Squamous Cell Lung Cancer

Etiology

Approximately 80% of lung cancer cases in men and 90% of cases in women are associated with smoking.[1][2] SCC is more strongly associated with smoking than any other type of NSCLC. Other risk factors for SCC include age, family history, exposure to second-hand smoke, and exposure to minerals, metal particles, or asbestos.

Epidemiology

In 2023, lung cancer was the third most common cancer in terms of incidence and the most common cause of cancer-related mortality in the US, as per the National Cancer Institute's Surveillance Epidemiology and End Results (NCI SEER) database. Lung cancer incidence was estimated at 238,340 cases, accounting for 12% of the cancer burden in the US. The estimated mortality for lung cancer in 2023 was 127,070 deaths, constituting around 21% of all US cancer-related deaths. Approximately 85% of all lung cancers are NSCLCs. Adenocarcinoma and squamous cell carcinoma are the most common subtypes, accounting for 50% and 30% of NSCLC cases, respectively.[3]

Pathophysiology

SCC of the lungs originates from the transformation of the squamous cells lining the airways. Squamous cells are thin, flat cells that are found lining many organs of the human body. Squamous cell lung tumors often occur in the central part of the lung or the primary airway, such as the left or right bronchus. The primary causative agent of cellular transformation is tobacco smoke, which contains more than 300 harmful agents and 40 potential carcinogens. Transformed squamous cells are characterized by keratinization and intercellular bridges and often exhibit high mutation frequency.[4]

Histopathology

A correct histologic diagnosis is becoming increasingly important because it may predict response and toxicity to therapies.[5] A diagnosis of SCC is confirmed through histologic examination when a minimum of 10% of the tumor bulk of resected samples exhibits transformation features such as keratinization or intracellular bridges. If the differentiated squamous element of the tumor is minimal, a diagnosis of poorly differentiated SCC is made. An immunohistochemistry (IHC) panel and a mucin stain can help identify NSCLC subtypes. SCC also shows a strong expression of squamous biomarkers, including p63 and p40 proteins. In 2015, the World Health Organization revised the classification to recognize the 3 following variants of SCC based on histological examination:[6] 

• Keratinizing
• Nonkeratinizing
• Basaloid, when the basaloid component is more than 50% of the tissue with minimal areas of squamous differentiation

History and Physical

Clinical symptoms of NSCLCs include cough, chest pain, shortness of breath, blood in sputum, wheezing, hoarseness, recurring chest infections (eg, bronchitis and pneumonia), weight loss, loss of appetite, and fatigue. However, NSCLC patients often are asymptomatic in the early stages of the disease. Social history may include extensive smoking history or occupational exposure to heavy metals, asbestos, and radon exposure. Metastases may occur in advanced disease, and symptoms may include bone pain, brain metastasis, or spinal cord compression with neurologic symptoms (eg, headache, weakness or numbness of limbs, dizziness, and seizures).

Evaluation

Diagnostic Imaging Studies

Following the clinical examination,  computed tomography (CT) imaging is frequently utilized initially to evaluate SCC, provided the tumor is sufficiently sized to be detected on the CT. The presence of a cavity, filled by either gas or fluid, within a tumor mass is a classic sign of SCC.[1] Further signs may include pulmonary nodules, mass or infiltrate, mediastinal widening, atelectasis, hilar enlargement, or pleural effusion (see Image. Squamous Cell Carcinoma of the Lung).

Suspected lung malignancies require a thorough workup individualized to evaluate the extent of the disease efficiently. For small incidental nodules discovered on the chest CT, the Fleischner Society guidelines for management are typically followed. If a diagnosis of lung cancer is likely, then proceeding with the staging workup, rather than obtaining a tissue specimen first, can be more efficient in some patients, as this may allow metastatic areas to be detected. These areas could be more accessible and easier to biopsy, thus confirming the diagnosis and establishing the advanced stage. 

High-quality imaging is essential to the staging process. A Positron emission tomography (PET) scan, typically fused with a CT of the body, is utilized. False positives may occur in situations such as infection, sarcoidosis, rheumatoid nodules, etc. False negatives can occur with carcinoid tumors, ground glass opacities, and or lesions less than 1 cm in size. For lesions less than 1 cm in size, the false negative rate approaches 15%. Although PET/CT staging is generally widespread, they are not indicated in patients with pure ground glass opacities or peripheral cT1a type tumors.[7] MRI brain imaging also becomes essential in evaluating patients for possible brain metastasis. Usually, this is indicated in patients with at least clinical stage II disease and is considered optional for stage IB. 

Despite imaging advances, invasive mediastinal nodal evaluation is indicated in a broad cross-section of patients. Even with PET/CT scans, the false positive and false negative rates are 15% to 20% for mediastinal involvement.[7] Invasive mediastinal staging is generally indicated in patients with either discrete enlargement of mediastinal nodes on CT regardless of PET avidity or normal-appearing nodes on CT but is PET avid. Staging can be omitted in patients with established metastatic disease, small peripheral clinical T1a tumors, and bulky mediastinal adenopathy on imaging.[7]

Additional Diagnostic Studies

Multiple techniques can be utilized to sample the mediastinum, which can be divided into surgical, endobronchial, or esophageal, and differ in the number of locations of accessible nodes. Surgical techniques include mediastinoscopy, video-mediastinoscopy, anterior mediastinoscopy, and video-assisted thoracic surgery. Traditional mediastinoscopy can access lymph node stations 1, 2 right and left (R/L), 3, 4 R/L, and 7, and video-assisted mediastinoscopy can also obtain levels 5, 8, and 10 R. The false negative rates for these procedures are approximately 2%, but this is likely dependent on the operator.

Endobronchial techniques involve using an ultrasound probe to identify specific landmarks associated with certain mediastinal nodal levels. Endoscopic bronchial ultrasound with needle aspiration (EBUS-NA) is one of these techniques. It can access nodal levels 2 R/L, 3, 4 R/L, 7, 10, 11, and 12. Esophageal ultrasound with needle aspiration (EUS-NA) can access 4L, 5, 7,8, and 9. The false negative rate may be as high as 20% but highly depends on the operator's and institution's skill and experience. EBUS or EUS is typically the first approach offered to patients requiring mediastinal nodal evaluation. 

Baseline pulmonary function testing (PFT) is also essential, especially in patients who may be surgical candidates. (Refer to the Surgical Oncology section for more information on pulmonary function testing in presurgical evaluation). Furthermore, genetic assessment of PD-L1 status and EGFR mutations are also performed as they are targetable, including neoadjuvant and adjuvant therapies. However, EGFR mutations in SCC are rare, estimated at less than 5%.

Treatment / Management

The treatment varies with the stage of cancer. Surgical resection is the first line of therapy for stages I and II. For stage IA, chemotherapy typically has no role. For IB, surgical resection with adjuvant chemotherapy is considered in some cases if the tumor size is greater than 4 cm. Stage II is treated by surgery followed by chemotherapy; usually, lobectomy is preferred, but in poor surgical candidates, sub-lobar resection can be considered. In stages I and II, if postsurgical margins are positive and in poor surgical candidates, radiation therapy is considered.

Most stage III tumors are unresectable. Stage IIIA, which is definitively staged during resection surgery, can be considered followed by adjuvant chemotherapy, but chemotherapy with radiation is the usual choice. More recently, there is increasing evidence favoring the use of perioperative systemic therapy using chemoimmunotherapy combinations. For stage IIIB, combined chemotherapy and radiation are used, followed by maintenance immunotherapy for 1 year. In stage IV, systemic treatment with palliative radiation is used. Multiple randomized, controlled trials and large meta-analyses confirm the efficacy of combination chemotherapy and immunotherapy or single-agent immunotherapy regimens for advanced NSCLC.[2] Also, depending on mutation status, targeted therapy is used more often in non-squamous cell lung cancers. In advanced NSCLC, treatment should be based on the molecular features of the tumor.(B3)

In NSCLC with somatic-driven mutation, specific inhibitor therapy is indicated.[8] For epidermal growth receptor mutation, tyrosine kinase inhibitors (TKI) like erlotinib, gefitinib, and afatinib are used. NSCLC, which lacks this mutation depending on programmed cell death-ligand 1 (PD-L1) expression, immunotherapy alone or combined with chemotherapy is considered. Additionally, chemotherapy for neoadjuvant and adjuvant therapy may be considered, including cisplatin with paclitaxel, gemcitabine, or pemetrexed for non-squamous histologies. In patients who cannot tolerate cisplatin, paclitaxel with carboplatin is considered. Having all patients with tumors >4 cm or positive nodes be evaluated for preoperative therapy is recommended, including immunotherapy using nivolumab or pembrolizumab in addition to chemotherapy. However, if patients are not candidates for immune checkpoint inhibitors due to autoimmune diseases, being on immunosuppressants, or carrying EGFR mutations or ALK rearrangements, then combination chemotherapy alone is recommended. 

Targeted Therapy

For advanced cancers, treatment should be tailored according to genetic and molecular testing, including ALK rearrangement, ROS1 fusion, EGFR, BRAF, NTRK 1/2/3, MET exon 14 skipping, RET rearrangement, Her2 mutations, and PD-L1 testing. 

• PD-L1 ≥50%: In patients with advanced SCC of the lung with PD-L1 ≥50%, preferred options for first-line treatment include single-agent pembrolizumab, cemiplimab, or atezolizumab, the combination of carboplatin with paclitaxel or albumin-bound paclitaxel and pembrolizumab, or cemiplimab with chemotherapy.

• PD-L1 1% to 49%: For SCC of the lung in this category, preferred first-line treatment options include combination chemotherapy with either pembrolizumab or cemiplimab.

• EGFR exon 19 deletion or exon 21 L858R mutations: Osimertinib is the preferred agent.[9] At progression there, patients can be treated with doublet chemotherapy and immune checkpoint inhibitor therapy. Patients treated with either erlotinib, afatinib, gefitinib, or dacomitinib in the first-line setting can be switched to osimertinib at progression after confirming T790M mutation either on liquid biopsy or tumor sample.[10] 

• EGFR S768I, L861Q, or G719X mutations: Preferred agents for these groups of patients include afatinib or osimertinib.

• KRAS G12C: These patients are initially treated based on PD-L1 status and, at progression, are treated with either sotorasib or adagrasib.[11][12]

• ALK rearrangement: When ALK rearrangement is detected before the initiation of any systemic therapy for advanced SCC of the lung, it is preferred to use TKI therapy using agents alectinib, brigatinib, or lorlatinib.[13][14][15]

• ROS1 rearrangement: Patients with advanced ROS1 rearrangement cancers can be treated in a first-line setting with TKI therapies, including entrectinib, crizotinib, or repotrectinib.[16] 

• BRAF V600E mutation: In patients with BRAF V600E mutation that is identified before any systemic therapies, it is preferred to BRAF/MEK inhibitor therapy, including either a combination of dabrafenib and trametinib or encorafenib and binimetinib.[17]

• NTRK 1/2/3 fusion: Larotrectinib or entrectinib can be used first-line to treat advanced SCC of the lung harboring NTRK gene fusion.[18][16]

• MET exon 14 skipping mutation: Advanced NSCLC patients with MET exon 14 skip mutation now have the option of first-line targeted therapy with capmatinib or tepotinib.[19][20] 

• RET rearrangement: Preferred first-line targeted therapies of either selpercatinib or pralsetinib are currently available for NSCLC harboring RET rearrangements.[21] 

• Her2 mutation: For patients with NSCLC in advanced stages harboring her2 mutations, trastuzumab deruxtecan is currently approved for second-line use after progression on first-line systemic chemotherapy to chemoimmunotherapy.[22]

Differential Diagnosis

SCC of the lung must be differentiated from other lung cancers, including small cell lung cancers (SCLC) and other NSCLCs such as adenocarcinoma and large cell carcinoma.

Surgical Oncology

Surgical resection is considered the standard of care for early-stage lung cancers in all medically fit patients.[23] Conventionally, Stage IIIA (T3N1) was considered the limit of surgical resection. Anatomic pulmonary resection, largely consisting of a lobectomy, is considered the gold standard. Video Assisted Thoracic Surgery (VATS) is the preferred noninvasive approach to anatomic lung resections. It has reduced the length of hospital and recovery times for patients compared to an open thoracotomy. Long-term oncologic outcomes appear to be equivalent.[24][25] 

More limited resections consisting of segmentectomy or wedge resection for T1N0 NSCLC result in higher local recurrence rates (6% versus 18%) and higher death rates than a lobectomy but with better pulmonary function.[26] Despite this, more limited resections may be necessary in patients with poor pulmonary reserve or small nodules lesser than or equal to 2 cm that are pure AIS, doubling times more than 400 days, or greater than or equal to 50% GG on CT.[23] Indications for a VATS lobectomy include stage I to II disease, tumor sizes less than 6cm, more than 3cm from carina, more than 1cm from fissure line, and no mediastinal lymph node involvement. A pneumonectomy, which consists of total lung removal, may be necessary, but only after less radical interventions have been considered. They are usually indicated when the tumor is centrally located, involving a mainstem bronchus, or crosses major fissure lines. Pneumonectomies can have higher mortality rates and a substantial reduction in pulmonary reserve.[27] The representative N1 and ipsilateral N2 nodal stations should be evaluated regardless of the resection type. A minimum of 3 N2 nodal stations should be sampled.[23] This is critical for pathologic staging and determination of the need for adjuvant chemotherapy. The more extensive T3 and T4 tumors will require en-bloc resection.

Preoperative assessment is critical in identifying suitable candidates for surgery. A patient's history of cardiac disease, prior lung resections, COPD, bronchiectasis, and chronic pulmonary infections (eg, tuberculosis, interstitial lung diseases, pulmonary hypertension) can all affect the patient's ability to tolerate surgery. Determining a patient's pulmonary reserve and predicting their postoperative lung capacity is essential. The consequences of not taking this into account are severe disability and death. A simple and vital first step in preoperative assessment is the chest CT scan, which the patient would have already received. This can be used to count the number of lung segments, determine the extent of surgery required (ie, lobectomy versus pneumonectomy), and predict postoperative lung volumes. 

Quantitative pulmonary function testing with spirometry and diffusion capacity is essential to determining a patient's eligibility for surgery. Forced expiratory volume in 1 second (FEV1) and diffusion capacity for carbon monoxide (DLCO) are considered the most important predictors of postoperative complications. The American College of Chest Physicians (ACCP) endorses these metrics and provides a valuable algorithm to determine the need for further testing. If a patient's FEV1 and DLCO is greater than or equal to 80%, no further testing is required; if DLCO or FEV1 falls below 80%, then predicted postoperative lung function testing should be performed.[28] Predicted postoperative values are determined by the preoperative values, the amount of lung to be resected, and its overall contribution to lung function. This is accomplished with either segment counting on CT chest (preferred in lobectomy) or lung scintigraphy, preferred in pneumonectomy.[28] From this information, a predicted postoperative FEV1 or predicted postoperative DLCO can be determined. No further testing is required if the predicted postoperative FEV1 or predicted postoperative DLCO is greater than or equal to 60%.[28] Below 60%, further risk stratification is needed, usually with a cardiopulmonary exercise test or a simple walking test would be indicated. Based on the VOmax, the patients are risk stratified into low, moderate, and high risk. In low-risk patients, mortality is less than 1%, while in high-risk patients, the risk of morbidity and mortality exceeds 10%.

Mortality for lobectomies ranges from 1.4% to 2.6%.[29][30] The most common complications include air leaks, with a reported incidence of 15% to 25%. Atrial fibrillation can occur in up to 40% of patients.[29] Pneumonia has been reported in 2.5% to 6% of all patients.[30] Less common complications include hemorrhage, chylothorax, phrenic nerve injury, recurrent laryngeal nerve injury, bronchopleural fistula, and right middle lobe torsion.[29] Pneumonectomies tend to carry higher rates of mortality and morbidity. Mortality ranges from 5% to 11%, and morbidity can be as high as 60%. The most common complications include bronchopulmonary fistula, cardiac arrhythmias (19%), pneumonia (3.5%), and empyema (4.8%).[31][32]

Radiation Oncology

Radiotherapy alone was a primary mode of treatment for patients with inoperable lungs before the introduction of chemotherapy in the 1980s. Since that time, the delivery and role of radiation therapy in squamous cell lung cancer and non-small cell lung cancer, in general, have evolved considerably. Early-stage lung cancers can be cured with radiotherapy alone, while more advanced disease typically requires the use of concurrent chemoradiation. Radiotherapy can be utilized in definitive, adjuvant, recurrent, and palliative settings with or without chemotherapy. Various techniques and fractionation schedules can be employed depending on the situation and treatment goals.

Definitive Radiotherapy

In general, patients with locally advanced inoperable squamous cell lung cancer and NSCLC are typically offered concurrent platinum-based chemoradiotherapy followed by adjuvant Durvalumab as the standard of care.[23] However, it may also be offered after induction chemotherapy as well.[23] The use of chemotherapy in this setting, in addition to radiotherapy, demonstrated a survival improvement over radiotherapy alone.[33] Further trials demonstrated that the ideal sequencing delivers radiotherapy and chemotherapy concurrently, improving 5-year survival rates by 5%.[34][35] A meta-analysis for concurrent versus sequential showed a 5.7% improvement in overall survival at 3 years.[35]

Preoperative Radiotherapy

Preoperative radiotherapy is typically accompanied by platinum-based chemotherapy. Doses are usually lower than definitive therapy, ranging from 45 to 50 Gy.[23] Indications for this approach are typically for resectable superior sulcus tumors but could be utilized in several circumstances. Randomized evidence comparing definitive chemoradiotherapy to 61Gy alone or preoperative chemoradiotherapy to 45Gy followed by surgical resection in technically resectable Stage IIIA NSCLC demonstrated no difference in overall survival.[27] However, subgroup analysis of the surgical patients found superior 5-year overall survival (18% versus 36%) in patients who received a lobectomy rather than a pneumonectomy. In patients with superior sulcus tumors (T3-4 N0-1 M0), the primary approach considered is preoperative chemoradiotherapy to 45Gy followed by resection if there is no progression on follow-up imaging.[23] This approach had excellent outcomes, with a 5-year overall survival rate of 44% for all patients and 53% for complete resections.[36] 

Postoperative Radiotherapy

Postoperative radiotherapy is typically indicated in patients who have residual disease postoperatively. Doses vary from 54 to 60 Gy for an R1 resection or extracapsular extension to 60 to 70 Gy for patients with gross residual disease. The use of postoperative radiotherapy for those with N2 disease has been controversial until recently. The LUNG-ART trial randomized patients with completely resected N2 NSCLC to receive 54 Gy to the primary surgical bed and mediastinal nodes or no radiation. No difference in disease-free survival was found.[37] 

Hypofractionated Radiotherapy

Hypofractionated radiotherapy utilizes doses that exceed more than 2 Gy/fraction but are lower than what can be delivered with SBRT and is typically a more protracted course. It can be employed in early-stage disease where the 5 fraction dose constraints for SBRT cannot be met, such as in ultra-central tumors defined as the GTV or PTV abutting or overlapping the proximal bronchial tree, trachea, or esophagus, tumors more than 5 cm, or in palliative cases.[38] Doses typically range from 60 to 70 Gy in 8 to 15 fractions.[23][39][40] Local control rates range from 85% to 92% at 2 years with acceptable toxicity.[40][41][42] Several ongoing trials, such as the SUNSET and LUSTRE trials, are currently examining the role of hypofractionated regimens.[43][44] 

Radiotherapy Dosing and Constraints

The ideal dosing for conventionally fractionated radiotherapy was established by the RTOG 7301 trial from the 1970s, which tested doses ranging from 30 to 60 Gy delivered continuously or as a split course.[45] It asserted that the ideal dosing was 60 Gy in 2 Gy per fraction. NCCN guidelines allow a range of 60 to 70 Gy in 2Gy/fraction.[23] Several dose-escalation trials have been attempted with varying degrees of success since that time. Randomized evidence of 60 Gy versus 74 Gy for unresectable stage III NSCLC resulted in inferior overall survival at 5 years (32% versus 23%) and higher rates of pneumonitis and esophagitis.[46] More contemporary trials, such as CRTOG 1601, have attempted selective dose escalation based on positron emission tomography (PET) or computed tomography (CT) adaptive planning, demonstrating an improvement in median survival of 44.6 versus 28 months. Patients were randomized to 60 Gy in 30 fractions or underwent dose escalation with an extra 22 to 32 Gy in 10 fractions based on PET or CT adaptive planning.

Dose constraints have been established for various organs at risk (OARs) that clinicians may encounter in the thorax. The most common include the spinal cord, heart, esophagus, normal lung, and brachial plexus. The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) guides appropriate dose constraints relative to the risk of toxicity. The spinal cord should generally be less than 45 Gy point max dose for a near zero risk of cord myelopathy. The mean esophagus dose should be kept at less than 34 Gy and V50 less than 35%. Normal lung dose constraints have been studied with various metanalysis. Ideally, the lung V20 less than 20%, which had an 18% pneumonitis rate with no deaths.[47] Unfortunately, it may not be possible to attain this, and clinical decisions will need to be made regarding target coverage relative to the risk of acute and late toxicities.

Radiotherapy Complications

Intensity-modulated radiotherapy has modestly reduced the rates of toxicity associated with conventional radiation compared to 3D conformal but without a change in oncologic outcomes.[46] Pneumonitis is a common complication with lung radiotherapy that can result in significant long-term disability and death in some cases. Historically, pneumonitis rates were approximately 30% in the 3D conformal era, but with IMRT, the rate is now around 8%.[46] The V20 is the most frequently used dosimetric parameter to evaluate radiation plans, and the risk of pneumonitis A V20 Gy ranging from 20% to 40% has a 30% to 40% rate of pneumonitis.[48] The addition of chemotherapy agents such as carboplatin/paclitaxel can increase this risk.[48] Esophagitis occurs in roughly 30% to 40% of patients and depends on the tumor's location and the dose to the esophagus. Cardiovascular toxicity ranges from 5% to 8% and is correlated with the V40 parameter. For each additional gray received by the heart, there appears to be a 7.4% increase in the relative risk of major coronary events with no apparent threshold dose.[49]

Stereotactic Body Radiotherapy

Stereotactic body radiotherapy (SBRT) is defined as the use of imaged guided high-dose radiation therapy delivered in 5 fractions or less to ablate the tumor.[50] In the setting of lung SCC, it typically has a role in the treatment of central and peripheral early-stage primary lung tumors (T1-T3N0) and an emerging role in the treatment of oligometastatic disease, defined as less than 3 to 5 sites of metastasis.[51] [52] 

While VATS lobectomy remains the standard of care for early-stage lung cancers, SBRT can be considered in patients who are medically inoperable, technically inoperable, or who refuse surgery. SBRT is a noninvasive and well-tolerated technique with 3-year primary tumor control rates exceeding 90% for peripheral and 80% for centrally located tumors.[52][53][54] Prospective trials comparing surgery to SBRT have been attempted but have closed due to poor accrual.[55] However, the results suggest comparable rates of disease control with acceptable toxicity but do suggest comparable relapse-free survival rates (80% surgery versus 86% SABR).[55] 

These trials had several caveats, specifically low patient enrollment (58 patients) and very few patients who underwent VATS lobectomy, which would be expected to improve outcomes compared to open resection. Current prospective trials are again investigating resection versus SBRT. The STABL-MATES trial (NCT02468024) is investigating sub lobar resection versus 54 Gy in 3 fractions of SBRT, while the VALOR trial (NCT02984761) is investigating anatomic resection compared to SBRT. Larger retrospective reviews examining SBRT versus surgery for the early-stage disease have found comparable cancer-specific survival despite having inferior overall survival.[56] Other studies have shown similar OS and DFS after adjusting for age and operability. Local control was also comparable (85% versus 87% at 3 years).[57] 

A unique approach utilizing neoadjuvant SBRT followed by resection has been investigated in the MISSILE trial, demonstrating 100% 2-year local control and 77% 2-year overall survival with excellent quality of life.[58] The pathologic complete response rate was 60%, and it was lower than expected, which may have been due to the short interval between SBRT and surgery.[58] Other caveats include short follow-up and a small number of enrolled patients.[58]

Stereotactic body radiotherapy dosing and constraints

Local control is highly dependent on the biologically equivalent dose (BED). Tumors receiving BED <100 Gy have a 5-year local control rate of 36.5%, while those with ≥100 Gy are 84.2%.[59] The 5-year overall survival in patients receiving BED less than 100 Gy was 19.7% and 53.9% for those greater than or equal to 100 Gy. Therefore, the dose and fractionation are critical but must be balanced against potential toxicity. Peripheral tumors are defined as being at least 2 cm away from the proximal bronchial tree. They can typically receive higher doses in smaller fractions than centrally located tumors within 2 cm of the bronchial tree.[54][60] 

NCCN guidelines provide a comprehensive list of potential SBRT doses and fractionation schedules.[23] Peripheral tumors less than 2 cm in size and more than 1 cm from the chest wall can receive 25 to 34 Gy in a single fraction, and larger tumors can receive 45 to 60 Gy in 3 fractions, provided they are more than 1 cm from the chest wall. Doses of 50 to 55 Gy in 5 fractions are more versatile and can be used with peripheral tumors less than 1 cm from the chest wall and central tumors. More protracted hypofractionated regimens can also be considered for central tumors. SBRT dose constraints for these regimens can be found in the NCCN guidelines for non-small cell lung cancer or the AAPM Task-group 101.[23][61] Major structures of concern in the thorax include the spinal cord, normal lung, heart, great vessels, and ribs. These constraints are meant to help minimize the risk of late adverse toxicities and should be followed closely. If there are difficulties meeting dose constraints, a more fractionated approach with a lower dose per fraction can be considered. Target coverage evaluation is also critical, and certain metrics have been developed to evaluate and compare target coverage. Conformity less than 1.2 to 1.5, gradient R ranging from 2.9 to 5.9 dependent on target volume, and overall coverage V-100% are evaluated.[60][62] 

Set-up and planning

Given the high doses and the small number of fractions in SBRT, it is critical to have highly reproducible positioning and targeting accuracy. A CT simulation is typically the first step with the patient placed in the supine position on a stereotactic body frame and a CT slice thickness of ≤5 mm but recommended 1 to 3 mm.[61] The scan range should be from the cricoid superiorly to the L2 vertebrae inferiorly. 

The movement of the target caused by the respiratory cycle is an inherent problem with lung SBRT. While there is relatively little movement with tumors in the upper lobes of the lung, the closer the tumor is to the diaphragm, the more tumor motion can be expected. If tumor motion exceeds 5 mm, it is recommended that some motion management techniques be employed.[63] Several techniques to mitigate this issue include 4-dimensional CT (4D-CT), respiratory gating, abdominal compression, and fiducial marker tracking. 

A 4-dimensional CT is a simulation scan containing both spatial and temporal information regarding the tumor's location in each respiratory cycle phase. A series of "slow" CT scans are acquired and binned according to the respiratory phase. They are typically divided into 10 phases. These sequences can then be "played," and tumor motion can be appreciated. If the tumor motion exceeds 1 cm, additional devices, such as abdominal compression, may be used to limit tumor motion. Abdominal compression devices can range from a relatively simple belt placed around the patient's abdomen to more sophisticated devices that are attached to the treatment table and apply pressure to the abdomen in predetermined increments.

Respiratory gating is another technique that isolates a particular portion of the respiratory cycle to deliver radiation. Breathing is monitored with either spirometry or surface monitoring.[64] The spirometric techniques typically occlude breathing either by a valve (ie, active breathing control) or voluntarily (ie, deep inspiratory breath hold). These techniques typically require coaching the patient and determining the most comfortable degree of inspiration for optimal breath hold, usually 70% to 80% of inspiration.[64] The surface monitoring technique uses a plastic box with markers that reflect infrared light. The apparatus is placed on the patient and can be tracked in 3 dimensions in real-time. These techniques tend to result in longer treatment times but can reduce the volume of uninvolved lung radiated.   

Fiducial marker tracking is another option for targeting. Depending on the tumor's location, it requires implanting a radiopaque marker, typically gold, either with endoscopy or CT guidance. The fiducial markers can be tracked using cone beam CT, kilovoltage x-ray imaging (kV imaging), or an automated tracking system to identify the offset and calculate the required shifts. The disadvantage is that it can add additional time, cost, and treatment complications but allows for smaller expansions, thus sparing additional uninvolved lung tissue. Each marker must remain in the same place relative to the other markers and the tumor. The markers also risk migration, requiring a second implantation. Migration rates range from 1% to 19%, depending on the type of marker implanted.[65]

Once the patient has been simulated, target delineation can begin. The CT from the initial simulation and a fused PET/CT can ensure the target is completely outlined. Contouring in lung windowing is especially helpful. Once the gross tumor volume has been outlined, expansions to the volume account for tumor motion and set-up uncertainty. If the institution has 4D-CT capabilities, the GTV is contoured on every phase of respiration and then combined to form an internal target volume (ITV). Alternatively, the maximal intensity projection (MIP) could also be used to construct an ITV. However, it is vulnerable to error in cases of irregular breathing or close proximity to the diaphragm. A planning target volume expansion (PTV) is typically 5 mm.

Stereotactic body radiotherapy delivery 

Treatment delivery of SBRT can be delivered with dedicated stereotactic systems such as Cyberknife or with various linac-based systems utilizing intensity modulation. What is critical in SBRT delivery is the need for onboard image guidance to ensure accurate targeting. This can be accomplished with kV imaging, megavoltage (MV)-based planar imaging, or volumetric with cone beam CT.

Stereotactic body radiotherapy complications

SBRT is generally well tolerated, but the risk of acute or long-term toxicities should be considered when recommending treatment. The risks are determined by the tumor's location (eg, peripheral, central, or ultra-central), dose, and volume of irradiated tissue. Radiation pneumonitis is a significant source of toxicity in lung radiotherapy and can result in lung fibrosis, the need for oxygen therapy, and even mechanical ventilation. The incidence ranges from 0% to 29%. Still, the severity is usually non-life threatening, even in patients with known lung disease, which is likely due to the smaller volumes radiated with SBRT in general.[66]

Centrally located tumors treated tend to have higher toxicity rates than peripheral lesions. They also have a unique set of complications according to their location. Esophageal toxicity ranging from stenosis to tracheoesophageal fistula has been reported with an overall incidence of 12%.[67] Other complications, such as spontaneous pneumothorax, fatal hemoptysis, and vascular injury, are uncommon but have been reported in the literature and have a higher risk in the repeated irradiation setting.

Chest wall pain is usually observed with peripherally located tumors in approximately 30% of cases several months to years posttreatment. Rib fractures can occur up to 2 years posttreatment with an incidence of 5%, provided threshold volume and dose thresholds are met.[66] Skin toxicity is not as common, ranging from 1.2% to 14%.[66] It depends on the body's habitus and the distance between the overlying skin and the tumor. Brachial plexopathy is unique to tumors in the apex of the lungs.[66] The incidence is dose-dependent, but if the max dose to the brachial plexus can be kept at less than 26 Gy, the risk of plexopathy is around 8%. 

Repeated Irradiation

Most evidence for reirradiation of lung tumors after primary definitive radiotherapy is confined mainly to retrospective studies. Local relapse for NSCLC can occur within 2 years in about one-third of patients, and the rate of second primary lung tumors is 14% at 10 years.[68] Any patient being evaluated for repeated irradiation should also be assessed for repeated resection. Reirradiation is increasing with time, likely due to more posttreatment surveillance CT scans and improved radiation delivery methods, which allow for more normal tissue sparing. The survival rates in locally recurrent lung cancer are quite poor, with 2-year survival rates of 21%.[69]

Several technical challenges are associated with reirradiation, including the lack of a standard definition of what constitutes reirradiation, disagreement regarding an acceptable time interval between treatments, the ideal method of delivering radiation, and the lack of readily accepted cumulative dose tolerances. Several papers have attempted to address these issues with varying degrees of success. To establish a consensus, an expert survey was taken. Although a consensus failed to emerge, most experts defined reirradiation as any overlap in the previously radiated PTV or organs at risk.[68] The question of how much overlap is considered significant is traditionally considered at the 50% isodose line; however, this is also controversial. The minimum interval of 6 months is generally considered acceptable, although no official consensus exists.[68] Patients are unlikely to benefit from retreatment if they progressed in such a short amount of time or had Grade 3 or higher toxicity from the initial course.

Highly conformal radiation delivery with SBRT, IMRT/VMAT, or proton therapy can be considered.[68] Using conventional fractionation or moderate hypofractionation, 60 Gy in 30 or 55 Gy in 20 fractions are deemed acceptable. SBRT dosing depends on the location of the lesion being treated (ie, central versus peripheral) and ranges from 20 to 60 Gy in 1 to 5 fractions.[68] It is the preferred treatment method for peripheral recurrences and may be considered for central disease. However, SBRT is not regarded as appropriate for retreatment of ultra-central recurrences due to high rates of toxicity and death.[70] 

Devising acceptable dose constraints has been particularly challenging due to the lack of data regarding normal tissue recovery and dose or toxicity data in humans. Several groups have attempted to assemble cumulative dose constraints. However, there is no agreed-upon set of constraints or agreement on how to evaluate or report cumulative doses. The methods used to compare and report cumulative doses are the equieffective dose in 2Gy fractions (EQD2) or the biologic effective dose (BED). Both of these methods attempt to ensure a uniform comparison of doses delivered. There are several published putative cumulative dose constraints listed in EQD2.[68]

Complications resulting from retreatment include radiation pneumonitis, esophagitis, chest wall pain, cardiac toxicity, and death. Esophagitis was the most commonly reported toxicity, with a rate of 17%, followed by pneumonitis, with a rate of 12.3%. Rib fractures and spinal cord myelopathy occurred in <1% of cases. The risk of cardiac toxicity is related to the mean heart dose, and the relative risk increases by 7% for every additional 1Gy.[70] Treatment-related deaths were 1.6%.[71]

Pulmonary function testing should be considered, although there are no defined thresholds under which retreatment should not be offered. PFTs may be unnecessary for small peripheral recurrences treated with SBRT.[68] Retreatment should be individualized and discussed in a multidisciplinary tumor board setting. 

Palliative Radiotherapy

There are several circumstances where radiotherapy can be used for palliative purposes, including chest wall pain, bronchial obstruction, superior vena cava syndrome, hemoptysis, bone metastasis, and brain metastasis. Chest wall pain can be treated with doses ranging from 20 to 30 Gy in 5 to 10 fractions daily or in patients with particularly poor functional status, 17 Gy in 2 fractions given weekly.[23] Superior vena cava syndrome is not considered an oncologic emergency if the patient is stable. Typical doses range from 30 to 45 Gy in 10 to 15 fractions. Bone metastasis can be treated to 8 to 30 Gy in 1 to 10 fractions. Radiation is also helpful in promoting hemostasis in low-volume hemoptysis with doses of 8 to 30 Gy in 1 to 10 fractions. Various means can treat brain metastasis depending on the number of lesions, size of the brain lesions, and institutional resources. In patients with >10 lesions, whole brain radiotherapy is usually recommended at a dose of 30 Gy in 10 fractions.

Staging

Staging in lung cancer is based on CT scan images according to the Tumor-Node-Metastasis (TNM) staging system. The following is a summary of the eighth Edition of TNM in Lung Cancer, issued by the IASLC (International Association for the Study of Lung Cancer) and replaced by the TNM seventh edition.[72]

 Table. Eighth Edition of TNM Staging in Lung Cancer

• a: The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1a.
• b: Solitary adenocarcinoma, ≤3 cm with a predominately lepidic pattern and ≤5 mm invasion in any focus.
• c: T2 tumors with these features are classified as T2a if ≤4 cm in greatest dimension or if the size cannot be determined, and T2b if >4 cm but ≤5 cm in greatest dimension.
• d: Most pleural (pericardial) effusions with lung cancer are due to tumors. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is non-bloody and not an exudate. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
• e: This includes the involvement of a single distant (nonregional) lymph node. 

Table. Summary of TNM Staging for Lung Cancer, Eight Edition. 

Note: Changes from the seventh edition are in bold.

Prognosis

SCC of the lungs can spread to multiple sites, including the brain, spine, bones, adrenal glands, and liver. Due to the lower incidence of biologically relevant molecular targets for SCC and the late detection stage, the prognosis is often poor for these patients. However, it is to be noted that in advanced stages with higher levels of PD-L1 expression, checkpoint inhibitor therapies have provided better and prolonged responses in comparison to nonsquamous histologies. 

Complications

Complications from SCC of the lung can include:

• Shortness of breath if the tumor obstructs the major airways or causes fluid to accumulate around the lungs (ie, pleural effusion)
• Bleeding in the airway, resulting in hemoptysis
• Metastasis resulting in pain and neurological complications