General Information

Cellular Classification

Stage Information

Treatment Option Overview

Occult Non-small Cell Lung Cancer

Stage 0 Non-small Cell Lung Cancer

Stage I Non-small Cell Lung Cancer

Stage II Non-small Cell Lung Cancer

Stage IIIA Non-small Cell Lung Cancer

Stage IIIB Non-small Cell Lung Cancer

Stage IV Non-small Cell Lung Cancer

Recurrent Non-small Cell Lung Cancer

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GENERAL INFORMATION

Non-small cell lung cancer (NSCLC) is a heterogeneous aggregate of at least 3 distinct histologies of lung cancer including epidermoid or squamous carcinoma, adenocarcinoma, and large cell carcinoma. These histologies are often classified together because, when localized, all have the potential for cure with surgical resection. Systemic chemotherapy can produce objective partial responses and palliation of symptoms for short durations in patients with advanced disease. Local control can be achieved with radiation in a large number of patients with unresectable disease, but cure is seen only in a small minority of patients.

At diagnosis, patients with NSCLC can be divided into 3 groups that reflect the extent of disease and treatment approach:

The first group of patients has tumors that are surgically resectable (generally stages I and II). This is the group with the best prognosis, depending on a variety of tumor and host factors. Patients with resectable disease who have medical contraindications to surgery can be considered for curative radiation therapy.

The second group includes patients with either locally (T3-T4) or regionally (N2-N3) advanced lung cancer who have a diverse natural history. This group is treated with radiation therapy or, more commonly, with radiation therapy in combination with chemotherapy or other therapy modalities. Selected patients with T3 or N2 disease can be treated effectively with surgical resection alone.

The final group of patients have distant metastases (M1) found at the time of diagnosis. This group can be treated with radiation therapy or chemotherapy for palliation of symptoms from the primary tumor. Patients with good performance status, women, and patients with distant metastases confined to a single site appear to live longer than others.[1] Cisplatin-based chemotherapy has been associated with short-term palliation of symptoms and a small survival advantage. Currently no single chemotherapy regimen can be recommended for routine use.

For patients with operable disease, prognosis is adversely influenced by the presence of pulmonary symptoms, large tumor size (>3 centimeters), and presence of the erbB-2 oncoprotein.[1-6] Other factors that have been identified as adverse prognostic factors in some series of patients with resectable non-small cell lung cancer include mutation of the K-ras gene, vascular invasion, and increased numbers of blood vessels in the tumor specimen.[3,7,8]

For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of greater than 10%. In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy.[9]

Since treatment is not satisfactory for almost all patients with NSCLC, with the possible exception of a subset of patients with pathologic stage I (T1, N0, M0) disease treated surgically, eligible patients should be considered for clinical trials.

References:

1. Albain KS, Crowley JJ, LeBlanc M, et al.: Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. Journal of Clinical Oncology 9(9): 1618-1626, 1991.
2. Macchiarini P, Fontanini G, Hardin MJ, et al.: Blood vessel invasion by tumor cells predicts recurrence in completely resected T1 N0 M0 non-small-cell lung cancer. Journal of Thoracic and Cardiovascular Surgery 106(1): 80-89, 1993.
3. Harpole DH, Herndon JE, Wolfe WG, et al.: A prognostic model of recurrence and death in stage I non-small cell lung cancer utilizing presentation, histopathology, and oncoprotein expression. Cancer Research 55(1): 51-56, 1995.
4. Ichinose Y, Yano T, Asoh H, et al.: Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer: an analysis in each pathologic stage. Journal of Thoracic and Cardiovascular Surgery 110(3): 601-605, 1995.
5. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. Journal of Thoracic and Cardiovascular Surgery 109(1): 120-129, 1995.
6. Strauss GM, Kwiatkowski DJ, Harpole DH, et al.: Molecular and pathologic markers in stage I non-small-cell carcinoma of the lung. Journal of Clinical Oncology 13(5): 1265-1279, 1995.
7. Slebos RJ, Kibbelaar RE, Dalesio O, et al.: K-RAS oncogene activation as a prognostic marker in adenocarcinoma of the lung. New England Journal of Medicine 323(9): 561-565, 1990.
8. Fontanini G, Bigini D, Vignati S, et al.: Microvessel count predicts metastatic disease and survival in non-small cell lung cancer. Journal of Pathology 177: 57-63, 1995.
9. Earle CC, Tsai JS, Gelber RD, et al.: Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. Journal of Clinical Oncology 19(4): 1064-1070, 2001.

CELLULAR CLASSIFICATION

Bronchoalveolar carcinoma represents 10% to 25% of adenocarcinomas and sometimes has a distinct presentation and biologic behavior.[3-5] Bronchoalveolar cancer may present as a more diffuse lesion than other types of cancer; 30% to 40% of patients undergoing an attempt at surgical resection present with an infiltrate on their chest radiograph. Bronchoalveolar cancer is more common in women and in patients who do not smoke cigarettes than other histologic types of lung cancer.

Histologic classification of non-small cell lung cancer:

• squamous cell (epidermoid) carcinoma
  • spindle cell variant
• adenocarcinoma
  • acinar
  • papillary
  • bronchoalveolar [4,5]
  • solid tumor with mucin
• large cell carcinoma
  • giant cell
  • clear cell
• adenosquamous carcinoma
• undifferentiated carcinoma

References:

1. Kreyberg L, Liebow AA, Uehlinger EA: International Histologic Classification of Tumours: No. 1. Histological Typing of Lung Tumours. Geneva: World Health Organization, 2nd ed., 1981.
2. Thomas P, Rubinstein L: Cancer recurrence after resection: T1 N0 non-small cell lung cancer: Lung Cancer Study Group. Annals of Thoracic Surgery 49(2): 242-246, 1990.
3. Harpole DH, Bigelow C, Young WG, et al.: Alveolar cell carcinoma of the lung: a retrospective analysis of 205 patients. Annals of Thoracic Surgery 46: 502-507, 1988.
4. Grover FL, Piantadosi S: Recurrence and survival following resection of bronchioloalveolar carcinoma of the lung: the Lung Cancer Study Group experience. Annals of Surgery 209(6): 779-790, 1989.
5. Daly RC, Trastek VF, Pairolero PC, et al.: Bronchoalveolar carcinoma: factors affecting survival. Annals of Thoracic Surgery 51(3): 368-377, 1991.

STAGE INFORMATION

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical (physical examination, radiologic, and laboratory studies) and pathologic (biopsy of lymph nodes, bronchoscopy, mediastinoscopy, or anterior mediastinotomy) factors.[1] The distinction between clinical stage and pathologic stage should be considered when evaluating reports of survival outcome. Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy. The Radiology Diagnostic Oncology Group reported that the sensitivity and specificity of computed tomographic (CT) scanning is only 52% and 69%, respectively.[2] Magnetic resonance imaging does not appear to improve the accuracy of staging.[2] Early evaluation of the role of positron emission tomography (PET) suggests that the combination of CT and PET may have greater sensitivity and specificity than CT alone.[3] A report evaluating the staging of 1,400 patients undergoing tumor resection found that clinical staging by radiologic studies accurately assessed the T stage in 78% of patients and the N stage in only 47% of patients. Errors in clinical staging were equally divided between overstaging and understaging.[4]

The Revised International Staging System for Lung Cancer

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[6]

TNM definitions

TX: Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1: A tumor that is 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, and without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)*
T2: A tumor with any of the following features of size or extent: More than 3 cm in greatest dimension Involves the main bronchus, 2 cm or more distal to the carina Invades the visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung
T3: A tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung
T4: A tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or separate tumor nodules in the same lobe; or tumor with a malignant pleural effusion **

**Note: Most pleural effusions associated with lung cancer are due to tumor. However, there are a few patients in whom multiple cytopathologic examinations of pleural fluid are negative for tumor. In these cases, fluid is nonbloody and is not an exudate. When these elements and clinical judgement dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be staged as T1, T2, or T3.

Regional lymph nodes (N)

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes including involvement by direct extension of the primary tumor
N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis present

Specify sites according to the following notations:

        BRA = brain             EYE = eye                HEP = hepatic
        LYM = lymph nodes       MAR = bone marrow        OSS = osseous
        OTH = other             OVR = ovary              PER = peritoneal
        PLE = pleura            PUL = pulmonary          SKI = skin

AJCC stage groupings

Occult carcinoma

TX, N0, M0

Stage 0

Tis, N0, M0

Stage IA

T1, N0, M0

Stage IB

T2, N0, M0

Stage IIA

T1, N1, M0

Stage IIB

T2, N1, M0
T3, N0, M0

Stage IIIA

T1, N2, M0
T2, N2, M0
T3, N1, M0
T3, N2, M0

Stage IIIB

Any T, N3, M0
T4, Any N, M0

Stage IV

Any T, Any N, M1

References:

1. Ginsberg RJ: Invasive and noninvasive techniques of staging in potentially operable lung cancer. Seminars in Surgical Oncology 6(5): 244-247, 1990.
2. Webb WR, Gatsonis C, Zerhouni EA, et al.: CT and MR imaging in staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic Oncology Group. Radiology 178(3): 705-713, 1991.
3. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al.: Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. Journal of Clinical Oncology 16(6): 2142-2149, 1998.
4. Bulzebruck H, Bopp R, Drings P, et al.: New aspects in the staging of lung cancer: prospective validation of the International Union Against Cancer TNM classification. Cancer 70(5): 1102-1110, 1992.
5. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111(6): 1710-1717, 1997.
6. Lung. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 127-137.

TREATMENT OPTION OVERVIEW

Current areas under evaluation include combining local (surgery), regional (radiation therapy), and systemic (chemotherapy and immunotherapy) treatments and developing more effective systemic therapy. Several new agents, including paclitaxel (Taxol), docetaxel (Taxotere), topotecan, irinotecan, vinorelbine, and gemcitabine have been shown to be active in the treatment of advanced NSCLC. Chemoprevention of second primary cancers of the upper aerodigestive tract is also under clinical evaluation in patients with early-stage lung cancer.[5]

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References:

1. Souquet PJ, Chauvin F, Boissel JP, et al.: Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 342(8862): 19-21, 1993.
2. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. British Medical Journal 311(7010): 899-909, 1995.
3. Hardy JR, Noble T, Smith IE: Symptom relief with moderate dose chemotherapy (mitomycin-C, vinblastine and cisplatin) in advanced non-small cell lung cancer. British Journal of Cancer 60(5): 764-766, 1989.
4. Ellis PA, Smith IE, Hardy JR, et al.: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. British Journal of Cancer 71(2): 366-370, 1995.
5. Pastorino U, Infante M, Maioli M, et al.: Adjuvant treatment of stage I lung cancer with high-dose vitamin A. Journal of Clinical Oncology 11(7): 1216-1222, 1993.

OCCULT NON-SMALL CELL LUNG CANCER

TX, N0, M0

STAGE 0 NON-SMALL CELL LUNG CANCER

Tis, N0, M0

Standard treatment options:

1. Surgical resection using the least extensive technique possible
(segmentectomy or wedge resection) to preserve maximum normal pulmonary tissue since these patients are at high risk for second lung cancers.

2. Endoscopic photodynamic therapy.[2,3]

References:

1. Woolner LB, Fontana RS, Cortese DA, et al.: Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clinic Proceedings 59(7): 453-466, 1984.
2. Furuse K, Fukuoka M, Kato H, et al.: A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. Journal of Clinical Oncology 11(10): 1852-1857, 1993.
3. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102(5): 1319-1322, 1992.

STAGE I NON-SMALL CELL LUNG CANCER

T1, N0, M0 or T2, N0, M0

Another study of stage I patients showed that those treated with wedge or segment resections had a local recurrence rate of 50% (31 of 62) despite having undergone complete resections.[4] Exercise testing may aid in the selection of patients with impaired pulmonary function who can tolerate lung resection.[5] The availability of video-assisted thoracoscopic wedge resection permits limited resections in patients with poor pulmonary function who are not usually considered candidates for lobectomy.[6]

Patients with inoperable stage I disease and with sufficient pulmonary reserve may be considered for radiation therapy with curative intent. In a single report of patients older than 70 years of age who had resectable lesions smaller than 4 centimeters but who had medically inoperable disease or who refused surgery, survival at 5 years following radiation therapy with curative intent was comparable to a historical control group of patients of similar age resected with curative intent.[7] In the 2 largest retrospective radiation therapy series, patients with inoperable disease treated with definitive radiation therapy achieved 5-year survival rates of 10% and 27%.[8,9] Both series found that patients with T1, N0 tumors had better outcomes, with 5-year survival rates of 60% and 32% in this subgroup.

Primary radiation therapy should consist of approximately 6,000 cGy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation. A boost to the cone-down field of the primary tumor is frequently used to further enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results and requires the use of a simulator.

Many patients treated surgically subsequently develop regional or distant metastases.[10] Therefore, patients should be considered for entry into clinical trials evaluating adjuvant treatment with chemotherapy or radiation therapy following surgery. A meta-analysis of 9 randomized trials evaluating postoperative radiation versus surgery alone showed a 7% reduction in overall survival with adjuvant radiation in patients with stage I or II disease.[11][Level of evidence: 1iiA] It will be important to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals. Trials of adjuvant chemotherapy regimens have failed to demonstrate a consistent benefit.

In the Lung Cancer Study Group trial of 907 stage T1, N0 resected patients, the rate of nonpulmonary second cancers was 1.8% per year and 1.6% per year for new lung cancers.[12] Others have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.[4] A randomized trial of vitamin A versus observation in patients with resected stage I disease showed a trend toward decreased second primary cancers in the vitamin A arm with no difference in overall survival rates.[13] Smokers who undergo complete resection of stage I NSCLC are also at risk for second malignant tumors.

An intergroup trial evaluated the role of isotretinoin in the chemoprevention of second cancers in patients with resected stage I NSCLC: 1,116 patients were randomly assigned to receive isotretinoin (30 mg/day) for 3 years or placebo.[14][Level of evidence: 1iiA] (Refer to the PDQ summary on Prevention of Lung Cancer for more information.) After a median follow-up of 3.5 years, there were no differences between the arms with respect to time-to-development of second primary tumors, disease recurrence, or survival.

Standard treatment options:

1. Lobectomy or segmental, wedge, or sleeve resection as appropriate.

2. Radiation therapy with curative intent (for potentially resectable patients
who have medical contraindications to surgery).

3. Clinical trials of adjuvant chemotherapy following resection.[15,16]

4. Adjuvant chemoprevention trials.[13,14,17]

5. Endoscopic photodynamic therapy (under clinical evaluation in highly
selected T1, N0, M0 patients).[18]

References:

1. Ginsberg RJ, Hill LD, Eagan RT, et al.: Modern thirty-day operative mortality for surgical resections in lung cancer. Journal of Thoracic and Cardiovascular Surgery 86(5): 654-658, 1983.
2. Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Annals of Thoracic Surgery 60(5): 615-623, 1995.
3. Warren WH, Faber LP: Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Journal of Thoracic and Cardiovascular Surgery 107(4): 1087-1094, 1994.
4. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. Journal of Thoracic and Cardiovascular Surgery 109(1): 120-129, 1995.
5. Morice RC, Peters EJ, Ryan MB, et al.: Exercise testing in the evaluation of patients at high risk for complications from lung resection. Chest 101(2): 356-361, 1992.
6. Shennib HA, Landreneau R, Mulder DS, et al.: Video-assisted thoracoscopic wedge resection of T1 lung cancer in high-risk patients. Annals of Surgery 218(4): 555-560, 1993.
7. Noordijk EM, Clement EP, Hermans J, et al.: Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiotherapy and Oncology 13(2): 83-89, 1988.
8. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. International Journal of Radiation Oncology, Biology, Physics 24(1): 3-9, 1992.
9. Gauden S, Ramsay J, Tripcony L: The curative treatment by radiotherapy alone of stage I non-small cell carcinoma of the lung. Chest 108(5): 1278-1282, 1995.
10. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. Journal of Thoracic and Cardiovascular Surgery 109(1): 120-129, 1995.
11. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 352(9124): 257-263, 1998.
12. Thomas P, Rubinstein L: Cancer recurrence after resection: T1 N0 non-small cell lung cancer: Lung Cancer Study Group. Annals of Thoracic Surgery 49(2): 242-246, 1990.
13. Pastorino U, Infante M, Maioli M, et al.: Adjuvant treatment of stage I lung cancer with high-dose vitamin A. Journal of Clinical Oncology 11(7): 1216-1222, 1993.
14. Lippman SM, Lee JJ, Karp DD, et al.: Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. Journal of the National Cancer Institute 93(8): 605-618, 2001.
15. Feld R, Rubinstein L, Thomas PA, et al.: Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small-cell lung cancer. Journal of the National Cancer Institute 85(4): 299-306, 1993.
16. Niiranen A, Niitamo-Korhonen S, Kouri M, et al.: Adjuvant chemotherapy after radical surgery for non-small-cell lung cancer: a randomized study. Journal of Clinical Oncology 10(12): 1927-1932, 1992.
17. Karp DD, Eastern Cooperative Oncology Group: Phase III Randomized Chemoprevention Study of Selenium in Participants With Previously Resected Stage I Non-Small Cell Lung Cancer (Summary Last Modified 01/2002), E-5597, clinical trial, active, 10/06/2000.
18. Furuse K, Fukuoka M, Kato H, et al.: A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. Journal of Clinical Oncology 11(10): 1852-1857, 1993.

STAGE II NON-SMALL CELL LUNG CANCER

T1, N1, M0 or T2, N1, M0 or T3, N0, M0

Patients with inoperable stage II disease and with sufficient pulmonary reserve may be considered for radiation therapy with curative intent.[1] Among patients with excellent performance status, up to a 20% 3-year survival rate may be expected if a course of radiation therapy with curative intent can be completed. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC treated with definitive radiation therapy achieved a 5-year overall survival rate of 10%; however, the 44 patients with T1 tumors achieved an actuarial disease-free survival rate of 60%. This retrospective study also suggested that improved disease-free survival was obtained with radiation therapy doses greater than 6,000 cGy.[2] Primary radiation therapy should consist of approximately 6,000 cGy delivered with megavoltage equipment to the midplane of the volume of known tumor using conventional fractionation. A boost to the cone-down field of the primary tumor is frequently used to further enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results and requires the use of a simulator.

Many patients treated surgically subsequently develop regional or distant metastases.[3] Therefore, patients should be considered for entry into clinical trials evaluating the use of adjuvant treatment with chemotherapy or radiation therapy following surgery. One controlled trial has failed to demonstrate an overall survival benefit for patients with carefully staged squamous cell carcinoma receiving postoperative irradiation, although local recurrences were significantly reduced.[4] A meta-analysis of 9 randomized trials evaluating postoperative radiation versus surgery alone showed a 7% reduction in overall survival with adjuvant radiation in patients with stage I or II disease.[5][Level of evidence: 1iiA] It will be important to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals. An intergroup trial comparing postoperative radiation therapy alone to postoperative radiation therapy with concurrent cisplatin and etoposide did not demonstrate either a disease-free or overall survival advantage with the combined therapy.[6][Level of evidence: 1iiA] Based on these data, adjuvant therapy should be considered under clinical evaluation and participation in clinical trials evaluating adjuvant therapy after surgical resection should be encouraged.[7-9]

Standard treatment options:

1. Lobectomy; pneumonectomy; or segmental, wedge, or sleeve resection as
appropriate.

2. Radiation therapy with curative intent (for potentially operable patients
who have medical contraindications to surgery).

3. Clinical trials of adjuvant chemotherapy with or without other modalities
following curative surgery.[10]

4. Clinical trials of radiation therapy following curative surgery.[10]

References:

1. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. American Journal of Clinical Oncology 8(5): 362-370, 1985.
2. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. International Journal of Radiation Oncology, Biology, Physics 24(1): 3-9, 1992.
3. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. Journal of Thoracic and Cardiovascular Surgery 109(1): 120-129, 1995.
4. Weisenburger TH, Holmes EC, Gail M, et al.: Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. New England Journal of Medicine 315(22): 1377-1381, 1986.
5. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 352(9124): 257-263, 1998.
6. Keller SM, Adak S, Wagner H, et al.: A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. New England Journal of Medicine 343(17), 1217-1222, 2000.
7. Winton T, NCIC-Clinical Trials Group: Phase III Randomized Study of Adjuvant Vinorelbine and Cisplatin Versus No Adjuvant Chemotherapy in Patients With Completely Resected Non-Small Cell Lung Cancer (Summary Last Modified 07/2001), CAN-NCIC-BR10, clinical trial, closed, 04/30/2001.
8. Strauss GM, Cancer and Leukemia Group B: Phase III Randomized Study of Paclitaxel and Carboplatin Versus No Adjuvant Chemotherapy After Resection in Patients With Stage IB Non-Small Cell Lung Cancer (Summary Last Modified 05/2001), CLB-9633, clinical trial, active, 10/15/1996.
9. Bunn PA, Southwest Oncology Group: Phase III Randomized Study of Surgery With or Without Preoperative Paclitaxel and Carboplatin in Patients With Stage IB, II, or Selected IIIA Non-Small Cell Lung Cancer (Summary Last Modified 08/2001), SWOG-S9900, clinical trial, active, 10/15/1999.
10. Holmes EC: Adjuvant treatment in resected lung cancer. Seminars in Surgical Oncology 6(5): 263-267, 1990.

STAGE IIIA NON-SMALL CELL LUNG CANCER

T1, N2, M0 or T2, N2, M0 or T3, N1, M0 or T3, N2, M0

The addition of chemotherapy to radiation therapy has been reported to improve survival in prospective clinical studies that have used modern cisplatin-based chemotherapy regimens.[4-7] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[8] The optimal sequencing of modalities and schedule of drug administration remains to be determined and is under study in ongoing clinical trials.[9]

The use of preoperative (neoadjuvant) chemotherapy has been shown to be effective in 2 small randomized studies of a total of 120 patients with stage IIIA NSCLC.[10,11] The 58 patients randomized to 3 cycles of cisplatin-based chemotherapy followed by surgery had a median survival more than 3 times as long as patients treated with surgery but no chemotherapy in both studies. Two additional single-arm studies have evaluated either 2 to 4 cycles of combination chemotherapy or combination chemotherapy plus chest irradiation for 211 patients with histologically confirmed N2 stage IIIA NSCLC.[12] Sixty-five percent to 75% of patients were able to have a resection of their cancer, and 27% to 28% were alive at 3 years. These results are encouraging, and combined-modality therapy with neoadjuvant chemotherapy with surgery and/or chest radiation therapy should be considered for patients with good performance status who have stage IIIA NSCLC.

Although most retrospective studies suggest that postoperative radiation therapy can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival.[13,14] One controlled trial in patients with completely resected stage II or III squamous cell lung cancer failed to demonstrate a survival benefit for patients who received postoperative irradiation, although local recurrences were significantly reduced.[15] A meta-analysis of 9 randomized trials evaluating postoperative radiation therapy versus surgery alone showed no difference in overall survival for the entire postoperative radiation therapy group or for the subset of N2 patients.[16][Level of evidence: 1iiA] It will be important to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals. In a trial conducted from 1986 to 1994, patients with completely resected lung cancers that were stage I, II, or IIIA were randomly assigned to resection alone or to resection plus postoperative radiation therapy. The addition of postoperative radiation therapy did not improve overall survival or local recurrence for the whole group or for the subset of patients with stage IIIA disease.[17][Level of evidence: 1iiA] An intergroup trial comparing postoperative radiation therapy alone to postoperative radiation therapy with concurrent cisplatin and etoposide did not demonstrate either a disease-free or overall survival advantage with the combined therapy.[18][Level of evidence: 1iiA] Based on these data, adjuvant therapy should be considered under clinical evaluation and participation in clinical trials evaluating adjuvant therapy after surgical resection should be encouraged.[19-21]

No consistent benefit from any form of immunotherapy has been demonstrated thus far in the treatment of NSCLC.

Standard treatment options:

1. Surgery alone in operable patients without bulky lymphadenopathy.[22-24]

2. Radiation therapy alone, for patients who are not suitable for neoadjuvant
chemotherapy plus surgery.[1,2]

3. Chemotherapy combined with other modalities.[4-6,12]

Superior sulcus tumor (T3, N0 or N1, M0)

Standard treatment options:

1. Radiation therapy and surgery.

2. Radiation therapy alone.

3. Surgery alone (selected cases).

4. Chemotherapy combined with other modalities.

5. Clinical trials of combined modality therapy.

Chest wall tumor (T3, N0 or N1, M0)

Standard treatment options:

1. Surgery.[24,26]

2. Surgery and radiation therapy.

3. Radiation therapy alone.

4. Chemotherapy combined with other modalities.

References:

1. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. American Journal of Clinical Oncology 8(5): 362-370, 1985.
2. Johnson DH, Einhorn LH, Bartolucci A, et al.: Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Annals of Internal Medicine 113(1): 33-38, 1990.
3. Saunders M, Dische S, Barrett A, et al.: Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. Lancet 350(9072): 161-165, 1997.
4. Dillman RO, Seagren SL, Propert KJ, et al.: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. New England Journal of Medicine 323(14): 940-945, 1990.
5. LeChevalier T, Arriagada R, Quoix E, et al.: Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. Journal of the National Cancer Institute 83(6): 417-423, 1991.
6. Schaake-Koning C, Van dan Bogaert W, Dalesio O, et al.: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. New England Journal of Medicine 326(8): 524-530, 1992.
7. Sause WT, Scott C, Taylor S, et al.: Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. Journal of the National Cancer Institute 87(3): 198-205, 1995.
8. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. British Medical Journal 311(7010): 899-909, 1995.
9. Curran WJ, Radiation Therapy Oncology Group: Phase III Randomized Study of Standard Thoracic Irradiation Following VBL/CDDP vs Standard Thoracic Irradiation and Concurrent VBL/CDDP vs Hyperfractionated Thoracic Irradiation and Concurrent VP-16/CDDP for Locally Advanced, Unresectable, non-Small Cell Lung Cancer (Summary Last Modified 09/98), RTOG-9410, clinical trial, closed, 07/31/1998.
10. Rosell R, Gomez-Codina J, Camps C, et al.: A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. New England Journal of Medicine 330(3): 153-158, 1994.
11. Roth JA, Fossella F, Komaki R, et al.: A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Journal of the National Cancer Institute 86(9): 673-680, 1994.
12. Albain KS, Rusch VW, Crowley JJ, et al.: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA(N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. Journal of Clinical Oncology 13(8): 1880-1892, 1995.
13. Emami B, Kaiser L, Simpson J, et al.: Postoperative radiation therapy in non-small cell lung cancer. American Journal of Clinical Oncology 20(5): 441-448, 1997.
14. Sawyer TE, Bonner JA, Gould PM, et al.: Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks. Annals of Thoracic Surgery 64(5): 1402-1408, 1997.
15. Weisenburger TH, Holmes EC, Gail M, et al.: Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. New England Journal of Medicine 315(22): 1377-1381, 1986.
16. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 352(9124): 257-263, 1998.
17. Dautzenberg B, Arriagada R, et al., for the Groupe d'Etude et de Traitement des Cancer Bronchiques: A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Cancer 86(2): 265-273, 1999.
18. Keller SM, Adak S, Wagner H, et al.: A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. New England Journal of Medicine 343(17), 1217-1222, 2000.
19. Winton T, NCIC-Clinical Trials Group: Phase III Randomized Study of Adjuvant Vinorelbine and Cisplatin Versus No Adjuvant Chemotherapy in Patients With Completely Resected Non-Small Cell Lung Cancer (Summary Last Modified 07/2001), CAN-NCIC-BR10, clinical trial, closed, 04/30/2001.
20. Strauss GM, Cancer and Leukemia Group B: Phase III Randomized Study of Paclitaxel and Carboplatin Versus No Adjuvant Chemotherapy After Resection in Patients With Stage IB Non-Small Cell Lung Cancer (Summary Last Modified 05/2001), CLB-9633, clinical trial, active, 10/15/1996.
21. Bunn PA, Southwest Oncology Group: Phase III Randomized Study of Surgery With or Without Preoperative Paclitaxel and Carboplatin in Patients With Stage IB, II, or Selected IIIA Non-Small Cell Lung Cancer (Summary Last Modified 08/2001), SWOG-S9900, clinical trial, active, 10/15/1999.
22. Shields TW: The significance of ipsilateral mediastinal lymph node metastasis (N2 disease) in non-small cell carcinoma of the lung: a commentary. Journal of Thoracic and Cardiovascular Surgery 99(1): 48-53, 1990.
23. Mountain CF: The biological operability of stage III non-small cell lung cancer. Annals of Thoracic Surgery 40(1): 60-64, 1985.
24. Van Raemdonck DE, Schneider A, Ginsberg RJ: Surgical treatment for higher stage non-small cell lung cancer. Annals of Thoracic Surgery 54(5): 999-1013, 1992.
25. Komaki R, Mountain CF, Holbert JM, et al.: Superior sulcus tumors: treatment selection and results for 85 patients without metastasis (M0) at presentation. International Journal of Radiation Oncology, Biology, Physics 19(1): 31-36, 1990.
26. McCaughan BC, Martini N, Bains MS, et al.: Chest wall invasion in carcinoma of the lung: therapeutic and prognostic implications. Journal of Thoracic and Cardiovascular Surgery 89(6): 836-841, 1985.

STAGE IIIB NON-SMALL CELL LUNG CANCER

Patients with stage IIIB disease with poor performance status are candidates for chest irradiation to palliate pulmonary symptoms (e.g., cough, shortness of breath, hemoptysis, or pain).[7][Level of evidence: 3iiiC]

T4 or N3, M0

Because of the poor overall results, these patients should be considered for clinical trials; trials examining new fractionation schedules, radiosensitizers, and combined modality approaches may lead to improvement in the control of disease.

Patients with NSCLC can present with superior vena cava syndrome. (Refer to the PDQ summary on Superior Vena Cava Syndrome for more information.) Regardless of stage, this problem should generally be managed with radiation therapy with or without chemotherapy.

Standard treatment options:

1. Radiation therapy alone.[7]

2. Chemotherapy combined with radiation therapy.[1-3,9]

3. Chemotherapy and concurrent radiation therapy followed by resection.[13,14]

4. Chemotherapy alone.

References:

1. LeChevalier T, Arriagada R, Quoix E, et al.: Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. Journal of the National Cancer Institute 83(6): 417-423, 1991.
2. Morton RF, Jett JR, McGinnis WL, et al.: Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer. Annals of Internal Medicine 115(9): 681-686, 1991.
3. Dillman RO, Seagren SL, Propert KJ, et al.: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. New England Journal of Medicine 323(14): 940-945, 1990.
4. Schaake-Koning C, Van dan Bogaert W, Dalesio O, et al.: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. New England Journal of Medicine 326(8): 524-530, 1992.
5. Sause WT, Scott C, Taylor S, et al.: Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. Journal of the National Cancer Institute 87(3): 198-205, 1995.
6. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. British Medical Journal 311(7010): 899-909, 1995.
7. Langendijk JA, ten Velde GP, Aaronson NK, et al.: Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study. International Journal of Radiation Oncology, Biology, Physics 47(1): 149-155, 2000.
8. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. American Journal of Clinical Oncology 8(5): 362-370, 1985.
9. Ihde DC: Chemotherapy combined with chest irradiation for locally advanced non-small cell lung cancer. Annals of Internal Medicine 115(9): 737-739, 1991.
10. Blanke C, Ansari R, Mantravadi R, et al.: Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: a Hoosier Oncology Group protocol. Journal of Clinical Oncology 13(6): 1425-1429, 1995.
11. Pignon JP, Stewart LA, Souhami RL, et al.: A meta-analysis using individual patient data from randomised clinical trials (RCTS) of chemotherapy (CT) in non-small cell lung cancer (NSCLC): (2) survival in the locally advanced (LA) setting. Proceedings of the American Society of Clinical Oncology 13: A-1109, 334, 1994.
12. Curran WJ, Radiation Therapy Oncology Group: Phase III Randomized Study of Standard Thoracic Irradiation Following VBL/CDDP vs Standard Thoracic Irradiation and Concurrent VBL/CDDP vs Hyperfractionated Thoracic Irradiation and Concurrent VP-16/CDDP for Locally Advanced, Unresectable, non-Small Cell Lung Cancer (Summary Last Modified 09/98), RTOG-9410, clinical trial, closed, 07/31/1998.
13. Rusch VW, Albain KS, Crowley JJ, et al.: Surgical resection of stage IIIA and stage IIIB non-small-cell lung cancer after concurrent induction chemoradiotherapy: a Southwest Oncology Group trial. Journal of Thoracic and Cardiovascular Surgery 105(1): 97-106, 1993.
14. Albain KS, Rusch VW, Crowley JJ, et al.: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA(N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. Journal of Clinical Oncology 13(8): 1880-1892, 1995.

STAGE IV NON-SMALL CELL LUNG CANCER

Any T, any N, M1

1iiA]

Reports of taxane/platinum combinations have shown relatively high response rates, significant 1-year survival, and palliation of lung cancer symptoms.[4] In single institution phase II studies that evaluated the paclitaxel plus carboplatin regimen, response rates have been in the range of 27% to 53% with 1-year survival rates of 32% to 54%.[4,5] In a multicenter phase III study, the combination of cisplatin and paclitaxel was shown to have a higher response rate than the older combination of cisplatin and etoposide.[6][Level of evidence: 1iiD] A prospective randomized study compared 4 commonly used platinum-based chemotherapy regimens for patients with stage IIIB or IV non-small cell lung cancer: cisplatin/paclitaxel, gemcitabine/cisplatin, cisplatin/docetaxel, and carboplatin/paclitaxel.[7] No regimen was found to have a significantly better response rate or survival.[7][Level of evidence:

1iiA] The response rate for all 1158 eligible patients was 19%, while the median survival was 7.9 months (95% confidence interval, 7.3 to 8.5 months). Patients with a performance status of 2 had significantly worse toxic effects and survival compared to patients with a performance status of 0 to 1.[8] Another prospective randomized study compared the combination of carboplatin/paclitaxel with vinorelbine/cisplatin. This study also found no significant difference in efficacy between these 2 standard regimens.[6][Level of evidence: 1iiD]

Although these results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced non-small cell lung cancer (NSCLC), efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Appropriate patients should be encouraged to participate in clinical trials evaluating the role of platinum-based and non-platinum-based chemotherapy. Outside of a clinical trial setting, chemotherapy should be given only to patients with good performance status and evaluable tumor lesions who desire such treatment after being fully informed of its anticipated risks and limited benefits.

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC such as tracheal, esophageal, or bronchial compression, bone or brain metastases, pain, vocal cord paralysis, hemoptysis, or superior vena cava syndrome. In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[9] Such therapeutic intervention may be critical in the prolongation of an acceptable lifestyle in an otherwise functional patient. In the rare patient with synchronous presentation of a resectable primary tumor in the lung and a single brain metastasis, surgical resection of the solitary brain lesion is indicated with resection of the primary tumor and appropriate postoperative chemotherapy and/or irradiation of the primary tumor site and with postoperative whole-brain irradiation delivered in daily fractions of 180 cGy to 200 cGy to avoid long-term toxic effects to normal brain tissue.[10,11]

In asymptomatic patients kept under close observation, treatment may often be appropriately deferred until symptoms or signs of progressive tumor develop.

Standard treatment options:

1. External-beam radiation therapy, primarily for palliative relief of local
symptomatic tumor growth.

2. Chemotherapy. The following regimens are associated with similar survival
outcomes:

cisplatin plus vinblastine plus mitomycin [12]
cisplatin plus vinorelbine [3,13]
cisplatin plus paclitaxel [6,7]
cisplatin plus docetaxel [7,14]
cisplatin plus gemcitabine [7,15]
carboplatin plus paclitaxel [5,7,13]

4. Endobronchial laser therapy and/or brachytherapy for obstructing lesions.[9]

References:

1. Weick JK, Crowley J, Natale RB, et al.: A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study. Journal of Clinical Oncology 9(7): 1157-1162, 1991.
2. O'Connell JP, Kris MG, Gralla RJ, et al.: Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. Journal of Clinical Oncology 4(11): 1604-1614, 1986.
3. Le Chevalier T, Brisgand D, Douillard JY, et al.: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. Journal of Clinical Oncology 12(2): 360-367, 1994.
4. Johnson DH, Paul DM, Hande KR, et al.: Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. Journal of Clinical Oncology 14(7): 2054-2060, 1996.
5. Langer CJ, Leighton JC, Comis RL, et al.: Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. Journal of Clinical Oncology 13(8): 1860-1870, 1995.
6. Bonomi P, Kim K, Fairclough D, et al.: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. Journal of Clinical Oncology 18(3): 623-631, 2000.
7. Schiller JH, Harrington D, Sandler A, et al.: A randomized phase III trial of four chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Proceedings of the American Society of Clinical Oncology 19: A-2, 1a, 2000.
8. Schiller JH, Harrington D, Belani CP, et al.: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. New England Journal of Medicine 346(2): 92-98, 2002.
9. Miller JI, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Annals of Thoracic Surgery 50(2): 190-196, 1990.
10. Mandell L, Hilaris B, Sullivan M, et al.: The treatment of single brain metastasis from non-oat cell lung carcinoma: surgery and radiation versus radiation therapy alone. Cancer 58(3): 641-649, 1986.
11. DeAngelis LM, Mandell LR, Thaler HT, et al.: The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 24(6): 798-805, 1989.
12. Veeder MH, Jett JR, Su JQ, et al.: A phase III trial of mitomycin C alone versus mitomycin C, vinblastine, and cisplatin for metastatic squamous cell lung carcinoma. Cancer 70(9): 2281-2287, 1992.
13. Kelly K, Crowley J, Bunn PA, et al.: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. Journal of Clinical Oncology 19(13): 3210-3218, 2001.
14. Belani CP: Docetaxel (Taxotere) in combination with platinum-based regimens in non-small cell lung cancer: results and future developments. Seminars in Oncology 26(3 suppl 10): 15-18, 1999.
15. Sandler AB, Nemunaitis J, Denham C, et al.: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. Journal of Clinical Oncology 18(1): 122-130, 2000.
16. Kosmidis PA: A randomized phase III trial of paclitaxel plus carboplatin versus paclitaxel plus gemcitabine in advanced non-small cell lung cancer (NSCLC). A preliminary analysis. Lung Cancer 29(suppl 2): 147, 2000.

RECURRENT NON-SMALL CELL LUNG CANCER

Many patients with recurrent non-small cell lung cancer (NSCLC) are eligible for clinical trials. Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged disease-free survival with surgical excision of the brain metastasis and postoperative whole-brain irradiation.[1,2] Unresectable brain metastases in this setting may be treated radiosurgically.[3] Because of the small potential for long-term survival, radiation therapy should be delivered by conventional methods in daily doses of 180 to 200 cGy, while higher daily doses over a shorter period of time (hypofractionated schemes) should be avoided because of the high risk of toxic effects observed with such treatments.[4] Most patients not suitable for surgical resection should receive conventional whole-brain radiation therapy. Selected patients with good performance status and small metastases can be considered for stereotactic radiosurgery.[5]

Approximately one half of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment.[6] In those selected patients with good performance status and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiosurgery.[3,6] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[7][Level of evidence: 3iiiDii]

A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Determining whether the new lesion is a new primary cancer or a metastasis may be difficult. Studies have indicated that in the majority of patients the new lesion is a second primary tumor, and following resection some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected if possible.[8,9]

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[10][Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[11,12] Informed patients with good performance status and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed following platinum-based chemotherapy, second-line treatment can be considered. Two prospective randomized studies have shown an improvement in survival with the use of docetaxel compared to vinorelbine, ifosfamide, or best supportive care.[13,14] However, criteria for the selection of appropriate patients for second-line treatment are not well-defined.[15]

Standard treatment options:

1. Palliative radiation therapy.

2. Chemotherapy alone. For patients who have not received prior chemotherapy,
the following regimens are associated with similar survival outcomes:

cisplatin plus vinblastine plus mitomycin [16]
cisplatin plus vinorelbine [17]
cisplatin plus paclitaxel [18,19]
cisplatin plus gemcitabine [19,20]
carboplatin plus paclitaxel [19,21,22]
cisplatin plus docetaxel [19]

4. Laser therapy or interstitial radiation therapy for endobronchial
lesions.[23]

5. Stereotactic radiosurgery (highly selected patients).[3,5]

References:

1. Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. New England Journal of Medicine 322(8): 494-500, 1990.
2. Mandell L, Hilaris B, Sullivan M, et al.: The treatment of single brain metastasis from non-oat cell lung carcinoma: surgery and radiation versus radiation therapy alone. Cancer 58(3): 641-649, 1986.
3. Loeffler JS, Kooy HM, Wen PY, et al.: The treatment of recurrent brain metastases with stereotactic radiosurgery. Journal of Clinical Oncology 8(4): 576-582, 1990.
4. DeAngelis LM, Mandell LR, Thaler HT, et al.: The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 24(6): 798-805, 1989.
5. Alexander E, Moriarty TM, Davis RB, et al.: Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. Journal of the National Cancer Institute 87(1): 34-40, 1995.
6. Arbit E, Wronski M, Burt M, et al.: The treatment of patients with recurrent brain metastases: a retrospective analysis of 109 patients with nonsmall cell lung cancer. Cancer 76(5): 765-773, 1995.
7. Hazuka MB, Kinzie JJ: Brain metastases: results and effects of re-irradiation. International Journal of Radiation Oncology, Biology, Physics 15(2): 433-437, 1988.
8. Salerno TA, Munro DD, Blundell PE, et al.: Second primary bronchogenic carcinoma: life-table analysis of surgical treatment. Annals of Thoracic Surgery 27(1): 3-6, 1979.
9. Yellin A, Hill LR, Benfield JR: Bronchogenic carcinoma associated with upper aerodigestive cancer. Journal of Thoracic and Cardiovascular Surgery 91(5): 674-683, 1986.
10. Souquet PJ, Chauvin F, Boissel JP, et al.: Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 342(8862): 19-21, 1993.
11. Ellis PA, Smith IE, Hardy JR, et al.: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. British Journal of Cancer 71(2): 366-370, 1995.
12. Girling DJ, et al.: Randomized trial of etoposide cyclophosphamide methotrexate and vincristine versus etoposide and vincristine in the palliative treatment of patients with small-cell lung cancer and poor prognosis. British Journal of Cancer 67(Suppl 20): A-4;2, 14, 1993.
13. Fossella FV, DeVore R, Kerr RN, et al.: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platiinum-containing chemotherapy regimens. Journal of Clinical Oncology 18(12): 2354-2362, 2000.
14. Shepherd FA, Dancey J, Ramlau R, et al.: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. Journal of Clinical Oncology 18(10): 2095-2103, 2000.
15. Huisman C, Smit EF, Giaccone G, et al.: Second-line chemotherapy in relapsing or refractory non-small-cell lung cancer: a review. Journal of Clinical Oncology 18(21): 3722-3730, 2000.
16. Veeder MH, Jett JR, Su JQ, et al.: A phase III trial of mitomycin C alone versus mitomycin C, vinblastine, and cisplatin for metastatic squamous cell lung carcinoma. Cancer 70(9): 2281-2287, 1992.
17. Le Chevalier T, Brisgand D, Douillard JY, et al.: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. Journal of Clinical Oncology 12(2): 360-367, 1994.
18. Bonomi P, Kim K, Fairclough D, et al.: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. Journal of Clinical Oncology 18(3): 623-631, 2000.
19. Schiller JH, Harrington D, Sandler A, et al.: A randomized phase III trial of four chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Proceedings of the American Society of Clinical Oncology 19: A-2, 1a, 2000.
20. Sandler AB, Nemunaitis J, Denham C, et al.: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. Journal of Clinical Oncology 18(1): 122-130, 2000.
21. Johnson DH, Paul DM, Hande KR, et al.: Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. Journal of Clinical Oncology 14(7): 2054-2060, 1996.
22. Langer CJ, Leighton JC, Comis RL, et al.: Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. Journal of Clinical Oncology 13(8): 1860-1870, 1995.
23. Miller JI, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Annals of Thoracic Surgery 50(2): 190-196, 1990.

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