eMedicine Specialties > Oncology > Carcinomas of the Lung and Other Intrathoracic Carcinomas

Lung Cancer, Non-Small Cell: Treatment & Medication

Author: Syed Huq, MD, Fellow, Division of Hematology-Oncology, Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Ellis Fischel Cancer Center
Coauthor(s): Irfan Maghfoor, MD, Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia; Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri/Ellis Fischel Cancer Center
Contributor Information and Disclosures

Updated: Nov 10, 2009

Treatment

Medical Care

The roles of surgery, chemotherapy, and radiation therapy for non-small cell lung cancer are discussed in this section. For an overview, see the image below. Because most lung cancers cannot be cured with currently available therapeutic modalities, the appropriate application of skilled palliative care is an important part of the treatment of patients with non-small cell lung cancer.

• Surgery
  • Surgical resection remains the mainstay of treatment for all patients with stage I and II non-small cell lung cancer, that is those patients with no evidence of mediastinal disease or invasion of local organs. The role of surgery for stage III disease is controversial (see discussion below). Patients with completely resectable primary tumors (ie, T4 N0) have a much better prognosis than those with spread to ipsilateral mediastinal or subcarinal lymph nodes (ie, N2), signifying that spread beyond the primary tumor is associated with a poor prognosis. Patients with stage IIIB or IV tumors are almost never surgical candidates.
  • Lobectomy: The standard surgical approach remains a lobectomy, which helps preserve pulmonary function, while allowing a good resection. Hilar and other proximal tumors may require more extensive surgery, including a pneumonectomy, which carries significant operative mortality and long-term morbidity. In such patients, alternative approaches such as sleeve resection may be of value.⁹
  • Wedge resection/segmentectomy: Sublobar resections are used for patients with poor pulmonary reserve and are increasingly being used in conjunction with video-assisted thoracoscopic surgery (VATS). An older Lung Cancer Study Group trial of stage IA cancers randomized to standard lobectomy versus sublobar resections, suggested a much higher local recurrence rate (75%), with a near-significant trend towards an increased cancer-specific mortality of 50% (P =0.09).¹⁰ A retrospective SEER analysis, however, showed no difference in overall survival in patients older than 74 years. However, smaller single institution studies show good long-term survival in stage I patients treated with sublobar approaches. An ongoing Cancer and Leukemia Group B (CALGB) phase III trial randomizing patients to lobectomy or limited resection for small peripheral IA lesions is ongoing, and should provide more clarity in this area.
  • Video-assisted thoracoscopic surgery (VATS): This is a minimally invasive surgical modality being used for both diagnostic and therapeutic lung cancer surgery. It offers low perioperative morbidity and mortality as well as decreased pain and hospitalization. Patients appear to have similar recurrence rates, 5-year and long-term overall survival as compared to traditional open thoracotomies. This approach is also better tolerated in older populations.¹¹ Finally, patients treated with VATS appear to have fewer delays and dose reductions in adjuvant chemotherapy. Practice guidelines suggest that VATS is feasible as long as adequate resection is possible.^12,13
  • Mediastinal lymphadenectomy: The role of routine mediastinal lymphadenectomy versus lymph node sampling remains controversial. A large randomized trial comparing these modalities for patients with N0 or Hilar N1 disease is still in progress. The authors recommend that an adequate mediastinal lymphadenectomy should include exploration and removal of lymph nodes from stations 2R, 4R, 7, 8, and 9 for right sided cancers and stations 4L, 5, 6, 7, 8, and 9 for left sided cancers.¹⁴
  • Preoperative evaluation: This should include a careful assessment of resectability, cardiopulmonary reserve, and perioperative risk.
  • Pulmonary function tests: As a general guideline, most patients with a preoperative forced expiratory volume in one second of greater than 2.5 L are able to tolerate pneumonectomy. With a forced expiratory volume in one second of 1.1-2.4 L, a lobectomy is possible. With a forced expiratory volume in one second of less than 1 L, patients are not considered candidates for surgery. These factors are further modified by the presence of cardiac disease or other comorbid conditions.
  • Postoperative evaluation: Residual pulmonary function after surgical resection is estimated using pulmonary function tests and radionuclide lung scans.
  • Complications: The perioperative mortality rate is 6% for pneumonectomy, 3% for lobectomy, and 1% for segmentectomy. These rates reflect improvements in anesthesia and surgical techniques.
• Radiation therapy
  • In the treatment of stage I and stage II non-small cell lung cancer, radiation therapy alone is considered only when surgical resection is not possible because of limited pulmonary reserve or the presence of comorbidities.¹⁵
  • Radiation therapy alone as local therapy, in patients who are not surgical candidates, has been associated with 5-year cancer specific survival rates of 13-39% in early-stage non-small cell lung cancer (ie, T1 and T2 disease).¹⁶
  • This inferior survival reflects the poor functional status of these patients, as well as the likelihood of these patients actually having a higher stage, given the known limitations of clinical staging. Survival appears to be enhanced by the use of hyperfractionation schedules, such as continuous hyperfractionated accelerated radiotherapy (CHART) at 1.5 Gy 3 times a day for 12 days, as opposed to conventional radiation therapy at 60 Gy in 30 daily fractions. Overall survival at 4 years was 18% vs 12%.
  • Other techniques for nonoperative treatment for early stage lung cancers include stereotactic body radiotherapy (SBRT) that uses precise targeting of high-dose radiation to the tumor typically in 1-2 fractions, while minimizing toxicity to normal tissues. A large Japanese retrospective analysis showed that patients treated with SBRT at doses higher than 100 Gy had a local recurrence rate of 8.4%, and a 5-year overall survival of 70.8%.¹⁷ This is being studied in a randomized fashion by Radiation Therapy Oncology Group (RTOG). Patients best suited for SBRT include those with a peripheral node-negative tumor that is less than 5 cm, in whom definitive surgery is contraindicated.
  • Radiofrequency ablation (RFA) has also been used for inoperable patients who have peripheral tumors that are less than 3 cm in size, and occasionally in a palliative setting. In a single small nonrandomized prospective study, 2-year overall survival with stage I non-small cell lung cancer was 75% (45-92%). This may be an option for patients in whom both surgery as well as traditional external beam radiation therapy may be contraindicated.¹⁸
  • The role of adjuvant radiation therapy after resection of the primary tumor remains controversial.^19,20 Radiation therapy reduces local failures in completely resected (stages II and IIIA) non-small cell lung cancer but has not been shown to improve overall survival rates. In one study, 5-year overall survival was actually worse (30% vs 53%). A retrospective SEER analysis also showed that survival was lower for this population. A single phase III study using small fractions, with 3D treatment planning, showed a 5-year survival benefit in the radiation treatment arm (67% vs 48%). This finding has not been replicated; hence, at this time, postoperative radiation therapy for stage I and II lung cancer is reserved for positive margins, until further trials are conducted with modern radiation therapy planning and delivery.
• Combined chemoradiation therapy
  • The current standard of care in the management of good-risk (ie, Karnofsky performance score of 70-100, minimal weight loss) patients with locally advanced unresectable (stage IIIA) non-small cell lung cancer is combined-modality therapy consisting of platinum-based chemotherapy and radiation. This results in statistically significant improvement in both disease-free and overall survival rates compared with either modality used alone.^21,22
  • Randomized studies show longer survival in patients with unresectable stage III disease when treated with concurrent (rather than sequential) platinum-based chemotherapy and radiation therapy.^23,24 An RTOG study compared cisplatin/vinblastine either given concurrently with radiation therapy or followed by radiation therapy. The concurrent group showed better median survival as well as overall survival (17 vs 14.6 mo and 21% vs 12%, respectively).^25,26,27
  • Chemotherapy regimens that have been studied in combination with radiation therapy include cisplatin/vinblastine and cisplatin/etoposide (5-y survival of 15%).²³ In elderly patients or those with comborbidities and contraindications to cisplatin, weekly carboplatin/paclitaxel may be used, based on a phase II study that showed a median survival of 16.7 months.^28,29,30
  • Consolidation chemotherapy after chemoradiation had initially been shown to be beneficial in phase II studies, with docetaxel after chemoradiation with cisplatin/etoposide showing a median survival of 26 months, and 5-year survival of 29%. This regimen did not show improved survival in a phase III setting, and proved to be more toxic, hence, is no longer recommended outside a clinical trial setting.³¹
  • Chemoradiation followed by surgical resection has been studied given the high locoregional failure rate with chemoradiation alone.^32,20,33 Uncontrolled phase II studies suggested possible survival benefit from this approach, but a phase III study showed only a nonsignificant trend towards better 5-year overall survival (27% vs 20%) despite an improvement in progression-free survival. There was higher postoperative mortality in those patients undergoing surgical resection.
  • A recent European Organization for Research and Treatment of Cancer (EORTC) study failed to show any benefit of resection over radiation therapy after neoadjuvant chemotherapy in patients with stage IIIA (N2) disease.
• Systemic therapy: chemotherapy
• Only 30-35% of patients with non-small cell lung cancer present with sufficiently localized disease at diagnosis to attempt curative surgical resection (stages IA and IB, IIA and IIB, and IIIA). Approximately 50% of patients who undergo surgical resection experience local or systemic relapse; thus, approximately 80% of all patients with lung cancer are considered for chemotherapy at some point during the course of their illness.
• At present, chemotherapy alone has no role in potentially curative therapy for non-small cell lung cancer. Relapse rate after surgical resection of localized non-small cell lung cancer is high. Recent trials have shown a survival benefit with adjuvant chemotherapy (ie, chemotherapy given after surgery) in resected stage IIA, IIB, and IIIA non-small cell lung cancer.^32,34 (See discussion on stage I and II cancers below.)
• Two small, randomized trials have suggested that neoadjuvant chemotherapy (ie, chemotherapy given prior to surgery) prolongs survival in subjects with stage IIIA disease. Other similarly designed trials fail to confirm this. (See discussion below.) Chemotherapy may be considered as part of multimodality therapy for locally advanced non-small cell lung cancer and is used alone in the palliative treatment of stage IIIB non-small cell lung cancer (owing to malignant pleural effusion) and stage IV non-small cell lung cancer.
• In advanced non-small cell lung cancer, patients with good performance status (ie, 0-2 on the Zubrod or Eastern Cooperative Oncology Group scale), greater than 70% on Karnofsky scale (see Image 7), and less than 10% body weight loss are good candidates for chemotherapy. Large meta-analyses from 16 randomized trials showed a significant survival advantage to patients getting chemotherapy as opposed to best supportive care. One-year survival in the chemotherapy arm was 29% as opposed to 20% in those receiving supportive care alone. This survival benefit was present irrespective of age or histology. There appears to be no detriment in quality of life in the patients treated with chemotherapy, hence palliative chemotherapy should be offered to all patients who are willing and able to receive chemotherapy.^35,36
• Non-small cell lung cancer is only moderately sensitive to chemotherapy, with single-agent response rates in the range of 15% or better. Newer agents (eg, gemcitabine, pemetrexed, docetaxel, vinorelbine) have shown promising single-agent activity, with response rates from 20-25%. Multiple randomized, controlled trials and large meta-analyses all confirm the superiority of combination chemotherapy regimens upfront for advanced non-small cell lung cancer. Two drug combinations showed better response rate (26% vs 13%) as well as improved 1-year survival (35% vs 30%). Addition of a third cytotoxic drug increased toxicity with a modest improvement in response rate, but no survival benefit.³⁷ (See discussion on biologics below.) Hence, most first-line patients should be offered a chemotherapy doublet.
• Cisplatin has been the cornerstone of most combination regimens studied in advanced non-small cell lung cancer.³⁸ A recent meta-analysis of 16 trials comparing platinum-based regimens to nonplatinum agents, showed a statistically significant improved response rate as well as 1-year survival favoring cisplatin. A beneficial trend was noted with carboplatin-based combinations but this was not significant. Gastrointestinal toxicity was higher with cisplatin.³⁹ ASCO guidelines recommend that first-line treatment for non-small cell lung cancer should include a platinum combination. In younger patients, with a good performance status or in the adjuvant setting, cisplatin is preferred, but in older patients or those with significant comorbidities, carboplatin may be substituted. Some recent trials have studied nonplatinum combinations such as gemcitabine with a taxane, which have shown noninferiority, and may be an option for selected patients. (Also see newer chemotherapy combinations below.)
• Several randomized controlled trials have failed to show a clear superiority of one platinum-containing combination over another. A landmark ECOG trial comparing cisplatin-gemcitabine, cisplatin-paclitaxel, cisplatin-docetaxel, and carboplatin-paclitaxel, suggested similar overall response rates (approximately 19%), and median survival (7.9 mo). One- and 2-year overall survival was also similar at 33% and 11%, respectively. The cisplatin-gemcitabine did appear to have an increased progression free survival, compared to the standard treatment arm of cisplatin-paclitaxel (4.2 mo vs 3.4 mo), with increased renal toxicity. This finding was confirmed by 2 Italian and Japanese studies, which showed similar efficacy of these combinations as measured by response rates or survival. However, a meta-analysis comparing cisplatin-gemcitabine with other platinum-containing regimens suggested an improved median survival (9 vs 8.2 mo), and an absolute improvement in 1-year overall survival of 3.9% as compared to nongemcitabine combinations. This effect was not sustained when compared against other third-generation cisplatin combinations.⁴⁰
• For some time, non-small cell lung cancer histology was thought to not impact chemotherapy responsiveness. A recent phase III trial compared upfront cisplatin-pemetrexed to cisplatin-gemcitabine in stage III and IV non-small cell lung cancer showed similar response rates (30.6% vs 28.2%), median survival (10.3 mo each), and 2-year overall survival (18.9% vs 14%). These were statistically similar. However, in a preplanned subset analysis, patients with nonsquamous histology had a statistically better median survival with the cisplatin-pemetrexed combination: for adenocarcinoma (12.6 vs 10.9 mo), and large cell histology (10.4 vs 6.7 mo). In contrast, the patients with squamous cell histology did better with the cisplatin-gemcitabine combination (10.8 vs 9.4 mo). Cisplatin-pemetrexed is now the preferred combination for adenocarcinoma.⁴¹
• Selected patients with good responses to first-line chemotherapy, good performance status, and a long disease-free period between initial chemotherapy and relapse may be candidates for second-line chemotherapy. Docetaxel (Taxotere) and pemetrexed (Alimta) have been approved by the FDA in this clinical setting, but other drugs (eg, gemcitabine, vinorelbine), if not used in the first-line regimen, may result in similar palliation and clinical benefit. A phase III study published in 2009 compared immediate and delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small cell lung cancer and found a statistically significant improvement in progression-free survival when docetaxel was administered immediately after front-line gemcitabine plus carboplatin, without increasing toxicity or decreasing quality of life. The increase in overall survival was not statistically significant.⁴² Another phase III trial of pemetrexed versus docetaxel showed similar efficacy for both agents in recurrent non-small cell lung cancer when administered as single-agent chemotherapy in second-line settings. Response rates (9.1% vs 8.8%) and overall survival (8.3 mo vs 7.9 mo) were similar.⁴³
• Although platinum-based chemotherapy is currently standard of care in non-small cell lung cancer, recent data suggest that certain individual tumors may have inherent resistance to platinum compounds. Excision Repair Cross-Complementation Group 1 (ERCC1) is one such genetic abnormality and high levels of ERCC1 mRNA in tumor tissue have been associated with resistance to platinum. Holm et al found that, in patients receiving carboplatin and gemcitabine for inoperable non–small cell lung cancer, the expression of ERCC1 had different effects on survival in men and women. In a retrospective study in 163 patients, men whose tumors were ERCC1 negative survived significantly longer than men with ERCC1 -positive tumors (median survival, 11.8 mo vs 7.9 mo; P = .005). Conversely, ERCC1 status had no effect on survival in women.⁴⁴
• As with ERCC1, increased expression of Ribonucleotide Reductase subunit 1 (RRM1) has been associated with decreased response to gemcitabine and platinum.
• In future, therapy for non-small cell lung cancer may need to be tailored based on genetic characteristics of individual tumors. Gene expression profiling has been studied for accurate classification of histology of non-small cell lung cancer as well as prognostication, but this remains experimental.
• Systemic therapy: the biologics
• With the increased understanding of molecular abnormalities in lung cancer, recent research efforts have focused heavily on identifying molecular targets and using this knowledge to develop molecular-targeted therapies.
• One such abnormality, which is common in non-small cell lung cancer, is overexpression of the epidermal growth factor receptor (EGFR). Stimulation of the EGFR pathway leads to increased autophosphorylation of a tyrosine kinase pathway associated with EGFR. This leads to a series of intracellular events culminating in increased mitotic and growth potential, increased ability to metastasize, and increased angiogenesis (new blood vessel formation) in the cancer cells. Cancers overexpressing EGFR have been shown to have increased resistance to therapy, increased metastatic potential, and poorer prognoses.
• Gefitinib (Iressa) represents a class of EGFR tyrosine kinase inhibitors (TKI) that act intracellularly to block activation of EGFR pathway.^45,46 Two large phase II trials led to the expedited approval of gefitinib in the United States as a third-line therapy. However, a large phase III randomized trial compared gefitinib to placebo in patients who had progressed following first-line chemotherapy. There was no significant improvement in median survival (5.6 vs 5.1 mo) overall and also in the adenocarcinoma subset (6.3 vs 5.4 mo). Planned subset analyses in those who have never been smokers and those of Asian ethnicity showed significantly longer survival (8.9 vs 6.1 mo and 9.5 vs 5.5 mo) as compared to placebo. The INTEREST trial studied gefitinib in comparison to docetaxel in the second-line setting, which showed no significant difference in survival (7.6 vs 8 mo). Based on these data, gefitinib is no longer available in the United States to new patients. In a recent large phase III study in Asian populations, who had adenocarcinoma and had never smoked or were former light smokers (none in last 15 years), gefitinib was compared to carboplatin-paclitaxel in the first-line setting. Gefitinib had a higher response rate (43% vs 32%), with similar median survival (18.6 vs 17.3 mo). Patients with EGFR mutations had a significantly better progression-free survival in the gefitinib arm.⁴⁷
• A second EGFR TKI, erlotinib (Tarceva), improved survival rates compared to placebo in the second- and third-line setting.^48,49 Erlotinib demonstrated improved response rates (8% vs <1%), and overall survival (6.7 vs 4.6 mo). This led to the FDA approval of erlotinib in the second-line setting. Similar to the experience with gefitinib, no benefit was seen when erlotinib was combined with chemotherapy. Earlier studies also showed better response rates and survival with females, Asian persons, nonsmokers, particularly those with adenocarcinoma histology especially bronchioalveolar cancer, as was seen with gefitinib.
• Cetuximab, a monoclonal antibody that binds the EGFR receptor is used in colorectal cancer as well as squamous cell cancer of the head and neck. It was studied in the first-line setting, in combination with cisplatin-vinorelbine, compared to cisplatin-vinorelbine alone, in patients with non-small cell lung cancer that expressed EGFR by immuno-histochemistry.⁵⁰ The chemotherapy was given in combination with cetuximab for up to 6 cycles, and in responding patients, the cetuximab was continued until progression. Patients receiving cetuximab had an increased response rate (36% vs 29%), and improved median survival (11.3 vs 10.1 mo). Whites appeared to benefit more than Asian persons who seemed to do worse with this regimen. K -ras mutations have been shown to demonstrate resistance to cetuximab in colon cancer, and this probably holds true for non-small cell lung cancer as well. Further studies on these molecular markers are ongoing, and are awaited to determine optimal strategies for the use of these agents.
• A recent ECOG study has shown that addition of an anti-angiogenesis agent bevacizumab (Avastin) to standard first-line carboplatin-paclitaxel resulted in significant prolongation of survival. Bevacizumab was continued in patients who appeared to respond to 4-6 cycles of chemotherapy. The median overall survival was improved (12.3-10.3 mo), as was the response rate (35% vs 15%) compared to chemotherapy alone. Patients with squamous cell histology, brain metastases, clinically significant hemoptysis and ECOG performance status of greater than 1 were excluded. Despite increased hemorrhagic complications and treatment-related deaths, bevacizumab has now been approved for use in this setting in combination with chemotherapy.⁵¹ Bevacizumab has also been studied in combination with cisplatin-gemcitabine as first-line therapy for nonsquamous non-small cell lung cancer, with improved response rates (20.1% vs 34.1%) with modest improvement in progression-free survival (6.7 vs 6.1 mo). Overall survival was not different.⁵²
• In a phase II trial, Karp et al studied the effect of combined anti-insulinlike growth factor 1 receptor antibody CP-751,871 (figitumumab) with paclitaxel and carboplatin in advanced treatment-naive non-small-cell lung cancer (NSCLC). Patients were randomized (2:1) to receive paclitaxel 200 mg/m², carboplatin (area under the concentration-time curve [AUC] of 6), and CP-751,871 10-20 mg/kg (ie, PCI(10), PCI(20)) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to 6 cycles. In this phase II trial, PCI(20)/PC hazard ratio for progression-free survival was 0.8-0.56, concluding PCI(20) to be safe and effective in NSCLC. A randomized, open-label, phase III trial is currently underway.⁵³

Stage-based management

• Stage I (T1N0M0 and T2N0M0)
  • Surgery is the treatment of choice for stage I non-small cell lung cancer. A careful preoperative assessment of residual pulmonary reserve should be carried out prior to surgical planning. Although lobectomy is generally considered to be optimum procedure, those with limited pulmonary reserve may be considered for more limited resection with either a segmental or a wedge resection. The risk of local recurrence is higher with limited resection but no adverse effect on overall survival was reported in a randomized trial by the Lung Cancer Study Group. VATS may be used for surgical resection, given the apparently similar resection capability, and decreased postoperative morbidity. Patients with insufficient pulmonary reserve to undergo a resection may be treated with radiation therapy alone with curative intent. Retrospective data report a 5-year survival ranging from 10-25% with radiation therapy alone in this setting. Selected patients may be candidates for either stereotactic body radiotherapy or radiofrequency ablation for isolated lesions.
  • The role of postoperative radiation has been explored and a meta-analysis of 9 randomized trials revealed a reduction in overall survival with postoperative radiation therapy in stage I and II non-small cell lung cancer. However, it remains to be seen that with use of modern radiation techniques with better definition of target volume and cardiac sparing could alter these outcomes.
  • Adjuvant chemotherapy has been extensively explored in non-small cell lung cancer.⁵⁴ A recent meta-analyses concluded that adjuvant cisplatin-based therapy improved survival in resected stage IB, II, and III non-small cell lung cancer. The absolute benefit in survival at 5 years was 6.9%, but in subset analyses, the benefit in stage IB was not statistically significant. No impact of age, sex, histology, or type of surgery was noted. The CALGB 9633 study randomized resected stage IB patients to 4 cycles of carboplatin-paclitaxel versus observation. This study initially showed improved overall survival at 4 years (71% vs 59%), but a longer term follow-up at 74 months showed no change in overall survival, except in patients with a tumor size greater than 4 cm.⁵⁵ This contrasted with the results of a Canadian study that showed significantly improved 5-year survival for stage IB and II patients treated with adjuvant cisplatin-vinorelbine for 4 cycles. Patients with resected stage IB non-small cell lung cancer should, therefore, be counseled about risks and benefits of adjuvant chemotherapy and may be offered either 4 cycles of platinum-based doublet chemotherapy, preferably cisplatin or observation.
• Stage II (T1N1M0, T2N1M0, T3N0M0)
  • Surgical resection is the treatment of choice, except for those who are not surgical candidates because of comorbid conditions or poor pulmonary reserve. A long-term survival of 10-25% has been reported in patients with radiation therapy alone delivered with curative intent. In such cases, however, the dose of radiation therapy should be approximately 60 Gy with careful planning to define tumor volume and avoid critical structures. Frequently a cone-down boost is used to enhance local control. Patient with resected stage II disease are candidates for platinum-based adjuvant chemotherapy (see discussion above) and should be offered 4 cycles of platinum-based adjuvant chemotherapy.
• Stage IIIA (T1N2M0, T2N2M0, T3N1M0, T3N2M0)
  • The management of stage IIIA non-small cell lung cancer is quite controversial, and surgical resection, chemotherapy, radiation therapy, or a combination of any of these modalities may be the optimal choice based on the clinical situation. Overall 5-year survival of stage IIIA (N2) ranges from 10-15%. Stage IIIA has been an area of active research due to poor long-term result because of low resectability rates and very few patients (5-10%) who achieve long-term benefit with radiation therapy alone.
  • Patients who have mediastinal nodes involved with non-small cell lung cancer (N2 or N3 stage) have poor results from surgery, hence should be considered for definitive chemoradiation therapy. (See discussion above.) Cisplatin-based combinations (eg, with etoposide) are preferred, with carboplatin an acceptable alternative in patients with contraindications. Radiation is usually given in daily fractions for a total of 60 Gy. A cone-down boost may be useful. Hyperfractionation schedules appear to be better, but are not widely available. There does not appear to be significant survival benefit for further chemotherapy or surgery in patients treated upfront with chemoradiation.
  • A recently reported large randomized trial conducted by EORTC compared surgery versus radiation therapy following neoadjuvant chemotherapy and found no significant difference between the 2 approaches in stage IIIA N2 disease. Neoadjuvant chemotherapy followed by surgery may, however, be considered for younger patients with good performance status with stage IIIA disease.
  • Patients with stage III (T3-4, N1) disease of the superior sulcus are usually treated with neoadjuvant chemotherapy followed by surgical resection, since 2-year survival in this group is 50-70%.
  • Patient with stage IIIA (T3, N1) disease who are candidates for surgical resection should be offered adjuvant chemotherapy after a definitive surgical resection, based on the results of IALT (International Adjuvant Lung Trial) and meta-analysis of adjuvant chemotherapy trials showing a hazard ratio of 0.87 with adjuvant chemotherapy. These patients should also undergo a mediastinal node dissection. In patients with positive margins, radiation therapy may be considered concurrently with chemotherapy. Several retrospective series have suggested that postoperative radiation therapy may improve local control in those with involved mediastinal nodes. Prospective trials also have revealed similar results and have been conflicting with regard to reduction in local recurrence with postoperative radiation therapy. A meta-analysis of 9 randomized trials of postoperative radiation therapy did not result in survival benefit in the entire group as well as the subgroup with N2 disease.
  • Neoadjuvant chemotherapy: Two small reports have shown improvement in disease-free and overall survival rates with neoadjuvant cisplatin-based chemotherapy for stage IIIA non-small cell lung cancer; this approach may be considered in patients with good performance status. This approach may also be employed for patients who have tumors that are too large for a radiation port, prior to definitive chemoradiation.
• Stage IIIB (T4 any N M0 or any TN3M0)
  • Patients with satellite lesions (T4 N0-1) should undergo a surgical resection if possible, followed by adjuvant chemotherapy.
  • All other patients with stage IIIB disease are usually not candidates for surgical resection and are best managed with chemotherapy, combination of chemotherapy and radiation therapy, or radiation therapy alone, depending on extent of disease, sites of involvement, and performance status of the patient. Patients who have malignant pleural effusion are not candidates for radiation therapy and are managed as stage IV (see below).
  • A meta-analysis of 10 randomized trials of combined chemoradiation therapy revealed a 10% reduction in risk of death with combined modality therapy compared with radiation alone. It appears that in appropriate candidates (with good performance status), chemotherapy given concurrently with radiation results in superior survival compared to chemotherapy followed by radiation therapy. Patient with stage IIIB non-small cell lung cancer and poor performance status are not good candidates for chemotherapy or combined modality approach. These patients may benefit from radiation therapy alone to palliate the symptoms of shortness of breath, cough, and hemoptysis. Patients with invasive airway obstruction may be candidates for palliative endobronchial curettage or stenting to relieve obstructive atelectasis and dyspnea.
• Stage IV (distant metastases)
• Patients with advanced non-small cell lung cancer should be evaluated for the presence of distant metastases. Patients with solitary brain lesions may benefit from a surgical resection, or stereotactic radiosurgery, if their primary disease is well controlled. Isolated adrenal masses should be resected, since many adrenal masses are benign and even oligometastatic adrenal disease can occasionally be well controlled.
• Patients with isolated synchronous nodules (either in same or opposite lung) should be treated as 2 separate primaries. These patients may need PET scanning to identify occult metastases or serial scans prior to definitive surgical resection that may be counter-productive.
• In first-line systemic therapy for stage IV disease, cisplatin-based regimens have provided clear evidence of improved median survival and reductions in risk of death. Patients with good performance status should be offered chemotherapy with a platinum-based combination. Older patients (>70 y) or those with contraindications may be treated with a carboplatin-based regimen, such as carboplatin-paclitaxel.
• Younger patients (<70 y) with nonsquamous histology may be candidates for treatment with cisplatin-pemetrexed, which appears to be somewhat better than cisplatin-gemcitabine. Patients with nonsquamous histology, absence of cranial metastases and no hemoptysis may be candidates for treatment with bevacizumab, which has been studied in combination with carboplatin-paclitaxel and cisplatin-gemcitabine. Antiangiogenic therapy is very expensive and potentially toxic even in carefully selected patients, hence a detailed discussion with patients about its modest benefits versus the risks and costs is important.
• Two drug combinations have been found to be superior to single-agent treatment and no therapeutic advantage is obtained with the use of 3 drugs. No additional benefit is obtained with more than 4 cycles of chemotherapy. There is no clear survival benefit from maintenance non-cross resistant chemotherapy, though this is being studied with agents such as pemetrexed.
• Small-molecule epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors such as gefitinib and erlotinib may benefit nonsmokers with adenocarcinomas, particularly bronchio-alveolar carcinoma, especially those females of Asian origin. In such patients, it may be helpful to evaluate for EGFR mutations and use these agents first line.
• Similarly, patients with EGFR expression and absence of K -ras mutations may be considered for the addition of cetuximab to first-line chemotherapy. The combination of anti-VEGF agents such as bevacizumab with anti-EGFR antibodies appears to detrimental in other settings, and its use in non-small cell lung cancer should be avoided.
• Patients with progressive disease and good performance status may be candidates for treatment with single agent cytotoxic drugs such as docetaxel, pemetrexed, or gemcitabine, if not exposed to these drugs in the first-line setting. Selected patients can also be treated with erlotinib, though this is typically used in the third-line setting.
• Patients with ECOG/Zubrod performance scores greater than 2 should be considered for palliative care, focused on symptom control. These patients should be recommended enrollment in hospice care programs.

Consultations

The management of lung cancer is best achieved with a multidisciplinary approach; therefore, after diagnosis, consultations should be sought from the following specialists:

• Thoracic surgeon
• Radiation oncologist
• Medical oncologist
• Pulmonologist
• Social worker

Activity

The activity level as measured by a performance status scale (eg, Zubrod, Karnofsky) is an important prognostic factor. Patients should be encouraged to remain active during and after treatment for lung cancer. A declining activity level usually signifies progressive or recurrent disease but also may be due to adverse effects of treatment.

Medication

Unresectable non-small cell lung cancer is treated with chemotherapy or a combination of chemotherapy and radiation therapy. Aggressive antiemetic support and growth-factor support, when appropriate, are other integral parts of medical treatment of affected patients. Antibiotics are commonly required for treatment of infectious complications but are not discussed in this article. Aggressive antiemetic support to prevent, not treat, nausea and vomiting is essential because of the highly emetogenic potential of chemotherapy drugs and the doses used in the treatment of non-small cell lung cancer. This holds especially true for platinum-based chemotherapeutic regimens. The most common and effective agents are corticosteroids and the serotonin receptor antagonists, which include ondansetron (Zofran), granisetron (Kytril), and dolasetron (Anzemet).

Antiemetic agents

Antiemetic agents are useful in the treatment of symptomatic nausea caused by chemotherapy.

Ondansetron (Zofran)

Blocks serotonin 5-HT3 receptor antagonists. Not clear whether effect is mediated centrally, peripherally, or both. Indicated in prevention of chemotherapy-induced nausea and vomiting.

Granisetron (Kytril)

Blocks serotonin 5-HT3 receptor antagonists. Not clear whether effect is mediated centrally, peripherally, or both. Indicated in prevention of chemotherapy-induced nausea and vomiting.

Dolasetron (Anzemet)

Blocks serotonin 5-HT3 receptor antagonists. Not clear whether effect is mediated centrally, peripherally, or both. Indicated in prevention of chemotherapy-induced nausea and vomiting.

Palonosetron (Aloxi)

Selective 5-HT3 receptor antagonist with long half-life (40 h). Indicated for prevention and treatment of chemotherapy-induced nausea and vomiting. Blocks 5-HT3 receptors peripherally and centrally in chemoreceptor trigger zone.

Dexamethasone (Decadron)

Synthetic adrenocortical steroid with multiple indications. Widely used in prevention of nausea and vomiting caused by highly emetogenic agents (eg, cisplatin) in combination with serotonin receptor antagonists.

Antineoplastic agents

These drugs are used either to prolong survival or to palliate symptoms in advanced or unresectable lung cancer.

Carboplatin (Paraplatin)

Similar mechanism of action as cisplatin. Approved for ovarian cancer but used commonly in squamous cell carcinoma of head, neck, cervix, and lungs. Main advantages over cisplatin include less nephrotoxicity and ototoxicity (not requiring extensive prehydration) and reduced likelihood of inducing nausea and vomiting. More likely to induce myelotoxicity.

Vinorelbine (Navelbine)

Semisynthetic vinca alkaloid that inhibits tubulin polymerization during G2 phase of cell division, thereby inhibiting mitosis. Used alone or in combination with cisplatin for stage IV NSCLC.

Paclitaxel (Taxol)

Naturally occurring chemical derived from Pacific yew tree (Taxus brevifolia). Inhibits tubulin depolymerization in spindle during cell division.

Gemcitabine (Gemzar)

Antimetabolite that acts as inhibitor of DNA synthesis. Cell-cycle specific for S phase.

Docetaxel (Taxotere)

Semisynthetic taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking disassembly of microtubules, thereby preventing cancer cell division, leading to cell death.

Cisplatin (Platinol)

Alkylating agent that causes intrastrand and interstrand cross-linking of DNA, leading to strand breakage. Has very broad range of antitumor activity and is approved for use in testicular, ovarian, and transitional cell carcinomas. Forms basis of currently available approved combination chemotherapy regimens for NSCLC. Administer as single-dose IV infusion or in divided doses over several days; can be repeated only after complete hematologic recovery; cycles are typically separated by 3-4 wk.

Erlotinib (Tarceva)

Pharmacologically classified as a HER1/EGFR tyrosine kinase inhibitor. EGFR is expressed on the cell surface of normal cells and cancer cells. Indicated for locally advanced or metastatic NSCLC after failure of at least 1 previous chemotherapy regimen.

Pemetrexed disodium (Alimta)

Disrupts folate-dependent metabolic processes essential for cell replication. Specifically inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in de novo biosynthesis of thymidine and purine nucleotides.
Also indicated for maintenance treatment if disease has not progressed after 4 cycles of platinum-based first-line chemotherapy.

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