Lung Cancer: Treatment

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Chapter 67 Lung Cancer

Treatment

Douglas Arenberg

Lung cancer is one of the most common solid tumors, particularly in industrialized nations, with an incidence similar to breast, colon, and prostate cancer. However, lung cancer accounts for more deaths than all these other cancers combined because of the inherent, often-aggressive biology of lung cancer; the nature of the lung itself, which can readily harbor an advanced tumor in the absence of symptoms; the poor response to treatment; and until recently the lack of an effective screening test.

As with many cancers, therapy for lung cancer includes surgery, chemotherapy, and radiation therapy, either alone or in combination. Definitive treatment increasingly includes combinations of two or all three of these modalities. Improved understanding of the molecular basis of cancer has led to treatments exploiting specific molecular abnormalities (targeted therapy). Lung cancer treatment has become more complex over time, in part because of recognition of tumor-specific and patient-specific traits that predict a greater likelihood of success, or lack of success, with specific drugs. This evolution of “personalized” cancer treatment should not overshadow the following principles of lung cancer treatment, which have remained largely constant over time:

1. Curative therapy should be used whenever feasible.

2. Curative therapy must address all grossly detectable disease, as well as reduce the likelihood of death from occult metastatic disease.

3. Toxicity or risk from treatment can outweigh the benefit when the patient is burdened by significant comorbid illness or when the risk of distant metastasis is extremely low.

Two competing principles are often cited as well: the treatment of lung cancer is strictly dependent on the stage of the disease, but accurate staging is often not possible before treatment (surgery) is rendered. This apparent paradox is resolved by recognizing that the first step in evaluating a patient with suspected lung cancer is the simultaneous determination of (a) whether cancer is the likely diagnosis on clinical grounds, (b) if cancer, whether it appears surgically resectable for cure, and (c) if “yes” to the first two questions, whether the patient can tolerate the required degree of surgical resection (see Chapter 66).

In the subset of patients for whom the answer to all three questions is “yes,” surgery is often the next step, and accurate pathologic staging of the disease is determined after complete resection. For patients in whom surgery is not feasible because of locally advanced or metastatic disease, or because of physiologic comorbidity, a biopsy that provides both a diagnosis and an accurate staging is necessary. For these patients, the appropriate treatments are chemotherapy and radiotherapy, either alone or in combination, depending on the stage and the likelihood of distant metastasis. However, a significant percentage of patients with advanced disease will be too sick to treat because of a poor performance status or extensive comorbidity.

This chapter divides lung cancer treatment on the basis of tumor anatomy (or staging) and patient physiology (or “performance status”). The following discussion of treatment by stage is restricted to non–small cell lung cancer (NSCLC); small cell lung cancer (SCLC) is considered in a separate section.

Non–Small Cell Lung Cancer

Stage I Lung Cancer

Stage I disease in NSCLC is completely confined to the lung parenchyma or airway, without nodal spread, and does not arise within 2 cm of the carina. The standard of care for patients with adequate lung function, no other significant comorbid illness (e.g., unstable coronary artery disease, debilitating arthritis), and a nodule with high probability of being lung cancer is surgical resection. Patients with stage I NSCLC who undergo surgery with complete resection of their disease have a high rate of cure with surgery alone (60%-80%).

Based on a randomized trial of NSCLC surgery conducted by the Lung Cancer Study Group, lobectomy is the standard surgery for lung cancer. Beginning in 1982, this study compared outcomes of patients who underwent lobectomy versus segmentectomy or wedge resection. The rate of local recurrence was 75% lower in the lobectomy group, and since then, lobectomy has remained the “gold standard” procedure for healthy patients with stage I disease.

Recent data and advances in imaging have led to a reevaluation of this standard. Specifically, several Japanese studies showed that small (≤2 cm) peripheral tumors with a ground-glass appearance on thin-section computed tomography (CT; ≤3 mm) had a low rate of nodal involvement, with 5-year survival of almost 100%, even after limited anatomic resection. Newer studies are re-addressing the appropriate degree of lung resection for patients with small, stage I tumors. One should also bear in mind that the time frame of the Lung Cancer Study Group trial comparing limited resection with lobectomy predated the widespread use of CT and positron emission tomography (PET) scans. Also, the increased use of CT scans to image the chest results in more tumors being detected at smaller sizes. This smaller average size of tumors should not be interpreted to justify abandoning lobectomy as a standard of care, but randomized controlled trials (RCTs) designed to determine the optimum degree of resection in this more modern setting are ongoing.

For now, the standard procedure for stage I NSCLC remains a lobectomy with lymph node dissection. Exceptions to this rule are usually applied for patients with peripheral tumors and limited pulmonary reserve from emphysema. Many surgeons will offer limited pulmonary resection, with or without concomitant lung volume reduction surgery (LVRS), to patients with severe emphysema. Published series demonstrating the feasibility of LVRS for patients with severe emphysema universally came from groups participating in RCTs of LVRS. This cannot be overlooked as a contribution to the better-than-expected outcomes in these highly select patients. Patients undergoing evaluation for LVRS who also had lung cancer surgery underwent rigorous pulmonary rehabilitation, with surgery in centers with regimented postoperative pain management, early mobilization, chest physiotherapy, and bronchodilator treatment. Lung cancer surgery for patients with severe emphysema should be done in centers with experience in all these strategies. Preoperative staging of these patients must be thorough, to avoid incomplete resection of tumors with nodal metastases.

The presence or absence of nodal involvement is the most important prognostic factor to determine after surgical resection. In addition to lobectomy, mediastinal lymph node dissection is essential to accurate staging of surgically resected lung cancer and must be done as part of any lung cancer resection. Some studies have found a direct correlation between survival and the number of lymph nodes removed at surgery, although this has not been widely validated.

The surgical approach to NSCLC has traditionally employed posterolateral thoracotomy as the standard procedure. The development of video-assisted thoracoscopic surgery (VATS) in the 1990s, followed by its spread through thoracic surgical training programs, has gradually resulted in a greater proportion of NSCLC surgeries being performed by this approach. Various studies show that VATS lobectomy is oncologically equivalent to open lobectomy, such that the tumor-containing lobe is removed intact, and mediastinal lymph node dissection or sampling is completed with equal effectiveness by either approach. VATS lobectomy is associated with less incision pain, reduced length of stay, and faster recovery of preoperative activity levels than open lobectomy. These advantages make VATS the approach of choice for most lobectomies, allowing well-trained thoracic surgeons to offer lobectomy to patients with a broader range of comorbid conditions.

Some patients are not candidates for VATS lobectomy, and occasionally an operation started with the VATS approach is converted to an open procedure at the surgeon’s discretion. The open approach is more suited to large (>3 cm) tumors or central tumors located close to the major blood vessels or airway. Patients with these tumors may benefit from the surgeon’s greater tactile access in an open chest to ensure resection margins are negative and arteries and airways are removed intact. In addition, patients who have had preoperative chemotherapy or radiation, or who have pleural adhesions or prior chest surgery, may not be candidates for VATS. Tumors with chest wall invasion requiring an en bloc resection usually require an open approach as well. When pneumonectomy is required for complete resection, it is generally performed by thoracotomy. In such situations the size of the specimen requires a large incision to facilitate removal of the specimen, reducing the advantages of VATS.

In general, centers that treat the largest number of patients have the best survival outcomes, for all treatment modalities, but especially for the surgical resection of lung cancer. In the United States, approximately 80% of lung cancer resections between 1996 and 2005 were performed by surgeons for whom lung cancer surgery was not the primary focus of their practice. In this same study, thoracic surgeons (those for whom noncardiac thoracic surgery was the primary focus of their practice) had the lowest operative mortality for patients requiring lobectomy or pneumonectomy. Current evidence-based guidelines from the American College of Chest Physicians (ACCP) advocates that patients being considered for lung cancer surgery should be seen by a “thoracic surgical oncologist with a prominent part of his/her practice focused on NSCLC.”

For patients with pathologically confirmed stage I disease, postoperative chemotherapy (adjuvant therapy) is not currently the standard of care. Based on RCT results of postoperative chemotherapy, patients with completely resected, pathologic stage I disease did not have a clear survival benefit with adjuvant chemotherapy. Subgroup analysis of RCTs suggests that patients with the highest risk (based on current understanding of such risk) may benefit from adjuvant therapy. These patients were generally those with large (>4 cm) primary tumors. Many oncologists offer discussions of risks and benefits of adjuvant chemotherapy to patients with large, stage IB tumors (>4 cm) or those with other possible risk factors, such as prominent vascular invasion. On an individualized basis, this practice is reasonable, but adjuvant chemotherapy cannot yet be considered the standard of care for completely resected stage I NSCLC.

For patients with clinical stage I NSCLC who are not candidates for resection because of comorbidity, there are still curative options, and the current standard of care is external beam radiation. An extensive discussion of radiotherapy methods is beyond the scope of this text, but the trend in thoracic oncology for inoperable stage I disease has been toward stereotactic body radiotherapy (SBRT) and away from conventionally fractionated external beam radiotherapy (EBRT). Conventional radiotherapy is given in doses of 60 to 70 grays (Gy), usually divided into 30 fractions of 2 to 2.5 Gy. SBRT is a form of radiotherapy employing many customized lower-dose beams converging into a volume that encompasses the tumor. These treatments are usually given up to a dose of 50 to 60 Gy over 3 to 5 days of treatment. Tumor motion caused by respiratory excursion can be significant, leading to undertreatment of tumor and overexposure of normal tissue to radiation, if the motion of the tumor is not tracked accurately. SBRT can be delivered more accurately with the use of fiducial markers placed in or near the tumor to track it during the respiratory cycle.

Cure rates with SBRT in stage I NSCLC for patients carefully staged can be excellent; 3-year disease-free survival in a large Phase II trial was close to 50%, with most recurrences being distant disease. Patients with large or centrally located tumors are more likely to be treated with conventionally fractionated EBRT; toxicity was greater in those with central tumors in a Phase II study of SBRT. Some groups treating large numbers of patients with SBRT report late development of chest wall pain or rib fractures. The risk factors for rib fracture include tumors within 2 cm of the chest wall and larger treatment volume. Complications in patients treated with SBRT should be tracked closely because it is a relatively new modality used in this patient population.

Thermal ablation is a minimally invasive therapy that can be used for local control of primary lung tumors. Radiofrequency ablation (RFA) uses a radiofrequency probe inserted percutaneously into the tumor, usually under CT guidance, to generate frictional heating that leads to cell death. RFA is the most frequently performed thermal ablation procedure used to treat lung tumors. Although the role of RFA is not clearly defined in lung cancer, small uncontrolled case series support its use for lung metastases. Although RFA is performed more often to treat hepatic and renal tumors, it may be well suited to the lung because of its ability to concentrate thermal energy focally within tumor tissue, with little or no energy spreading to the adjacent aerated normal lung parenchyma. There are no RCTs comparing RFA with radiotherapy in medically inoperable patients.

Based on published data, smaller tumors (<3 cm) may be more effectively treated with RFA than larger tumors. Peripheral tumors surrounded by lung parenchyma and away from hilar structures can be safely treated with RFA. The risk of pneumothorax is significant, as high as 50% in one series. Because this is a newer technology, the role for RFA in treating lung cancer has not been defined by large, well-controlled studies, but centers with experience in this approach can offer this option for inoperable patients, particularly if there is a contraindication to radiotherapy, such as prior irradiation.

A point of emphasis is necessary for defining the term “unresectable” stage I disease. In general, the most qualified person to determine a given patient’s suitability for surgery is an experienced thoracic surgeon with lung cancer as a major focus of practice. The benefits of surgery are being extended to more patients with more severe comorbid conditions because of improvements in preoperative care, surgical techniques, and postoperative care. Patients with severe COPD or other comorbid illnesses should not be denied surgery without at least seeing an experienced thoracic surgeon. Furthermore, decisions about any patient’s operability should be made in the context of optimum therapy for underlying lung disease.

In some patients a trial of bronchodilators and inhaled or oral corticosteroids might result in improvement in lung function sufficient to reduce surgical risk. The nature of these patients and the increased use of multimodality treatment across all stages of NSCLC make a compelling rationale for a multidisciplinary approach to treating patients with lung cancer.

Stage II Lung Cancer

Stage II NSCLC is defined as including mainly (1) tumors with hilar or intralobar nodal metastasis, with tumor confined to one lobe of the lung, or (2) tumors invading the chest wall, without nodal metastasis. Treatment of stage II NSCLC is still primarily surgical resection, and the same principles apply here as in stage I disease. One major difference is that adjuvant chemotherapy has proven survival benefit for patients with stage II disease. If one makes the safe assumption that the risk of systemic chemotherapy is the same whether the patient had stage I or stage II disease, then the favorable risk/benefit data for adjuvant chemotherapy in patients with stage II reflects that occult metastases are more likely to be present in patients with more advanced disease. Therefore, patients with pathologic stage II lung cancer have more to gain with adjuvant chemotherapy than stage I patients. After recovery from surgery, patients who undergo surgical resection of tumors with peribronchial or hilar nodal metastasis (stage II NSCLC) should be referred to a medical oncologist to discuss adjuvant chemotherapy.

Current recommendations suggest all patients with stage II or III disease should receive postoperative chemotherapy. However, metaanalyses of adjuvant trials suggest the number of patients who need to be treated with adjuvant chemotherapy to achieve one additional long-term cure is 24 to 39. To reduce this number, studies looked for additional patient or tumor-specific characteristics that predict benefit (or lack of) from adjuvant treatment. One oft-cited study found tumor biomarkers that may identify patients most likely to benefit from adjuvant chemotherapy. Retrospective examination of tumor specimens from patients enrolled in an adjuvant trial identified excision repair cross complementation 1 (ERCC1), an enzyme involved in repairing cisplatin-induced DNA damage, as a possible prognostic and predictive marker. High expression of ERCC1 was associated with a good prognosis, but also identified a patient subgroup who did not benefit from adjuvant (cisplatin-based) chemotherapy. Similarly, high expression of ribonucleotide reductase M1 (RRM1, which metabolizes gemcitabine) was identified by immunohistochemistry as predicting better overall survival, but poor response to gemcitabine-containing chemotherapy. Insufficient data are available to recommend the use of biomarker-based selection of any chemotherapy, including adjuvant chemotherapy, but studies are underway to determine whether this improves outcomes relative to empirically chosen chemotherapy and allows fewer patients to be treated while achieving the same survival benefit.

Postoperative radiotherapy for completely resected stage II NSCLC does not have proven survival benefit, may be associated with worse outcomes, and in general should not be used. However, for patients with stage II NSCLC who cannot tolerate surgical resection, definitive radiotherapy is the standard of care. Although radiotherapy can provide excellent local control rates, it does not reduce the likelihood of distant metastasis. An unanswered question is whether adjuvant chemotherapy would benefit patients with clinical stage II NSCLC treated with curative radiotherapy. If adjuvant chemotherapy reduces the likelihood of death after surgery for stage II disease, the same approach might benefit patients treated with radiotherapy. No data support this approach, however, and extrapolating surgical data to patients treated with radiotherapy for local control is not appropriate outside of a clinical trial.

Stage III Lung Cancer

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