Alternatives to Surgery for Early-Stage Non–Small Cell Lung Cancer





Lung cancer is the leading cause of cancer death worldwide. Diagnosis of early-stage disease is becoming more common. In an aging population, more and more patients have substantial comorbidities that might limit feasibility of surgical management of early-stage disease. Stereotactic body radiotherapy (SBRT) enables delivery of high-dose, precisely delivered radiation to early-stage lung cancers without surgical risk. This technique has rates of local control similar to surgery and can be considered in medically operable patients who refuse surgery. This article details the technique of SBRT, the data for its efficacy, as well as the potential toxicities of treatment.


Key points








  • Stereotactic body radiotherapy (SBRT) is an alternative to surgery for early-stage lung cancer, particularly in patients with multiple medical comorbidities or who decline surgery.



  • SBRT allows highly conformal, hypofractionated (fewer fractions, higher dose per fraction) radiation plans and delivery of a higher biological effective dose than conventional radiotherapy.



  • SBRT has been shown to have lower toxicity and improved local control over conventional radiotherapy.



  • SBRT is generally well tolerated, although there is a low risk of pneumonitis or chest wall toxicity. More severe toxicity can arise in centrally located tumors.




Introduction


Lung cancer is the most common malignancy in the world and is the most common cause of cancer death. Historically, lung cancer was often clinically occult and not diagnosed until it was locally advanced or metastatic; however, adoption of computed tomography (CT)–based screening has led to increased detection of early-stage lung cancer. However, only ∼25% of lung cancer cases are diagnosed at early stage, even in the modern era.


Lobectomy with mediastinal lymph node dissection remains the standard of care for early-stage lung cancer in medically operable patients, with 5-year overall survival of more than 70%. Although advanced age alone would not be considered a contraindication for surgical intervention, in the modern aging population, there are many patients who are not operative candidates by virtue of insufficient pulmonary reserve, compromised cardiovascular status, or overall frailty. In the past, nonsurgical candidates with non–small cell lung cancer (NSCLC) were treated with definitive radiation using conventional fractionation (1.8–2 Gy per fraction over a course of 6–7 weeks), 2D techniques (without image guidance), and often large radiation fields to account for tumor motion during respiration. These techniques were crude and outcomes were poor, with local control rates approximately 30%. The Radiation Therapy Oncology Group (RTOG) conducted a series of radiation dose-escalation trials in the 1980s in an attempt to improve outcomes after definitive radiotherapy for lung cancer. RTOG 8311 increased radiation doses from 60 Gy to 79.2 Gy with twice-daily fractionation in increments of 4.8 Gy. Survival improved up to a dose of 69.6 Gy, but 2-year survival rates were lower at 74.4 Gy and 79.2 Gy, likely because of the pulmonary toxicity of high-dose radiation delivered in a nonconformal manner. Consistent with this finding, comparisons of 2D (planned based on bony anatomy) versus 3D conformal (planned based on CT images) radiation plans have shown superior locoregional control with 3D conformal radiotherapy.


Four-dimensional CT simulation (to account for respiratory motion) and intensity-modulated radiotherapy (IMRT) planning are the basis for the current state-of-the-art for conventionally fractionated radiotherapy. Recent data show that treating patients with NSCLC with IMRT planned on a 4D CT simulation resulted in similar local regional control and significantly decreased rates of grade 3 pneumonitis compared with 3D conformal radiation. , In parallel with the development of IMRT, several technological advances have also allowed the development of stereotactic body radiation therapy (SBRT), which has transformed the treatment of early-stage NSCLC and provides local control similar to lobectomy. SBRT refers to high dose per fraction, highly conformal radiation (shaped precisely to the tumor target while avoiding surrounding normal tissues) that is generally delivered in 5 or fewer fractions and treats a target volume with small margins ( Fig. 1 ). This technique is made possible by CT-based treatment planning; 4D simulation to account for respiratory motion; strict patient immobilization; and, in some situations, real-time tumor tracking via fiducial markers or fluorimetry. These features allow precise positioning and alignment of the patient and tumor in 3 dimensions.




Fig. 1


Lung SBRT treatment planning. ( A ) Target delineation with gross tumor volume (GTV) and planning target volume (PTV) to account for setup variation. In linear accelerator–based SBRT, an internal target volume (ITV) is also generated as expansion of the GTV to account for internal motion (ie, breathing). ( B ) Representative image of a lung SBRT with isodose lines representing the various dose levels: 56.7 Gy ( pink ), 54 Gy ( yellow , prescription dose), 27 Gy ( blue ), 20 Gy ( gold ), and 10 Gy ( purple ).


SBRT allows highly conformal hypofractionated (fewer fractions, higher dose per fraction) radiation plans and delivery of a higher biological effective dose (BED; ie, measure of true cell kill per radiation dose delivered based on tissue type and fractionation) than conventionally fractionated radiation (30–35 fractions at 1.8–2 Gy per fraction), which is thought to be important for local control of NSCLC. Conventional fractionation leverages radiobiology to ensure safety for surrounding organs at risk, whereas SBRT maximizes tumor dose and minimizes dose to adjacent organs by geometry and localization. Consistent with this hypothesis, a recent randomized trial shows improved local control and survival with SBRT compared with patients receiving standard radiotherapy.


Stereotactic body radiation therapy: treatment technique and treatment planning


SBRT can be delivered on a variety of different treatment platforms with several varying techniques. As with other types of modern radiation therapy, the SBRT treatment planning process begins with CT simulation. This planning CT scanning is obtained with the patient immobilized in the treatment planning position (using a stereotactic body frame or a vacuum-locked body cast). Respiratory motion can introduce severe geometric distortion into a conventionally obtained 3D CT scan. To overcome this, contemporary CT simulation includes a 4D CT scan, during which multiple 3D CT image sets are obtained, each corresponding with a different portion of the breathing cycle. This method allows accurate delineation of the tumor throughout the respiratory cycle.


The radiation oncologist then delineates the gross tumor volume (GTV) on either the free-breathing CT or on the average of the 4D CT. Tumor motion with the respiratory cycle is addressed by 1 of 2 methods: by gating during treatment or by creating an internal target volume (ITV). In a gated treatment, either the tumor or fiducial markers placed within the tumor are tracked during treatment delivery, and radiation is delivered only when the tumor or fiducial markers are within a specified region. When gating is not used, an ITV is generated as an expansion of the GTV to account for internal motion (ie, breathing; see Fig. 1 ) using the phases of the 4D CT. A planning target volume (PTV) is then created as a geometric expansion of the GTV (with gating) or the ITV (without gating) to account for uncertainty in daily positioning or setup. The desired dose is prescribed to cover the PTV. Organs at risk (heart, normal lung parenchyma, esophagus, great vessels, spinal cord, and chest wall) are also delineated as avoidance structures.


The radiation treatment plan is then optimized by dosimetrists and medical physicists using multiple beams from different angles to deliver the prescribed dose to the PTV, while sparing the organs at risk. Once the plan is finalized, quality assurance is conducted by the medical physicist to ensure that the plan is physically deliverable and that the appropriate doses are delivered to the target and organs at risk. The patient is positioned on the treatment table in the same fashion as the simulation, imaging is obtained to ensure proper patient alignment, and respiration accounted for by real-time imaging or respiratory gating/breath-hold, respectively. When the appropriate position and tumor localization are verified, the prescribed radiation dose is delivered. SBRT for early-stage lung cancer is typically delivered in 3 to 5 fractions over the course of 1 to 2 weeks, although single-fraction regimens have been studied.


Stereotactic body radiation therapy for early-stage, inoperable non–small cell lung cancer


Investigators at the Karolinska Hospital in Sweden were the first to use SBRT-like hypofractionated radiotherapy for extracranial sites (liver, lung, and retroperitoneal tumors) in the mid-1990s. Their initial report of the outcomes of 31 patients treated with stereotactic radiotherapy as well as the radical radiotherapy (postage-stamp fields covering the primary tumor alone delivered using opposed beams) used in the Netherlands were promising. , Three-year locoregional control rate was reported at 94%. These findings, coupled with major advances in technology, led to widespread use of the technique over the next several years. Seminal work from Onishi and colleagues in Japan showed that achieving a BED greater than 100 Gy is important for local control of early-stage NSCLC. Local control of lesions receiving SBRT with BED greater than 100 Gy was 92% versus 74% for patients receiving SBRT with BED less than 100 Gy, which served as the foundation for prospective dose-escalation trials. Of note, the most common doses and fractionations for lung SBRT (50 Gy in 5 fractions, 48 Gy in 4 fractions, 54 Gy in 3 fractions) all have a BED greater than 100.


Several important dose-escalation trials were performed at Indiana University and have guided the standard lung SBRT dose/fractionation schemes now in use. The initial phase I dose-escalation trial by Timmerman and colleagues included 37 patients with T1-2N0 biopsy-proven NSCLC treated with SBRT and found the maximally tolerated dose to be 60 Gy in 3 fractions. There were local recurrences in 6 patients in this study, all of whom received less than 54 Gy in 3 fractions. A subsequent phase II trial confirmed an excellent 2-year local control rate of 95% but identified a high rate of severe toxicity for central tumors located within 2 cm of the proximal bronchial tree ( Fig. 2 ). Six patients had treatment-related deaths, and 4 of those 6 had central lesions. These initial single-institution studies led to a cooperative group trial run by the RTOG. RTOG 0236 was a phase II multi-institution trial of patients with medically inoperable, stage I to II NSCLC with peripherally located tumors less than 5 cm. Patients were prescribed 60 Gy in 3 fractions; however, when accounting for dose heterogeneity (the difference in tissue density between lung and soft tissue) in treatment planning, the equivalent dose was 54 Gy in 3 fractions. Long-term follow-up showed 5-year local control of 93%, lobar control of 80%, distant failure rate of 31%, and overall survival 40%, which are consistent with large retrospective series ( Table 1 ). Of note, the low overall survival in both prospective and retrospective series for SBRT for lung cancer in medically inoperable patients is often driven by deaths from intercurrent disease and not from cancer-related deaths.




Fig. 2


SBRT dosing by tumor location. (1) Peripheral early-stage NSCLC, 18 Gy × 3 = 54 Gy; (2) lesion abutting the chest wall, 10 to 11 Gy × 5 = 50 to 55 Gy; (3) central lesion within the so-called “no fly zone” ( red dotted line , 2 cm from proximal bronchial tree), 10 Gy × 5 = 50 Gy; (4) ultracentral lesion abutting critical structures (eg, trachea/mainstem bronchus, mediastinal vessels, heart, esophagus, vertebral body), moderately hypofractionated radiotherapy (5 Gy × 12 = 60 Gy).


Table 1

Summary of results from studies of stereotactic body radiation therapy for early-stage inoperable non–small cell lung cancer




































































































n Dose End Point Time (y) Local Control (%) OS (%) Grade 3+ Toxicity (%)
Slotman et al, 1996 31 4 Gy × 12 = 48 Gy 3 94 42 NA
Uematsu et al, 1998 45 30–75 Gy/5–15 fractions 0.9 97 NA Minimal
Onishi et al, 2007 257 3–12 Gy × 1–25 = 18–75 Gy 3 92 a 88 2
Nagata et al, 2005 45 12 Gy × 4 = 48 Gy 2.5 98 83 4
Nyman et al, 2006 45 15 Gy × 3 = 45 Gy 2 80 71 NA
Timmerman et al, 2006 22 20–22 Gy × 3 = 60–66 Gy 1.5 95 b 55 11
RTOG 0236, 2014 59 20 Gy × 3 = 60 Gy 5 93 40 29
RTOG 0915, 2019 84 34 Gy × 1 vs 12 Gy × 4 = 48 Gy 5 89 vs 93 30 vs 41 3 vs 11
RTOG 0813, 2019 120 10–12 Gy × 5 = 50–60 Gy 3 85 c ∼45 12
Washington University, 2018 74 10–11 Gy × 5 = 50–55 Gy 2 85 43 6
Chang (MDACC), 2014 100


  • 12.5 Gy × 4



  • Ultracentral: 7 Gy × 10

2.5 96 70 2

Abbreviations: MDACC, MD Anderson Cancer Center; NA, not available; OS, overall survival.

a BED10 greater than100 data only.


b Peripheral lesions only.


c Cohorts 11 to 12 Gy; bold, prospective studies.



These pilot SBRT studies led to several subsequent cooperative group trials, including RTOG 0813 for central lesions and RTOG 0915 (single-fraction SBRT). RTOG 0813 was a phase I/II dose-escalation study, in which medically inoperable patients with biopsy-proven, centrally located NSCLC were treated with 5-fraction SBRT ranging from 10 to 12 Gy per fraction (50–60 Gy total) delivered over 1.5 to 2 weeks. Three-year local control was excellent (approximately 85%) with these 5-fraction regimens for patients receiving 11 to 12 Gy per fraction. There were 5 dose-limiting toxicities (DLTs) in the first year after treatment in patients receiving 10.5 Gy to 12 Gy per fraction for a total DLT rate of 7.2% (less than the protocol-specified limit of 20%). In addition to DLTs, 4 grade 5 (fatal) toxicities were noted in patients in the cohorts receiving 11.5 to 12 Gy per fraction, 1 caused by esophageal ulcer and 3 bronchopleural hemorrhages. As such, careful selection of dose and fractionation for central lesions is critical to balance local control with risk of severe toxicities. Despite a maximum tolerated dose of 12 Gy per fraction that was found in this trial, the number of late severe toxicities prevent this dose from being uniformly accepted.


A phase I/II dose-escalation trial from Washington University also found 10 to 11 Gy × 5 to be safe and efficacious for early-stage, central NSCLC, with 2-year local control 85% for 11 Gy × 5. Toxicities were tolerable: 6% grade 3 to 4 cardiac or pulmonary toxicities and 27% grade 3, 12% grade 4 and 4% grade 5 late toxicities. A phase I/II trial conducted by investigators at MD Anderson Cancer Center has evaluated the safety and efficacy of 50 Gy in 4 fractions and 70 Gy in 10 fractions for central and ultracentral tumors, respectively. Central tumors were defined as those within 2 cm of the proximal bronchial tree, mediastinal structures (eg, esophagus, major vessels) or a vertebral body. Ultracentral lesions were those that did not meet the 4-fraction dose constraints, often because of direct abutment with an organ at risk. Three-year local control was excellent at 96.5%, and only 2% of patients had grade 3 or higher toxicity. Similarly, the group from the Netherlands has shown a high rate of local control with 60 Gy in 12 fractions in patients with tumors abutting the trachea or mainstem bronchus. However, like RTOG 0236, their experience highlights the potential risk of severe toxicity in this patient population, with 38% of patients developing a grade 3+ toxicity and 15% grade 5 pulmonary hemorrhage. Thus, patients with ultracentral tumors abutting major vessels, the esophagus, or the trachea are at risk for severe toxicity even with moderately hypofractionated (non-SBRT) regimens (10–12 fractions).


RTOG 0915 was a randomized phase II trial comparing single-fraction SBRT (34 Gy) versus 12 Gy × 4 = 48 Gy SBRT for medically inoperable stage I peripheral NSCLC. One-year toxicity rates were the primary end point. Eighty-four patients were eligible for analysis with a median follow-up of 4 years. Rates of grade 3 or higher toxicity were noted in 3% of patients in the 34-Gy arm and 11% of the 48-Gy arm. Local control rates were 89% and 93%, respectively, and overall survival of 30% versus 41% in this medically inoperable patient population. Distant failure was the most common site of failure, occurring in about 40% of patients. Taken together, prospective studies show that SBRT offers patients with early-stage NSCLC high rates of 5-year local control (∼93%), with patients primarily failing in the regional lymph nodes (∼20%) and distant metastases (∼30–40%; summarized in Table 1 ).


Stereotactic body radiation therapy for early-stage, operable non–small cell lung cancer


Since the landmark Hammersmith study in the 1950s showing that patients with early-stage NSCLC had improved overall survival with pneumonectomy or lobectomy compared with conventionally fractionated radiation, surgery has been the standard of care for this patient population. Compared with SBRT, surgical approaches have the benefit of staging the mediastinum, although PET-CT scans are fairly sensitive and specific in detecting mediastinal adenopathy and invasive mediastinal staging (via mediastinoscopy or endobronchial ultrasonography-guided lymph node aspiration) can be performed if there are concerning or questionable lymph nodes on chest CT or PET-CT. Given the excellent local control and favorable toxicity profile of SBRT, several groups have recently become interested in evaluating SBRT for patients with early-stage, operable NSCLC.


JCOG (Japan Clinical Oncology Group) 0403 was a phase II trial of patients with biopsy-proven T1N0 NSCLC, 40% of whom were surgical candidates. Patients received SBRT with a dose of 48 Gy in 4 fractions. The primary end point was 3-year overall survival. Consistent with modern lobectomy series, 3-year overall survival was 77%, local control 86%, with 25% regional and 33% distant failures. Grade 3+ toxicity rates were low at 6%, primarily related to dyspnea, pneumonitis, and chest pain.


RTOG 0618 was another recent phase II trial of 26 operable patients with peripheral T1N0 NSCLC (<5 cm). The SBRT dose was 54 Gy in 3 fractions. With a median follow-up in 4 years, local control rate was 96%, regional failure 12%, and distant metastases 12%. Four patients had grade 3 toxicity, and no grade 4 to 5 toxicities were reported.


Concurrent with these phase II trials, 2 randomized phase III trials (Randomized Study to Compare CyberKnife to Surgical Resection In Stage I Non-small Cell Lung Cancer [STARS] and Trial of Either Surgery or Stereotactic Radiotherapy for Early Stage (IA) Lung Cancer [ROSEL]) were being conducted in the United States and Europe. The trials were similar in that they recruited patients with early-stage operable NSCLC. The STARS trial was based out of MD Anderson, required pathologic diagnosis, and randomized patients to lobectomy with nodal dissection versus SBRT with 54 Gy in 3 fractions (peripheral lesions) or 50 Gy in 4 fractions (central lesions). The ROSEL trial was conducted in the Netherlands and permitted patients without a pathologic diagnosis (PET scan only without biopsy). Patients on this trial were required to have a peripheral lesion and were randomized to surgery (as in STARS) versus SBRT with 54 Gy in 3 fractions or 60 Gy in 5 fractions.


However, both trials failed to accrue and were closed early. A total of 58 patients were enrolled in the 2 trials, and a combined analysis was recently reported. With a median follow-up of approximately 3 years, overall survival was higher in the SBRT group (95%) versus 79% in the surgery group, although recurrence-free survival was similar in the 2 groups (86% vs 80%, respectively; P = .54). Toxicity was also worse in the surgery group: rates of any grade 3 to 4 toxicity were 10% for SBRT patients and 44% for surgical patients. Dyspnea and chest/chest wall pain were the most common grade 3 toxicities overall. Grade 3+ lung infections, bleeding, fistula, hernia, anemia, nausea, weight loss, and arrhythmia were noted only in the surgical group.


Consistent with the pooled STARS/ROSEL analysis, data from the National Cancer Database support the finding of increased toxicity with lobectomy. In an analysis of 76,000 surgical patients and 8000 SBRT patients, the 30-day mortalities were 2.4% in the surgery group versus 0.8% in the SBRT group. Ninety-day mortalities were also higher in the surgery group (4.8% vs 2.8%).


Although lobectomy remains the standard of care for early-stage NSCLC, SBRT seems to provide similar local control and survival to lobectomy , (summarized in Table 2 ). The STARS/ROSEL data are intriguing, but in no way definitively show superiority of SBRT. Its limitations include small sample size, inclusion of patients without pathologic diagnosis (ROSEL), higher surgical toxicity than other trials, and differing follow-up schedules. Several ongoing randomized trials (Veterans Affairs Lung Cancer Surgery Or Stereotactic Radiotherapy Trial (VALOR), Stablemates, SAbRtooth, and Radical Resection versus Ablative Stereotactic Radiotherapy in Patients With Operable Stage I NSCLC (POSTILV)) aim to answer this important question of whether lobectomy or SBRT has superior tumor control and/or toxicity profile for early-stage operable NSCLC. SBRT can now be considered a reasonable alternative to lobectomy in patients who are high-risk operable or decline surgery.


Aug 16, 2020 | Posted by in GENERAL | Comments Off on Alternatives to Surgery for Early-Stage Non–Small Cell Lung Cancer
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