Radiation Therapy for Early-Stage Non–Small Cell Lung Cancer

Etiology

Tobacco use is the primary risk factor for lung cancer. As a risk factor, tobacco accounts for 90% of 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 most common malignant cause of death 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 and, recently, in women.[6][7]

Pathophysiology

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

Histopathology

Thyroid transcription factor-1 helps distinguish if a tumor is a lung primary. Molecular diagnostic studies are increasingly utilized to determine genetic changes in the tumor, such as EGFR mutations, ALK gene rearrangements, ROS1 rearrangements, and PD-L1 expression. Increasing evidence shows that tumors with these specific gene mutations can respond to targeted therapies.[8]

History and Physical

Most patients with NSCLC present with symptoms of dyspnea, cough, hemoptysis, chest pain, and weight loss. They may also present with a change in mental status, clubbing, postobstructive pneumonia, pleural effusion, hoarseness due to recurrent laryngeal nerve involvement, and superior vena cava syndrome. Some patients present with superior sulcus tumors with Pancoast syndrome exhibiting symptoms of shoulder pain, brachial plexopathy, and Horner syndrome, which is characterized by ptosis, meiosis, and ipsilateral anhidrosis. Clinical factors associated with poor prognostic factors include advanced tumor stage, weight loss (>10% body weight over the past 6 months), Karnofsky Performance Status <90, pleural effusion, patients older than 70, use of chemotherapy, and nodal stage.

Evaluation

Diagnostic assessment for suspected lung cancer begins with a complete 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). Laboratory studies include a complete blood count, comprehensive metabolic panel, and liver function tests. Pulmonary function testing is needed for presurgical 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. Alternatively, diagnosis is obtained from surgical resection.[9][10] See StatPearls' companion reference, "Non–Small Cell Lung Cancer," for additional diagnostic and management information.

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

Treatment / Management

Radiation Oncology

While surgical resection with a lobectomy remains the standard of care in medically operable patients with early-stage NSCLC, radiotherapy is a well-tolerated, noninvasive alternative treatment modality for patients who are medically inoperable or refuse surgery. Stereotactic body radiotherapy (SBRT) or hypofractionated radiation courses are generally utilized.

Radiation Therapy Outcomes

When treating peripheral early-stage lung tumors, SBRT has demonstrated high local control rates ranging from 89% to 96%.[11][12] Central tumors treated with SBRT also have high local control rates at 89% at 2 years.[13] In cases where a 5-fraction regimen SBRT cannot be used, hypofractionated regimens have also been employed with 3-year local control rates of 81%. No difference in local control, disease-free survival, or overall survival has been shown when comparing SBRT to hypofractionated courses.[14] Ultra-central tumors can be particularly challenging to treat, given their proximity to mediastinal structures. Grade 5 toxicities have been reported with SBRT in the treatment of ultra-central lung tumors and are discouraged.[15] This may mandate a smaller dose per fraction and longer treatment courses to mitigate the risk of significant toxicity. The control rates may vary depending on the prioritization of the target or organs at risk. Patients receiving 50 Gy in 5 fractions or 60 Gy in 8 fractions have similar control rates (>90% at 2 years). However, patients receiving more protracted courses (eg, 60 Gy in 15 fractions) had significantly lower rates of control, especially if toxicity was prioritized over target coverage.[16](A1)

Radiation and Surgical Therapy Comparison

Radiation offers the advantage of being less invasive in medically inoperable patients. Prospective trials are slow to accrue patients, and existing evidence is confined to retrospective analysis. The ongoing Veterans Affairs Lung Cancer Surgery or Stereotactic Radiotherapy (VALOR) trial comparing SBRT to anatomic resection for NSCLC ≤5 cm still accrues patients. The combined analysis of the Stereotactic Ablative Radiotherapy for Operable Stage I Non-Small Cell Lung Cancer (STARS) and Radiosurgery or Surgery for Operable Early Stage Non-Small Cell Lung Cancer (ROSEL) trials demonstrated superior 3-year overall survival (95% versus 79%) and similar 3-year relapse-free survival (86% versus 80%).[17] However, this combined analysis contained only 58 patients; most surgical patients did not receive video-assisted thoracoscopic surgery (VATS) lobectomy. The results of the large meta-analysis have been somewhat conflicting, demonstrating similar or higher overall survival rates with surgery.[18][19][20] However, the biases inherent in these studies must be eliminated. Overall, radiotherapy is a safe alternative to surgery, but clinical equipoise has not been established.(A1)

Combination Therapy

SBRT and surgical resection combination in stage I (T1/2N0) patients has been investigated in small phase 2 trials. The Measuring the Integration of Stereotactic Ablative Radiotherapy Plus Surgery for Early-Stage Non-Small Cell Lung Cancer (MISSILE) trial combined SBRT followed by VATS lobectomy or sublobar resection after 10 weeks with a 2-year overall survival of 77% and local control rates of 100%. The pathologic complete response rate was lower than expected at 60%.[21] The introduction of immunotherapy has led to marked improvements in oncologic outcomes for patients with NSCLC. However, patients diagnosed with early-stage disease are typically not offered systemic therapy as definitive local therapy with surgery or radiation can be potentially curative. A phase 2 trial investigated the role of durvalumab combined with SBRT and surgical resection. The pathologic complete response was 27% versus 0% without immunotherapy. The low rate of pCR in the local therapy alone arm may have been due to the low doses of radiation (biologically equivalent dose 43 Gy) and the short time interval between SBRT and surgery.[22](A1)

Computed Tomography Simulation

Given the high doses and the small number of fractions in SBRT, highly reproducible positioning and targeting accuracy are essential. 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.[23] 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. Tumors in the upper lobes of the lung exhibit relatively little movement, while those closer to the diaphragm experience exhibit motion. If tumor motion exceeds 5 mm, motion management is recommended.[24] Several techniques to mitigate this issue include 4-dimensional CT (4D-CT), respiratory gating, abdominal compression, and fiducial marker tracking.(B3)

A 4D-CT is a simulation scan containing 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 are then "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. The spirometric techniques typically occlude breathing 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.[25] 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. The tracking requires the implantation of a radiopaque marker, typically gold, either with endoscopy or CT guidance, depending on the tumor's location. The fiducial markers can be tracked using cone beam CT, kilovoltage imaging, or an automated tracking system to identify the offset and calculate the required shifts. The disadvantages are additional time, cost, and treatment complications, but tracking allows for smaller expansions, 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.[26]

When the patient is simulated, target delineation can begin, and 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 gross tumor volume 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, ITV is vulnerable to errors in irregular breathing or proximity to the diaphragm. A planning target volume expansion is typically 5 mm.

Radiation Dosing

The location and size of the tumor are critical to determining the appropriate dose and fractionation. Recent protocols divide the tumor locations into 3 groups: peripheral, central, and ultra-central tumors. Peripheral tumors are typically defined as those at least 2 cm away from the proximal bronchial tree and other mediastinal structures. In comparison, central tumors are considered to be <2 cm of the proximal bronchial tree, trachea, heart, esophagus, and great vessels.[13] Ultra-central tumors are those where the planning target volume expansion overlaps with the proximal bronchial tree, esophagus, pulmonary vein, or pulmonary artery.[27] Although a lack of general agreement on the various definitions persists, the spatial relationship of the tumor to the mediastinal structures remains the primary concern.[28]

Local control is highly dependent on the biologically equivalent dose. Tumors receiving biologically equivalent doses <100 Gy have a 5-year local control rate of 36.5%, while those with ≥100 Gy are 84.2%. The 5-year overall survival in patients receiving biologically equivalent doses <100 Gy was 19.7% and 53.9% for those ≥100 Gy. Therefore, the dose and fractionation are critical but must be balanced against potential toxicity.[29](B2)

SBRT can be safely employed in treating peripheral and central lung tumors. Small peripheral tumors may be treated with 25 to 34 Gy in 1 fraction to 45 to 60 Gy in 3 fractions. Larger peripheral and central tumors may be treated with 48 to 55 Gy in 4 to 5 fractions. Longer courses with a lower dose per fraction may be employed in cases where there is a failure to meet dose constraints for organs at risk or an ultra-central location where toxicity may be considered unacceptable. Dosing in these cases varies from 60 to 70 Gy in 8 to 15 fractions.[14][27] Longer conventionally fractionated courses of radiation alone are generally not done and may be less efficacious than SBRT and hypofractionation.[30](A1)

Radiation Dose Constraints

Adhering to established dose constraints is critical to minimizing the risk of long-term toxicity, especially for central and ultra-central tumors. SBRT dose constraints for these regimens can be found in the National Comprehensive Cancer Network guidelines for NSCLC or the American Association of Physicists task group 101.[31][23] Major structures of concern in the thorax include the spinal cord, normal lung, heart, great vessels, and ribs.(A1)

These constraints are meant to minimize the risk of late adverse toxicities and should be followed closely. If difficulties exist in meeting dose constraints, a more fractionated approach with a lower dose per fraction can be considered. The Stereotactic Radiation for Ultracentral Non-Small-Cell Lung Cancer-A Safety and Efficacy Trial (SUNSET) contains dose constraints for hypofractionated radiotherapy in treating ultracentral lung tumors.[27] 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 (R² from 2.9 to 5.9 dependent on target volume), and overall coverage volume 100% are evaluated.[32][33](A1)

Radiation 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 (peripheral, central, or ultra-central), dose, and irradiated tissue volume. Radiation pneumonitis is a significant source of toxicity in lung radiotherapy and can result in lung fibrosis, the need for oxygen therapy, and mechanical ventilation. The incidence ranges from 0% to 29%; however, the severity is usually non–life-threatening in patients with known lung disease, likely due to the smaller volumes radiated with SBRT in general.

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%.[34] 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.(B2)

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. Skin toxicity is not as common, ranging from 1.2% to 14%. Toxicity 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.[35] The incidence is dose-dependent, but if the max dose to the brachial plexus is kept at <26 Gy, the risk of plexopathy is around 8%. 

Differential Diagnosis

The differential diagnosis should include:

• Bacterial overgrowth syndrome
• Colonic obstruction
• Diverticular bleed
• Gastrointestinal malignancy
• Hemorrhoids
• Inflammatory bowel disease
• Intestinal perforation
• Ischemic colitis
• Malabsorption
• Peptic ulcer disease
• Proctitis and sinusitis
• Small bowel obstruction

Radiation Oncology

The role of radiation in the management of early-stage lung cancer is limited. Radiation is only considered in patients who are not deemed surgical candidates or who have numerous comorbidities. 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 nonsurgical patients. To date, stereotactic body radiotherapy appears to have the highest survival rate compared to other techniques, with 3-year survival rates approaching 55%. The results of 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. Radiation therapy is reserved for patients with positive margins after resection.[36][37]