Radiation Therapy For Early Stage Non-Small Cell Lung Cancer

Article Author:
Catherine Kim
Article Editor:
Melenda Jeter
Updated:
6/30/2020 10:16:18 PM
PubMed Link:
Radiation Therapy For Early Stage Non-Small Cell Lung Cancer

Introduction

Lung cancer is the most common non-cutaneous cancer and the number one cause of cancer death worldwide.[1][2][3]

Etiology

Tobacco use is the primary risk factor for lung cancer. It accounts for 90% cases in men and 70% in women. Other environmental exposure risk factors include radon, asbestos, and occupational exposure such as arsenic, bis-chloromethyl ether, hexavalent chromium, mustard gas, nickel, and polycyclic aromatic hydrocarbon.[4][5]

Epidemiology

In the United States, lung cancer is the second most common cancer following breast cancer in women and prostate cancer in men, not including skin cancer. Lung cancers comprise about 14% of all new cancers. About 220,000 new lung cancers are diagnosed each year with about 155,000 deaths estimated. Lung cancer is the number one cancer killer in both men and women. The number of deaths due to lung cancer surpasses the deaths attributable to prostate, breast, and colon cancers combined. Over the past several decades, the incidence of lung cancer has been declining in men, but just only recently in women.[6][7]

Pathophysiology

Non-small lung carcinoma (NSCLC) accounts for approximately 80% to 90% of all lung cancers. Small-cell lung carcinoma (SCLC) makes up the remainder. Three major histologic types of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma is the most common type of NSCLC. It accounts for 50% of cases and has a high propensity to metastasize. Bronchoalveolar carcinoma is a subtype of adenocarcinoma which can present as a solitary nodule or multifocal disease. Typically, it is not associated with smoking.  Squamous cell carcinoma and large cell carcinoma comprise 35% and 15%, respectively.

Histopathology

Thyroid transcription factor (TTF)-1 helps to distinguish if a tumor is a lung primary. Increasingly, molecular diagnostic studies are being performed to determine the presence of certain gene alterations in the tumor such as EGFR mutations, ALK gene rearrangements, ROS1 rearrangements, and PD-L1 expression. There is increasing evidence to show that such tumors with these specific gene mutations or alterations can respond to targeted therapies.[8]

History and Physical

Most patients present with symptoms of dyspnea, cough, hemoptysis, chest pain, and weight loss. They may also present with a change in mental status, clubbing, post-obstructive pneumonia, pleural effusion, hoarseness due to recurrent laryngeal nerve involvement, and superior vena cava syndrome (SVC). Some patients present with superior sulcus tumor with Pancoast syndrome exhibiting symptoms of shoulder pain, brachial plexopathy, and Horner syndrome (ptosis, meiosis, and ipsilateral anhidrosis). Poor prognostic factors include an advanced stage, weight loss (more than 10% body weight over past six months), Karnofsky Performance Status (KPS less than 90), pleural effusion, age older than 70 years, use of chemotherapy, and nodal stage.

Evaluation

Workup for suspected lung cancer begins with a good history and physical examination with attention to performance status, weight loss, and tobacco history. Imaging includes computerized or computed tomography (CT) of the chest, abdomen, and pelvis, magnetic resonance imaging (MRI) of the brain, and positron emission tomography-computed tomography (PET-CT). Lab work includes a complete blood count (CBC), comprehensive metabolic panel (CMP), and liver function test (LFT). Pulmonary function testing is needed for pre-surgical evaluation. Tissue diagnosis and staging are crucial to helping guide treatment recommendations. Diagnosis can be obtained through bronchoscopy for central lung tumors. Biopsy via endobronchial ultrasound (EBUS) or mediastinoscopy is performed for suspected hilar or mediastinal nodes. CT-guided needle biopsy is performed for peripheral lung tumors. Other times, diagnosis is obtained from surgical resection. [9][10]

The stage at presentation typically breaks down to the following:  stage I 10%, stage II 20%, stage III 30%, and stage IV 40%. Unfortunately, the majority of patients present with advanced stage or metastatic disease.  Most common sites of distant metastases are bone, adrenal glands, and brain.  Survival depends on the stage at presentation, response to treatment, and physical tolerance to therapy.  In general, five-year survival for stage IA/IB is 40% to 70%, stage IIA/IIB is 30% to 55%, stage IIIA/IIIB 5% to 25%, and stage IV is 1% to 13%.

Treatment / Management

Surgery is typically recommended for early-stage NSCLC (Stage I-II). Surgery consists of lobectomy and lymph node sampling or dissection and occasionally, pneumonectomy or wedge resection. Depending on surgical findings, some patients may require adjuvant chemotherapy or radiation therapy. For T1 tumor, the local control is 94% for lobectomy and 82% for wedge resection. Therefore, if possible, lobectomy is preferred. The five-year overall survival for resected T1N0 and T2N0 tumors are 80% and 68%, respectively.[11][12]Some patients are not surgical candidates due to high operative risk from a poor cardiopulmonary function, comorbid conditions, or advanced age. Others refuse surgery. In these cases, definitive radiation therapy is given. For stage I, medically inoperable patients, stereotactic body radiation therapy (SBRT), also known as stereotactic ablative body radiation (SABR), has emerged as a safe and effective alternative option to surgery. SBRT or SABR involve giving a high dose of radiation therapy with precision to lung tumors. This technique maximizes tumor cell kill of the target while minimizing radiation-related injury to normal critical structures. Patient immobilization system along with image guidance is required for accurate patient positioning and tumor localization before the delivery of each treatment. SBRT is delivered in three to five sessions over one to two weeks. Studies have shown that three-year local tumor control is 85% to 95% and three-year overall survival is 55% to 91%. For Stage II inoperable patients, definitive conventional radiation therapy has been offered, although the results are not comparable to surgery. If patient physical fitness allows, three-dimensional conformal radiation therapy is given in standard fractionation over six to seven weeks with concurrent chemotherapy.

Radiation Oncology

The role of radiation for the management of early stage lung cancer is limited. It is only considered in patients not deemed surgical candidates or who have numerous co-morbidities. Radiation therapy also for early-stage lung cancer has poor 5-year survival. Several types of radiation delivery techniques have been used to treat early-stage lung cancer in non-surgical patients. To date, stereotactic body radiotherapy appears to have the highest survival compared to other techniques, with 3-year survival approaching 55%. Other studies have shown that radiation therapy does lower the recurrence rate but not the overall survival. The role of adjuvant radiation therapy after surgical resection of the primary lung cancer remains questionable. Radiation therapy has been shown to reduce local recurrence but not overall survival rates. At present, radiation therapy is reserved for patients with positive margins after resection.[13][14]

Pearls and Other Issues

TNM Staging (AJCC, 8th Edition)

Primary Tumor (T)

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 a primary tumor

Tis: Carcinoma in situ - tumor measuring 3 cm or less, no invasive component

T1: Tumor measuring 3 cm or less in greatest dimension, surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus  (i.e.  not in the main bronchus)

T1mi: Minimally invasive adenocarcinoma, tumor has an invasive component measuring 5 mm or less

T1a: Tumor ≤1 cm in greatest dimension, superficial spreading tumor in central airways (spreading tumor of any size but confined to the tracheal or bronchial wall)

T1b: Tumor >1 cm but ≤2 cm in greatest dimension

T1c: Tumor >2 cm but ≤3 cm in greatest dimension

T2: Tumor >3 cm but ≤5 cm or tumor with any of the following features: involves the main bronchus regardless of distance from the carina but without the involvement of the carina,      invades visceral pleura, associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung

T2a: Tumor >3 cm but ≤4 cm in greatest dimension

T2b: Tumor >4 cm but ≤5 cm in greatest dimension

T3: Tumor >5 cm but ≤7 cm in greatest dimension or associated with separate tumor nodule(s) in the same lobe as the primary tumor or directly invades any of the following:        parietal pleura, chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium, or separate tumor nodule(s) in the same lobe as the primary

T4: Tumor >7 cm in greatest dimension or any tumor invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in a different ipsilateral lobe than that of the primary tumor

Regional Lymph Nodes (N)

Nx: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Ipsilateral peribronchial and/or ipsilateral hilar nodes and intrapulmonary nodes, including involvement by direct extension

N2: Ipsilateral mediastinal and/or subcarinal nodes

N3: Supraclavicular/scalene nodes and/or contralateral mediastinal/hilar nodes

Distant Metastases (M)

M0: No distant metastasis

M1: Distant metastasis present

M1a: Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodule(s) or malignant pleural or pericardial effusions

M1b: Single extrathoracic metastasis, involving a single organ or a single distant (nonregional) node a single extrathoracic metastasis has a better survival and different treatment choices, reason why it has now been staged separately

M1c: Multiple extrathoracic metastases in one or more organs

Group Staging

Stage 0: Tis, N0, M0

Stage IA1: T1mi/T1a, N0, M0

Stage IA2: T1b, N0, M0

Stage IA3: T1c, N0, M0

Stage IB: T2a, N0, M0

Stage IIA: T2b, N0, M0

Stage IIB: T1/T2, N1, M0 or T3, N0, M0

Stage IIIA: T1/T2, N2, M0 or T3/T4, N1, M0 or T4, N0, M0

Stage IIIB: T1/T2, N3, M0 or T3/T4, N2, M0

Stage IIIC: T3/T4, N3, M0

Stage IVA: any T, any N with M1a/M1b

Stage IVB: any T, any N with M1c

Enhancing Healthcare Team Outcomes

It is important to appreciate that the definitive treatment for early lung cancer is surgery. Radiation is only considered in early cases when the patient is not deemed a surgical candidate. Overall, radiation therapy alone for managing early lung cancer has been disappointing. Over the past two decades, several newer modalities of delivering radiation have been developed with improved survival at three years.  Trials are now comparing surgery versus radiation therapy for early lung cancer. The best way to manage lung cancer is to try and prevent it. The public should be educated on the harms of smoking; cessation of this social habit would lead to a drastic reduction of not only lung cancer but many other disorders like a peripheral vascular disease, COPD, atherosclerosis and so on.[17][18] (Level V)


References

[1] Schonewolf CA,Heskel M,Doucette A,Singhal S,Frick MA,Xanthopoulos EP,Corradetti MN,Friedberg JS,Pechet TT,Christodouleas JP,Levin W,Berman A,Cengel KA,Verma V,Hahn SM,Kucharczuk JC,Rengan R,Simone CB 2nd, Five-year Long-term Outcomes of Stereotactic Body Radiation Therapy for Operable Versus Medically Inoperable Stage I Non-small-cell Lung Cancer: Analysis by Operability, Fractionation Regimen, Tumor Size, and Tumor Location. Clinical lung cancer. 2018 Sep 20     [PubMed PMID: 30337269]
[2] Wang X,Zamdborg L,Ye H,Grills IS,Yan D, A matched-pair analysis of stereotactic body radiotherapy (SBRT) for oligometastatic lung tumors from colorectal cancer versus early stage non-small cell lung cancer. BMC cancer. 2018 Oct 10     [PubMed PMID: 30305131]
[3] Lam A,Yoshida EJ,Bui K,Katrivesis J,Fernando D,Nelson K,Abi-Jaoudeh N, Patient and Facility Demographics Related Outcomes in Early-Stage Non-Small Cell Lung Cancer Treated with Radiofrequency Ablation: A National Cancer Database Analysis. Journal of vascular and interventional radiology : JVIR. 2018 Oct 4     [PubMed PMID: 30293735]
[4] Barrera-Rodríguez R, Importance of the Keap1-Nrf2 pathway in NSCLC: Is it a possible biomarker? Biomedical reports. 2018 Nov     [PubMed PMID: 30345037]
[5] Deng H,Liu C,Zhang G,Wang X,Liu Y, Lung adenocarcinoma with concurrent ALK and ROS1 rearrangement: A case report and review of the literatures. Pathology, research and practice. 2018 Oct 1     [PubMed PMID: 30327151]
[6] Fang P,He W,Gomez D,Hoffman KE,Smith BD,Giordano SH,Jagsi R,Smith GL, Racial disparities in guideline-concordant cancer care and mortality in the United States. Advances in radiation oncology. 2018 Jul-Sep     [PubMed PMID: 30202793]
[7] Rahouma M,Kamel M,Abouarab A,Eldessouki I,Nasar A,Harrison S,Lee B,Shostak E,Morris J,Stiles B,Altorki NK,Port JL, Lung cancer patients have the highest malignancy-associated suicide rate in USA: a population-based analysis. Ecancermedicalscience. 2018     [PubMed PMID: 30174721]
[8] Schaal CM,Bora-Singhal N,Kumar DM,Chellappan SP, Regulation of Sox2 and stemness by nicotine and electronic-cigarettes in non-small cell lung cancer. Molecular cancer. 2018 Oct 15     [PubMed PMID: 30322398]
[9] Sánchez M,Benegas M,Vollmer I, Management of incidental lung nodules <8 mm in diameter. Journal of thoracic disease. 2018 Aug     [PubMed PMID: 30345098]
[10] Bevilacqua A,Gavelli G,Baiocco S,Barone D, CT Perfusion in Patients with Lung Cancer: Squamous Cell Carcinoma and Adenocarcinoma Show a Different Blood Flow. BioMed research international. 2018     [PubMed PMID: 30255097]
[11] Turna A, ESTS staging guidelines for non-small cell lung cancer: a good guide to best ever accuracy and high survival rate. Journal of thoracic disease. 2018 Aug     [PubMed PMID: 30233910]
[12] Non-Small Cell Lung Cancer Treatment (PDQ®): Health Professional Version null. 2002     [PubMed PMID: 26389304]
[13] Miller CJ,Martin B,Stang K,Hutten R,Alite F,Small C,Emami B,Harkenrider MM, Predictors of Distant Failure After Stereotactic Body Radiation Therapy for Stages I to IIA Non-Small-Cell Lung Cancer. Clinical lung cancer. 2018 Sep 8     [PubMed PMID: 30279109]
[14] DeWees TA,Nikitas J,Rehman S,Bradley JD,Robinson CG,Roach MC, Defining Optimal Comorbidity Measures for Patients with Early Stage Non-small Cell Lung Cancer (NSCLC) Treated with Stereotactic Body Radiation Therapy (SBRT). Practical radiation oncology. 2018 Sep 19     [PubMed PMID: 30244094]
[15] Panunzio A,Sartori P, Lung Cancer And Radiological Imaging. Current radiopharmaceuticals. 2020 May 23;     [PubMed PMID: 32445458]
[16] Wu LL,Liu X,Jiang WM,Huang W,Lin P,Long H,Zhang LJ,Ma GW, Stratification of Patients With Stage IB NSCLC Based on the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual. Frontiers in oncology. 2020;     [PubMed PMID: 32373536]
[17] Randhawa S,Drizin G,Kane T,Song GY,Reilly T,Jarrar D, Lung Cancer Screening in the Community Setting: Challenges for Adoption. The American surgeon. 2018 Sep 1     [PubMed PMID: 30268168]
[18] Couraud S,Greillier L,Brignoli-Guibaudet L,Lhomel C,Viguier J,Morère JF,Eisinger F,Cortot AB, Current and Former Smokers: Who Wants To Be Screened? Clinical lung cancer. 2018 Jul 6     [PubMed PMID: 30107977]