Squamous Cell Lung Cancer

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Continuing Education Activity

Squamous cell carcinoma (SCC) of the lung, also known as squamous cell lung cancer, is a type of non-small cell lung cancer (NSCLC). Squamous cell lung tumors often occur in the central part of the lung or the main airway, such as the left or right bronchus. The main causative agent of cellular transformation is tobacco smoke. Approximately 80% of lung cancer cases in men and 90% of patients in women are associated with smoking. 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, mineral and metal particles, or asbestos. This activity reviews the evaluation and management of squamous cell carcinoma of the lung and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

  • Identify the etiology of squamous cell lung cancer.
  • Review the appropriate history, physical, and evaluation of squamous cell lung cancer.
  • Outline the management options available for squamous cell lung cancer.
  • Summarize interprofessional team strategies for improving care coordination and communication to enhance the care of patients with squamous cell lung cancer and improve outcomes.

Introduction

Squamous cell carcinoma (SCC) of the lung, also known as squamous cell lung cancer, is a type of non-small cell lung cancer (NSCLC). Among NSCLC, adenocarcinoma is the most common, followed by squamous cell carcinoma of the lung, especially in women. This is attributed to the change in the pattern of cigarette smoking, but there is no definitive evidence.

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, mineral and metal particles, or asbestos.

Epidemiology

Lung cancer is the most common cancer and cause of cancer-related mortality worldwide.[3] Lung cancer incidence was estimated at 2,093,876 cases globally in 2018, accounting for 11.6% of the global cancer burden. The estimated mortality for lung cancer in 2018 was 1,761,007 deaths globally, constituting around 18.4% of global cancer-related mortality.[4]

The global distribution for lung cancer incidence in 2018 was: Asia (58.5%), Europe (22.4%), North America (12.1%), LAC (4.3%), Africa (1.9%), and Oceania (0.81%).[4]

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 lung disease 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 main 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/or intercellular bridges and often exhibit a high degree of 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 can be confirmed 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, together with 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 three variants of SCC based on histological examination.[6] These three variants are:

  • Keratinizing
  • Non-keratinizing
  • Basaloid: basaloid component is greater than 50% of the tissue with minimal areas of squamous differentiation

History and Physical

Reported symptoms of NSCLCs can include cough, chest pain, shortness of breath, blood in sputum, wheezing, hoarseness, recurring chest infections (including bronchitis and pneumonia), weight loss, and loss of appetite and fatigue. However, NSCLC patients often show no symptoms 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, spinal cord impingement, and neurologic symptoms (headache, weakness or numbness of limbs, dizziness, seizures).

Evaluation

Following the physical examination, a complete blood count (CBC), a chest X-ray, or computed tomography (CT) scan may be used to evaluate SCC, provided that the tumor is of sufficient size. 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, and pleural effusion.

Suspected lung malignancies require a diligent workup tailored to the extent of the disease. For small incidental nodules discovered on the chest CT, please see the Fleischner Society guidelines for management recommendations. If a diagnosis of lung cancer is especially high, then proceeding with the staging workup rather than obtaining tissue as a first priority may actually be more efficient as areas of metastasis may be detected. These areas could be more accessible and easier to biopsy, thus confirming the diagnosis and establishing the 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 under 1.5 cm in size. For lesions under 1.5 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 important in evaluating patients for possible brain metastasis. Usually, this is indicated in patients with at least a clinical Stage II disease.

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 that have either discrete enlargement of mediastinal nodes on CT regardless of PET avidity or normal-appearing nodes on CT but are PET avid. It can be omitted in patients with established metastatic disease, small peripheral clinical T1a tumors, and bulky mediastinal adenopathy on imaging.[7]

Multiple techniques can be utilized to sample the mediastinum and 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 levels 1, 2R/L, 3, 4R/L, and 7, while video-assisted mediastinoscopy can also obtain levels 5, 8, and 10R. The false negative rates for these procedures are approximately 2%, but this is likely dependent on the operator.

Endobronchial techniques involve the use of 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 2R/L, 3, 4R/L, 7, 10, 11, and 12. Esophageal ultrasound with needle aspiration (EUS-NA) can be utilized to access 4L, 5, 7,8, and 9. The false negative rate may be as high as 20% but is highly dependent on the skill and experience of the operator and institution. EBUS or EUS is typically the first approach offered to patients requiring mediastinal nodal evaluation.  

Baseline pulmonary function testing is also important, especially in patients that may be surgical candidates. The use of PFTs as part of the evaluation will be discussed in the surgical oncology section of this article.

Assessment of PD-L1, EGFR, ALK fusion oncogene, and other mutations are also performed as there may be targetable mutations.

Treatment / Management

The treatment varies with the stage of cancer. Surgical resection is the first line of therapy for stages I and II. For 1A, there is no role for chemotherapy. For 1B, 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, radiation therapy is considered if there are positive margins post-surgically and also in poor surgical candidates.

Most stage III tumors are unresectable. Stage IIIA, which is definitely staged during resection surgery, can be considered followed by adjuvant chemotherapy but chemotherapy with radiation is the usual choice. For stage IIIB, combined chemotherapy and radiation are used. In stage IV, chemotherapy with palliative radiation is used. Multiple randomized, controlled trials and large meta-analyses confirm the superiority of combination chemotherapy regimens for advanced NSCLC.[2] Also, depending on mutation status, targeted therapy is used as well. In advanced NSCLC, treatment should be based on the molecular features of the tumor.

In NSCLC with somatic-driven mutation, specific inhibitor therapy is indicated.[8] For epidermal growth receptor mutation, tyrosine kinase inhibitors like erlotinib, gefitinib, and afatinib are used. For ALK mutation, crizotinib is the first line. NSCLC, which lacks this mutation depending on programmed cell death-ligand 1 (PD-L1) expression, immunotherapy alone or immunotherapy combined with chemotherapy is considered. Chemotherapy for neoadjuvant and adjuvant therapy includes cisplatin with vinorelbine or etoposide, vinblastine, gemcitabine, docetaxel, or pemetrexed are considered. In patients who cannot tolerate cisplatin, paclitaxel with carboplatin is considered. First-line systemic therapy for advanced-stage includes bevacizumab, carboplatin, and paclitaxel. Other options are cetuximab with cisplatin and vinorelbine or erlotinib with platinum-based chemotherapy.

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.[9] Conventionally, Stage IIIA (T3N1) was considered the limit of surgical resection. Anatomic pulmonary resection is considered the gold resection standard, largely consisting of a lobectomy. Video Assisted Thoracic Surgery (VATS) has emerged as the preferred non-invasive 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.[10][11] 

More limited resections consisting of segmentectomy or wedge resection for T1N0 NSCLC result in higher rates of local recurrence (6% vs. 18%) as well as higher rates of death compared to a lobectomy but with better pulmonary function.[12] Despite this, more limited resections may be necessary in patients with poor pulmonary reserve or small nodules <=2 cm that is pure AIS, doubling times >400 days, or >=50% GG on CT.[9] Indications for a VATS lobectomy include Stage I-II disease, tumor sizes <6cm, >3cm from carina, >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.[13]

Regardless of the resection type, the representative N1 and ipsilateral N2 nodal stations should be evaluated. A minimum of 3 N2 nodal stations should be sampled. [9] 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

Pre-operative assessment is critical in identifying suitable candidates for surgery. A patient's history of cardiac disease, prior lung resections, COPD, bronchiectasis, chronic pulmonary infections such as tuberculosis, interstitial lung diseases, pulmonary hypertension, etc., can all affect the patient's ability to tolerate surgery. It is essential to determine a patient's pulmonary reserve and predict their postoperative lung capacity. The consequences of not taking this into account are severe disability and death. A simple and important first step in pre-op assessment is the CT scan of the chest, which the patient would have already received. This can be used to count the number of lung segments, determine the extent of surgery required (i.e., lobectomy vs. pneumonectomy), and predict postoperative lung volumes. 

Quantitative pulmonary function testing with spirometry and diffusion capacity is an essential part of determining a patient's eligibility for surgery. Forced expiratory volume in 1 second (FEV1) and diffusion capacity for carbon monoxide (DLCO) is considered the most important predictors of post-op complications. The American College of Chest Physicians (ACCP) endorses the use of these metrics and provides a useful algorithm to aid in determining the need for further testing. If a patient's FEV1 and DLCO ≥ 80%, no further testing is required; if DLCO or FEV1 falls below 80%, then predicted postoperative (PPO) lung function testing should be performed.[14]

Predicted postoperative values are determined by the pre-op 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).[14] From this information, a ppoFEV1 or ppoDLCO can be determined. If the ppoFEV1 or ppoDLCO is ≥ 60%, then no further testing is required.[14] 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 <1%, while in high-risk patients, the risk of morbidity and mortality exceeds 10%.

Arterial blood gases are not helpful in predicting postoperative lung function or the risk of postoperative complications,

Mortality for lobectomies ranges from 1.4 to 2.6%.[15][16] 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.[15] Pneumonia has been reported in 2.5 to 6% of all patients.[16] Less common complications include hemorrhage, chylothorax, phrenic nerve injury, recurrent laryngeal nerve injury, bronchopleural fistula, and right middle lobe torsion.[15] 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%).[17][18]

Radiation Oncology

Radiotherapy alone was a primary mode of treatment for patients with inoperable lungs prior to 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.[9] Although, it may also be offered after induction chemotherapy as well.[9] The use of chemotherapy in this setting, in addition to radiotherapy, demonstrated a survival improvement over radiotherapy alone.[19] Further trials demonstrated that the ideal sequencing delivers radiotherapy and chemotherapy concurrently, improving 5-year survival rates by 5%.[20][21] A meta-analysis for concurrent vs. sequential showed a 5.7% improvement in overall survival at three years.[21]

Pre-operative radiotherapy

Pre-operative radiotherapy is typically accompanied by platinum-based chemotherapy. Doses are usually lower than definitive therapy ranging from 45-50Gy. [9] Indications for this approach are typically for resectable superior sulcus tumors but could be utilized in serval circumstances. Randomized evidence comparing definitive chemoradiotherapy to 61Gy alone or pre-op chemoradiotherapy to 45Gy followed by surgical resection in technically resectable Stage IIIA NSCLC demonstrated no difference in overall survival.[13] However, subgroup analysis of the surgical patients found superior 5-year overall survival (18% vs. 36%) in patients that received a lobectomy rather than a pneumonectomy. In patients with superior sulcus tumors (T3-4 N0-1 M0), the primary approach considered is pre-operative chemoradiotherapy to 45Gy followed by resection if there is no progression on follow-up imaging.[9] This approach had excellent outcomes, with a 5-year overall survival rate of 44% for all patients and 53% for complete resections.[22]  

Post-operative Radiotherapy

Post-operative radiotherapy is typically indicated in patients that have residual disease post-operatively. 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 post-op 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. [23]  

Hypofractionation

Hypofractionated radiotherapy utilizes doses that exceed >2Gy/fraction but is 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 five 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), large tumors (>5 cm), or in palliative cases.[24] Doses typically range from 60 to 70 Gy in 8 to 15 fractions.[9][25][26] Local control rates range from 85-92% at two years with acceptable toxicity.[26][27][28] Several ongoing trials, such as the SUNSET and LUSTRE trial, are currently examining the role of hypofractionated regimens.[29][30] 

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 30-60Gy delivered continuously or as a split course.[31] It asserted that the ideal dosing was 60Gy in 2Gy per fraction. NCCN guidelines allow a range of 60-70 Gy in 2Gy/fraction.[9] Several dose-escalation trials have been attempted since that time with varying degrees of success. Randomized evidence of 60 Gy vs. 74 Gy for unresectable Stage III NSCLC resulted in inferior overall survival at five years (32% vs. 23%) and higher rates of pneumonitis and esophagitis.[32] More contemporary trials, such as CRTOG 1601, have attempted selective dose escalation based on PET/CT adaptive planning, demonstrating an improvement in median survival of 44.6 vs. 28 months. Patients were randomized to 60Gy in 30 fractions or underwent dose escalation with an extra 22 to 32 Gy in 10 fractions based on PET/CT adaptive planning.

Dose constraints have been established for various organs at risk (OARs) that one 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) provides guidance on appropriate dose constraints relative to the risk of toxicity. The spinal cord should generally be <45 Gy point max dose for a near zero risk of cord myelopathy. The esophagus mean dose should be kept at <34 Gy and V50 <35%. Normal lung dose constraints have been studied with various metanalysis. Ideally, the lung V20 <20%, which had an 18% pneumonitis rate with no deaths.[33] 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.

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.[32] Pneumonitis is one of the most common complications with lung radiotherapy and 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%.[32] The V20 is the most frequently used dosimetric parameter to evaluate radiation plans, and the risk of pneumonitis A V20Gy ranging from 20 to 40% has a 30 to 40% rate of pneumonitis.[34] The addition of chemotherapy agents such as carboplatin/paclitaxel can increase this risk.[34] 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.[35]

Stereotactic Body Radiotherapy (SBRT)

SBRT is defined as the use of imaged guided high-dose radiation therapy delivered in 5 fractions or less with the intention of ablating the tumor.[36] 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 <3 to 5 sites of metastasis. [37] [38] 

While VATS lobectomy remains the standard of care for early-stage lung cancers, SBRT can be considered in patients that are medically inoperable, technically inoperable, or who refuse surgery. It is a non-invasive and well-tolerated technique with 3-year primary tumor control rates exceeding 90% for peripheral tumors and exceeding 80% for centrally located tumors.[38][39][40] Prospective trials comparing surgery to SBRT have been attempted but have closed due to poor accrual.[41] However, the results suggest comparable rates of disease control with acceptable toxicity but do suggest comparable relapse-free survival rates (80% surgery vs. 86% SABR).[41] 

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 sublobar 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.[42] Other studies have shown similar OS and DFS after adjusting for age and operability. Local control was also comparable (85% vs. 87% at three years).[43]  

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.[44] 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.[44] Other caveats include short follow-up and a small number of enrolled patients.[44]

Dosing and Constraints

Local control is highly dependent on the biological 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%.[45] The 5-year overall survival in patients receiving BED <100Gy was 19.7% and 53.9% for those ≥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 and can typically receive higher doses in a smaller number of fractions than centrally located tumors located within 2 cm of the bronchial tree.[40][46] 

NCCN guidelines provide a comprehensive list of potential SBRT doses and fractionation schedules.[9] Peripheral tumors <2 cm in size and >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 >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 <1 cm from the chest wall and central tumors. More protracted hypo-fractionated regimens can also be considered for central tumors, but this will be covered in another section. 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.[9][47] In general, 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 <1.2 to 1.5, gradient (R – range from 2.9 to 5.9 dependent on target volume), and overall coverage V-100% are evaluated.[46][48] 

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.[47] 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 kind of motion management technique is employed.[49] There are several techniques to mitigate this issue, including 4-dimensional CT (4D-CT), respiratory gating, abdominal compression, and fiducial marker tracking. 

A 4-dimensional CT is a type of simulation scan that contains both spatial and temporal information regarding the location of the tumor in each phase of the respiratory cycle. 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.[50] The spirometric techniques typically occlude breathing either by a valve (Active breathing control) or voluntarily (deep inspiratory breath hold). These techniques typically require coaching the patient and determining the most comfortable degree of inspiration for optimal breath hold, which is usually 70 to 80% of inspiration.[50] 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. It requires the implantation of a radiopaque marker, typically gold, either with endoscopy or CT guidance, depending on the location of the tumor. The fiducial markers can be tracked using cone beam CT, kV/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 of the markers 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.[51]

Once the patient has been simulated, target delineation can begin. The CT from the initial simulation, along with 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, although 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.

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, MV-based planar imaging, or volumetric with cone beam CT.

SBRT 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 location of the tumor (peripheral, central, or ultra-central), dose, and volume of tissue irradiated. Radiation pneumonitis is a major 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%, but 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.[52]

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%.[53] 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 re-irradiation setting.

Chest wall pain is usually observed with peripherally located tumors is seen in approximately 30% of cases several months to years post-treatment. Rib fractures can occur up to 2 years post-treatment with an incidence of 5%, provided threshold volume and dose thresholds are met.[52] Skin toxicity is not as common, with incidences ranging from 1.2 to 14%.[52] It depends on the body habitus and the distance between the overlying skin and the tumor. Brachial plexopathy is unique to tumors in the apex of the lungs.[52] The incidence is dose-dependent, but if the max dose to the brachial plexus can be kept <26Gy, then the risk of plexopathy is around 8%.  

Re-irradiation

Most evidence for re-irradiation of lung tumors after primary definitive radiotherapy is confined largely to retrospective studies. Local relapse for NSCLC can occur within two years in about one-third of patients and the rate of second primary lung tumors is 14% at ten years.[54] Any patient being evaluated for re-irradiation should also be evaluated for re-resection. The use of re-irradiation is increasing with time, likely due to more post-treatment surveillance CT scans and improved radiation delivery methods which allow more normal tissue sparing. The survival rates in locally recurrent lung cancer are quite poor, with 2-year survival rates of 21%.[55]

There are several technical challenges associated with re-irradiation: the lack of a standard definition of what constitutes re-irradiation, 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 re-irradiation as any overlap in the previously radiated PTV or organs at risk.[54] 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.[54] 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 either SBRT, IMRT/VMAT, or even proton therapy can be considered.[54] If using conventional fractionation or moderate hypofractionation, 60Gy in 30 fractions or 55 Gy in 20 fractions are considered acceptable. SBRT dosing is dependent on the location of the lesion being treated (i.e., central vs. peripheral) and ranges from 20 to 60 Gy in 1 to 5 fractions.[54] 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.[56] 

Devising acceptable dose constraints has been particularly challenging due to the paucity of data regarding normal tissue recovery and dose/toxicity data in humans. Several groups have attempted to assemble cumulative dose constraints. However, there is no agreed-upon set of constraints, nor is there any agreement on how to evaluate or report cumulative doses. Two methods exist for comparing and reporting cumulative dose: Equieffective dose in 2Gy fractions (EQD2) or 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.[54]

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.[56] Treatment-related deaths were 1.6%.[57]

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. [54] Retreatment should be individualized and discussed in a multi-disciplinary tumor board setting. 

Palliation

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, 17Gy in 2 fractions given weekly.[9] 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 useful in promoting hemostasis in low-volume hemoptysis with doses of 8 to 30 Gy in 1 to 10 fractions. Brain metastasis can be treated by a variety of means 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.

Pertinent Studies and Ongoing Trials

The immunotherapeutic atezolizumab (anti-PDL1, RG7446, MPDL3280A monoclonal antibody against PD-L1 (programmed death-ligand 1) is being evaluated in a phase III clinical trial as a potential first-line treatment for patients with non-squamous or squamous non-small cell lung cancer whose tumors express PDL1. A phase I trial is also ongoing, evaluating atezolizumab in combination with erlotinib or alectinib in patients with non-small cell lung cancer. IPA-3 or OTSSP167 and auranofin were highly synergistic in EGFR or KRAS mutant squamous cell carcinoma cell lines and decreased tumor volume in mice models.[58]

Toxicity and Side Effect Management

Platinum-based chemotherapy, along with second active cytotoxic agents, is usually considered in patients who require chemotherapy. The chance of toxicity increases beyond four to six cycles of therapy and is not recommended beyond that. In patients with no optimal response, maintenance therapy can be continued with one or more components, but platinum-based treatment is typically discontinued, given its severe toxicity.[59] The patients should be monitored for nephrotoxicity, ototoxicity, cytopenias, and significant neuropathy. Folic acid, vitamin b12, and sometimes dexamethasone are usually considered to avoid some side effects of chemotherapy.

Staging

Staging in lung cancer is based on CT scan images according to the Tumor-Node-Metastasis (TNM) staging system. This is a summary of the 8th Edition of TNM in Lung Cancer, which is issued by the IASLC (International Association for the Study of Lung Cancer) and replaces the TNM 7th edition.[60]

 Proposed T, N, and M descriptors for the eighth edition of TNM classification for lung cancer

T: Primary tumor
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
T1 Tumor ≤3 cm in its 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) 
  T1a(mi) Minimally invasive adenocarcinoma 
  T1a Tumor ≤1 cm in greatest dimension 
  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 structures: chest wall (including the parietal pleura and superior sulcus tumors), phrenic nerve, the parietal pericardium
T4 Tumor >7 cm in greatest dimension or associated with separate tumor nodule(s) in a different ipsilateral lobe than that of the primary tumor or invades any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina
N: Regional lymph node involvement
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
M: Distant metastasis  
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 effusion 
  M1b Single extrathoracic metastasis 
  M1c Multiple extrathoracic metastases in one or more organs

Note: Changes to the seventh edition are in bold.

  • 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, ≤ 3cm with a predominately lepidic pattern, and ≤ 5mm invasion in any one 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.    

Proposed stage groupings for the eighth edition of the TNM classification for lung cancer

Occult carcinoma TX N0 M0
Stage 0 Tis N0 M0
Stage IA1 T1a(mi) N0 M0
  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 T1a–c N1 M0
  T2a N1 M0
  T2b N1 M0
  T3 N0 M0
Stage IIIA T1a–c N2 M0
  T2a b N2 M0
  T3 N1 M0
  T4 N0 M0
  T4 N1 M0
Stage IIIB T1a–c N3 M0
  T2a–b N3 M0
  T3 N2 M0
  T4 N2 M0
Stage IIIC T3 N3 M0
  T4 N3 M0
Stage IVA Any T Any N M1a
  Any T Any N M1b
Stage IVB Any T Any N M1c

Prognosis

Squamous cell lung cancer can spread to multiple sites, including the brain, spine, and other bones, adrenal glands, and liver. Due to the lack of targeted therapies for SCC and the late stage of detection, the prognosis is often poor for these patients.

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 (pleural effusion)
  • Bleeding in the airway, resulting in hemoptysis
  • Metastasis resulting in pain and neurological complications

Postoperative and Rehabilitation Care

Preoperative exercises and rehabilitation program has shown significant postoperative outcomes and reduced postoperative pulmonary complications.[61] However, postoperative pulmonary rehabilitation alone without preoperative exercise showed only a small to moderate effect on postoperative exercise capacity on the short-term follow-up, but the long-term effect on functional capacity is unknown.[62]

Consultations

  • Pulmonology
  • Cardiothoracic surgery
  • Medical oncology
  • Surgical oncology
  • Palliative care
  • Psychiatry

Deterrence and Patient Education

Education on avoiding or mitigating risk factors such as tobacco products and causes of occupational disease (such as using personal protective equipment) can reduce SCC development. Education about early cancer screening with low-dose CT scan of the chest is important for early recognization and treatment to prevent tumor burden. Counseling patients about the stages of cancer and the chance of a complete cure in case of early detection and counseling on palliative care in advanced stages is critical to reducing stress both for patients and loved ones.

Enhancing Healthcare Team Outcomes

Given the complexity of care required in treating this condition, an interprofessional healthcare team, including primary clinicians, pulmonologists, cardiothoracic surgeons, medical oncologists, radiation oncologists, surgical oncologists, and palliative care, is needed. Nurses, pharmacists, and respiratory and physical therapists round out the care team. Strong collaboration and communication within the interprofessional team, along with meticulous record keeping allowing all care team members access to the most accurate and updated patient information, are vital to improving outcomes.

While clinicians will direct the overall direction of the case, with other specialties working in their particular discipline. Nurses will play a pivotal role in helping with patient assessment, assisting in surgery and providing post-surgical care, administering chemotherapy, and offering patient counsel. An oncology-specialized pharmacist should oversee all chemotherapy regimens and can also check for drug interactions, answer clinician and patient questions about the drugs, and help monitor the patient's progress. All interprofessional team members must be open to communication from the rest of the team and report any concerns to everyone involved in patient care. This interprofessional team approach to case management for squamous cell lung cancer will yield optimal benefits with minimal adverse events. [Level 5]



(Click Image to Enlarge)
Squamous cell carcinoma of lung.
Squamous cell carcinoma of lung.
New England journal of medicine. Images in Clinical Medicine. PUB MED ID:30207918. Dr.Bhanu Sabbula
Article Details

Article Author

Bhanusivakumar R. Sabbula

Article Author

David P. Gasalberti

Article Editor:

Fatima Anjum

Updated:

11/5/2022 6:43:23 PM

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