissuade an informed individual from considering the salutary "downstream" consequences of finding a screen-detected lung cancer.

Hence, there is a polarization of thought regarding lung cancer screening in the United States. At this time the procedure is not paid for by insurers, and individuals must consider both the benefits (early-stage lung cancer detection and reported survival benefit) versus the risks (anxiety regarding false-positive readings as well as the unsettled mortality debate). Individuals who make the personal choice to participate in such programs should be part of a prospective trial with meticulous attention to detailed follow-up with the clients and their primary care physicians.

Audio Commentary by Dr. Langer 

Case Continues

The patient enrolled in a LDHCT program, which followed the Institutional Review Board (IRB) approved guidelines for management of the individual. Initial CT was negative; however, subsequent scan 1 year later showed an 8-mm left lower lobe nodule.

Clinical Decision Point 2: Workup

Question 2: How should this lesion be worked up?

1. Repeat imaging in 3 months, with imaging every 6 months thereafter if no change
2. Fine needle aspiration under CT guidance
3. Video assisted thoracoscopic resection (VATS) thoracotomy and wedge resection
4. VATS thoracotomy with definitive resection if malignancy is confirmed

Discussion

(c) The presence of a new nodule on a yearly repeat scan merits investigation, which is both size and morphology dependent. For the annual screenings, if at least one of the noncalcified nodules is 5.0 mm or larger in diameter, then a 2-week course of a broad-spectrum antibiotic is recommended followed 1 month later by CT. If the lesion resolves, follow-up CT scanning at 1-year intervals is appropriate. If the nodule shows no resolution or growth, a PET scan may be useful, particularly if the lesion reveals fluorodeoxyglucose (FDG) avidity. Nevertheless, if the PET scan is indeterminate, histologic examination of the nodule should be performed since the limits of resolution and positivity of the lesion on PET are size dependent.⁹ This is particularly important if the nodule has an appearance of ground glass opacity (GGO). Without resolution of a GGO nodule by antibiotics, one must be concerned about the development of a bronchoalveolar lung cancer, which may not give a positive result by PET. Repeat imaging, therefore, if the nodule does not resolve on antibiotics, is not considered the standard of care unless the patient refuses biopsy or is considered to be a high risk for surgical biopsy or fine needle aspiration due to co-morbid illness, including emphysematous disease or coronary disease. Fine needle aspiration biopsy of a pulmonary nodule has a sensitivity of 80% to 95% and a specificity of 50% to 88%, but is very operator-dependent and influenced by the size and location of the nodule.¹⁰ Moreover, the ability to have on-site expert cytologic confirmation of successful biopsy limits the number of institutions where this technique would be useful for an 8-mm nodule. Nevertheless, if the patient desires an attempted biopsy prior to any surgical confirmation of pathology, then he/she should be informed of the 25% chance of pneumothorax possibly requiring evacuation of air.

Case Continues

On pulmonary function testing, the FEV1 is 80% of predicted, and there are no contraindications to surgery. Mr. B undergoes a VATS thoracotomy and wedge resection, with intraoperative confirmation of malignancy. A lobectomy was performed with a mediastinal lymph node dissection. The final pathology reveals a poorly differentiated adenocarcinoma measuring 8 x 9 mm; margins are negative. There is no evidence of perihilar, hilar, or mediastinal node invasion.

Clinical Decision Point 3: Staging

Question 3: What is the stage?

1. Stage IA
2. Stage IB
3. Stage IIA
4. Stage IIB

Discussion

(a) The surgeon has performed the appropriate operation with staging of the mediastinum. The lesion is less than 3 cm, does not involve the visceral pleura, and has no associated involved N1 or N2 nodes. This defines the lesion as stage IA,¹¹ a classic, albeit small, solitary pulmonary nodule. Despite the small size of the lesion, a lobectomy has been performed instead of a lesser resection, such as a wedge resection or a segmentectomy. For patients who have pulmonary function testing that predicts that they will be able to tolerate a lobectomy, lobectomy remains the preferred option to decrease the chance for local recurrence that is seen with lesser resections.¹² Nevertheless, because recent preliminary data from Japan have been encouraging in this regard, clinical trials are ongoing to determine whether lesions less than 20 mm, which have no lymph node involvement, can be handled by lung-sparing options, such as segmentectomy.¹³

Audio Commentary by Dr. Langer 

Clinical Decision Point 4: Ongoing Management

Question 4: How should this patient be managed?

1. Close monitoring with periodic imaging
2. Cis-retinoic acid
3. Selenium
4. Adjuvant chemotherapy with four cycles of a carboplatinum-based regimen

Discussion

(a) The patient has a stage IA lung cancer and merits close monitoring with periodic imaging. Although the methodology for this monitoring will differ among practitioners, the NCCN guidelines call for history and physical with contrast-enhanced chest CT every 6 months for 2 years, and then a history and physical with contrast-enhanced CT annually. Smoking cessation counseling should be instituted. The chief purpose of close surveillance is mainly to document the development of a second primary lung cancer since approximately 5% of patients with stage I lung cancer will develop a second primary at the rate of 2% per year.¹⁴ The use of cis-retinoic acid as a chemoprevention agent for lung cancer was discouraged by the results of a large intergroup phase III randomized trial, which did not find a benefit for the agent in preventing recurrences or second primary tumors after resection of stage I lung cancer.¹⁵ As of this date, an ongoing phase III trial sponsored by the Eastern Cooperative Oncology Group and open through the Cancer Trials Support Unit is investigating the role of postoperative selenium in preventing second lung cancers after resection, and is an option for patient recruitment into the trial.¹⁶ There are no data that support the use of adjuvant chemotherapy for individuals with stage IA lung cancer. In an unplanned subset analysis, patients on CALGB 9633 with tumors of at least 4 cm (close to 100 patients on each arm) sustained an overall survival advantage, with an HR of 0.66 (P = .04). Among the 74 patients in each arm with tumors <4 cm, there was no difference in survival rates between those receiving chemotherapy and those undergoing standard observation. The HR was 1.02 (P = .51).¹⁷ These results are not conclusive, but support the need for further studies evaluating patients with stage IB disease with larger tumors since a subset analysis of these data has revealed that there could be potential benefit for individuals with tumors >4 cm who receive adjuvant chemotherapy.

Audio Commentary by Dr. Langer 

Conclusion

This case outlines some of the controversy surrounding lung cancer screening. Before considering screening, a careful evaluation of an individual patient's risk profile is necessary. If screening seems appropriate, it is preferable to enroll the patient in an organized screening program in which protocols have been established to dictate next steps based on the results of initial and ongoing screening.

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