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2002 Selected Articles

Lung Cancer in Women

Lara Campagna, MHS, PA-C; David Coniglio, MPA, PA-C; Jennifer Garst, MD

Lung cancer is the leading cause of cancer death in the United States. The estimated number of new lung cancer cases in this country was 169,500 in 2001, of whom 78,800 are women. That same year, lung cancer claimed 157,400 lives, including 67,300 women. Although the incidence of lung cancer in women is half that of breast cancer, lung cancer deaths account for 25% of cancer-related female mortality compared with 15% for breast cancer.¹

Lung cancer is divided into two major subgroups: small cell lung cancer (SCLC), accounting for approximately 15% of all cases, and non-small cell lung cancer (NSCLC), accounting for the remaining 85%. The NSCLC group is made up of adenocarcinoma, squamous cell carcinoma, and large cell carcinoma histologic types. Although there are some differences in the pathologic and prognostic features within the NSCLC subgroup, the treatment is generally the same across all types of NSCLC. The incidence of lung cancer in women starts to rise after age 30, and peaks in the 70s.²

Studies have shown improved survival for women at every stage of the disease;^3-8 one study noted a 12-month survival benefit for women at any stage.⁴ This trend is especially noticeable in SCLC, where some studies have shown a median survival in women that either approximates or surpasses twice that in men.^7,8

Prevention

The primary risk factor for the development of lung cancer is smoking. Tobacco usage has also been implicated as a risk factor in cancers of the larynx, oral cavity, esophagus, stomach, pancreas, bladder, kidney, and cervix.⁹ A history of smoking is especially ominous in women. Many studies (including a meta-analysis) have shown a higher relative risk of developing lung cancer for women at every dosage level of nicotine exposure.^10-14 Although the relative risk of developing lung cancer declines after smoking cessation, the absolute risk remains.¹⁵ It is therefore important to remember that even former smokers remain at significant risk.

Family history is also a risk factor in lung cancer. This is especially pronounced in female smokers with a family history of lung cancer. One study pointed out that women who smoke and have a positive family history had a 5-fold higher risk of lung cancer than the risk associated with heavy smoking alone.¹⁶

Although the risk conferred by smoking cannot be entirely diminished by cessation, significant reductions in risk can occur.^10,13,15 Figure 1 shows a model estimate of lung cancer mortality by age based on the age at smoking cessation. Those who quit before age 40 had only a slight increase in risk compared with never-smokers. Even older women had a reduced risk when they quit by age 60. Patients who smoke often say that they don’t quit because they feel it is too late to reverse the damage. Figure 1 demonstrates that for many women, this is not the case.

FIGURE. Lung Cancer Death Rates by Age: Female Current, Former, and Never Smokers15

Smoking is both a physical and behavioral addiction, and most smokers continue despite the well-known health benefits of cessation. It is important to explore the individual’s reasons for smoking while assisting her with smoking cessation. In addition to the nicotine addiction, other behavioral habits should be assessed. Women who smoke to control weight or because of anxiety or depression are unlikely to succeed with quitting if their behavioral needs are not addressed. The authors often treat anxiety and depression medically. Patients who are concerned about "trading one addiction for another" should be encouraged to understand that use of psychotropics to aid in smoking cessation is far less risky than continuing to smoke.

Smoking cessation remains imperative even after lung cancer is diagnosed. Recent data have shown that continued tobacco use during treatment for SCLC dramatically decreases disease-free intervals and overall survival.¹⁷ It would appear that smoking cessation may offer survival benefits to SCLC patients on the order of those associated with active single-agent chemotherapy.¹⁷

Second-hand smoke has also been implicated as a risk factor for lung cancer, but quantifying exposure and risk are difficult. Other risk factors include exposure to industrial chemicals (eg, arsenic, asbestos, radon). Smokers exposed to these agents are at greater risk of developing lung cancer than are nonsmokers who are similarly exposed.¹

Screening

Is there a role for screening in lung cancer? The goal would be detection of malignancy at the earliest stage, with the hope of improving survival and decreasing relapse rates. Objections have been that screening leads to the diagnosis of slow-growing tumors that might not be associated with adverse outcomes, and that early detection will not change the survival of patients with more aggressive tumors. Tables 1 and 2 address the staging of lung cancer, and Table 3 shows the 5-year survival at each stage. It is clear that there is a significant survival reduction with increasing stage. Given the overall 5-year survival in lung cancer of 14%, it would seem that early detection could improve survival. Currently, only 15% of lung cancers are diagnosed in the early stages of the disease.¹

There is no uniformly recommended and accepted screening procedure for lung cancer. The Mayo Clinic has released data on a large-scale study randomizing at-risk patients to a screening arm offering free sputum cytology and chest radiography at 4- to 6-month intervals or recommending the same studies yearly. Although the study did not reveal improved survival in the screening arm, there have been criticisms of the study.¹⁸ The study was set up to look at survival differences between two screened populations. The study is generally considered to be a negative screening study as there was no survival benefit in the intensely screened group. Although this may be true, most subjects in the control arm received chest radiographs within the past 1 to 2 years of the study (50% and 73% respectively). This study was not designed to address whether chest radiographs and sputum cytology are appropriate screening tools, but if increased frequency of screening improves survival. It appears that it does not. Like many studies of its time, only male subjects were entered. Research continues to improve screening techniques with sputum cytology.¹⁸ The utility of regular screening with chest radiography remains unclear.

A more promising development in screening for lung cancer is the advent of spiral chest computed tomography (CT). Early studies have revealed encouraging results. The Early Lung Cancer Action Project (ELCAP) was the first major US study to evaluate spiral CT scanning for screening patients at high risk for lung cancer. Preliminary analysis of the ELCAP data revealed that initial screening diagnosed malignancy in 2.7% of the participants. Of these lesions, 85% were stage I, and only 4 of the 23 malignancies were detected on simultaneous chest radiography. Within the study population, stage I lung cancers were diagnosed six times more frequently by spiral CT scanning than by chest radiography.¹⁹ These results are similar to those of a retrospective study revealing that CT scanning is significantly more likely to reveal a stage I lung cancer than chest radiography.²⁰ Results of Japanese studies likewise demonstrate the utility of screening chest CT in confirming a high number of early-stage lung cancer.^21,22

The ELCAP study defined the at-risk population as patients older than 60 years of age and with at least a 10 pack-year smoking history.¹⁹ Issues of the appropriate age to start screening and how frequently screening should be performed remain undefined. The ELCAP study currently underway seeks to evaluate the efficacy of long-term screening and define the appropriate screening interval.¹⁹ Because the incidence of lung cancer is about 20 per 100,000 in women under the age of 65,² starting screening at age 60 will be too late for many women. Given the relationship between duration and intensity of smoking to the development of lung cancer, it would make sense to begin screening women with a higher pack-year smoking history at an earlier age.

Signs and Symptoms

In the absence of an accepted screening tool, physicians must rely on signs and symptoms to raise the index of suspicion for lung cancer. In patients with a smoking history exceeding 10-pack years, lung cancer should certainly be considered in the differential diagnosis of pulmonary illness. Any patient with recurrent pneumonia or bronchitis should be evaluated for lung cancer. If chest radiography remains abnormal following a reasonable course of antibiotic therapy, a chest CT should be obtained. Mediastinal adenopathy is not well evaluated by chest radiography, and can occur without an associated lung mass. In addition, other symptoms such as hoarseness, unrelenting shoulder pain, persistent cough, progressive shortness of breath, hemoptysis, or chest pain should be evaluated by chest radiography and chest CT to rule out lung cancer.

Clinicians must also remember that young people with no smoking history can get lung cancer. Although lung cancer incidence starts to rise in patients around age 30, any of the above symptoms in a younger person warrants evaluation. The fastest growing subtype of cancer, bronchioloalveolar carcinoma (BAC), is more likely to develop in younger women with no smoking history. The incidence of BAC more than doubled between 1978 and 1989,²³ and there was a 5-fold increase between 1955 and 1990.²⁴ It appears that the rise in adenocarcinomatous lung cancer, of which BAC is a subtype, is mostly attributable to the upsurge in BAC during the same time period.^24,25 The patient at risk for BAC does not fit the normal risk profile for lung cancer, and BAC has a higher incidence in women than men compared with other lung cancer types.²⁴ Women tend to be younger at diagnosis,^25,26 and never-smokers.^25-30 It is important to note that overall survival is higher for BAC compared with other lung cancers;^29,30 especially in female patients.^26,27,29 Looking at survival by stage (Table 3),³¹ the 5-year survival for BAC is clearly better than for other types of NSCLC. Because these women are more likely to be never-smokers, they would not be considered high-risk for the purpose of screening. The appropriate pursuit of diagnosis and treatment based on presenting symptoms could have a major impact on this patient population.

Diagnosis and staging

Several approaches are available to the clinician for diagnosing lung cancer. Central tumors or bulky adenopathy invading a primary airway are amenable to bronchoscopic biopsy. Aspiration biopsies can also be obtained through the airway. Bronchoscopy has a much lower yield in peripheral tumors, where CT-guided biopsies are more useful. Very small lesions or mediastinal adenopathy may require surgical biopsy. A nonmalignant biopsy that does not specifically define a benign process suggests a suspicious abnormality. In such cases, positron emission tomography (PET) scanning should be considered for screening a solitary lung nodule. A "hot" nodule on PET warrants biopsy, whereas a "cold" nodule may support a less aggressive course such as follow-up scanning. Some lower-grade malignant tumors (eg, BAC) and tumors of less than 1 cm are not well evaluated by PET. In any case, for a new mass where definitive diagnosis is unclear and surgical biopsy is not recommended or nondiagnostic, a follow-up CT should be obtained in 3 to 4 months. Any evidence of increase in the size of the lesion at follow-up CT may then warrant tissue diagnosis; this is also true for a cold PET scan of a lesion identified by another study.

Staging of lung cancer is important to define prognosis and treatment. Many lung cancers have metastasized by the time of diagnosis. The most common sites of metastasis are the lymph nodes in the chest and other sites in the lungs, liver, adrenal glands, bone, and central nervous system. A CT scan of the chest through the adrenals is recommended for staging, especially with larger tumors and evidence of mediastinal adenopathy. Brain CT and bone scanning are recommended based on symptomatology and candidacy for surgical resection. Recently, PET scanning has been approved for staging lung cancer, and can be helpful in identifying occult metastases.

Treatment

Treatment of lung cancer depends on stage and histology (Table 2). Small cell lung cancers are staged as either limited-stage disease (disease confined to the chest) or extensive-stage disease (distant metastasis or malignant pleural effusions). The disease is also considered limited-stage when the entire known tumor fits within a radiation port.

Limited-stage SCLC is predominantly treated with concurrent chemotherapy and radiation. Even a patient with a resected small cell tumor should receive adjuvant chemotherapy. Extensive-stage SCLC is treated with chemotherapy alone or chemotherapy with sequential radiation. The most active agents remain the platinums and etoposide. Patients with a good response to treatment should be considered for prophylactic cranial irradiation. Every patient with SCLC should see both a medical oncologist and a radiation oncologist, as most will receive both chemotherapy and radiation at some point during their course of treatment.

Treatment of NSCLC is more complicated. Stage I disease is primarily treated with surgery. Adjuvant chemotherapy is currently a subject of clinical research, but is not considered the standard of care and should not be recommended outside a clinical trial. Postoperative radiation is likewise not recommended in this population.

Treatment of stage II/IIIA NSCLC is under extensive investigation. The standard of care at this time is surgery alone. The role of adjuvant and/or neoadjuvant chemotherapy is still under study. However, neoadjuvant treatment with chemotherapy and radiation before surgical resection constitutes the standard of care for superior sulcus (Pancoast) tumors. Chemotherapy and radiation are the standard of care for non-Pancoast tumors only when resection cannot be undertaken or when surgery may result in incomplete resection of the tumor. Chemotherapy and radiation may be appropriate in selected patients who have undergone resection and who are not in a clinical trial, but are not considered the standard of care.

Stage IIIB disease is traditionally not considered surgically resectable, and is treated with concurrent chemotherapy and radiation. As concurrent treatment may be superior to sequential treatment,⁸ it is the standard of care in all patients with a performance status of 70% or more. Sequential treatment does have a role in treating patients with poor performance status, poor lung function, or large tumor volume. Stage IIIB disease (as defined by malignant pleural effusions) is typically treated with chemotherapy alone.

Stage IV disease can be treated with palliative chemotherapy and radiation, which offers a survival advantage over best supportive care to patients with a good performance status. In patients with an obstructing bronchial lesion or painful metastatic disease, radiation may provide more rapid symptomatic relief than chemotherapy. Several chemotherapy regimens are available that spare hair loss with no loss of efficacy. Newer targeted therapies promise to attack tumor cells specifically with less overall toxicity, and many can be administered orally as a daily tablet.

Many advances in surgical, chemotherapeutic, and radiation modalities are improving the efficacy of intervention in the typical elderly lung cancer patient. Surgical techniques such as video-assisted thorascopic surgery (VATS) are useful for both diagnosis and removal of small tumors. Because there is no rib removal or spreading during a VATS procedure, and because the surgical incision is usually less than 6 cm, the recovery period is significantly shortened. These procedures are becoming common in many tertiary health care centers, although they are rarely available in community hospitals. Radiation techniques such as conformal radiation using 3D imaging has improved the ability to deliver higher doses of radiation to the tumor, while protecting adjacent structures such as the esophagus and normal lung. Chemotherapy has been proved to provide a survival advantage and better quality of life in elderly patients with a good performance status.³² Chemotherapy can be as well tolerated in the healthy elderly population as in younger patients.³³

Advances in diagnostic techniques, as well as improved delivery of chemotherapy and radiation, can improve the quality of life to most lung cancer patients. Decisions regarding surgical intervention, chemotherapy, and radiotherapy should be based on potential benefit to quality of life and survival. For every patient with a new diagnosis of lung cancer, the authors recommend evaluation utilizing a multidisciplinary approach that includes surgical oncology, medical oncology, and radiation oncology.

Conclusion

Lung cancer is the leading cause of cancer death among women. The biggest decrease in lung cancer mortality can be achieved by reducing smoking rates and promoting early detection rather than improving treatment modalities. The primary health care provider has the best chance of effecting change in the natural history of lung cancer in female patients by encouraging and supporting women and their partners in smoking cessation. Hopefully, studies will soon document a role for early and high-risk screening. In this case, it will be the primary health care providers who identify at-risk patients for evaluation. Although the prognosis remains poor for patients diagnosed with advanced disease, better symptom palliation and modest improvement in survival are possible for most lung cancer patients who receive treatment.

Lara Campagna, MHS, PA-C, is senior physician assistant, Thoracic Oncology Program; David Coniglio, MPA, PA-C, is senior physician assistant, Division of Medical Oncology; Jennifer Garst, MD, is assistant professor of medicine, Thoracic Oncology Program, all at Duke University Medical Center, Durham, NC.

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