85: Radiotherapy for Inoperable Non–Small Cell Lung Cancer

The multimodality management of inoperable non–small cell lung cancer (NSCLC) – from early-stage disease to locally advanced presentations – has changed substantially over the past 20 years. With the exception of small, stage I NSCLC, most nonmetastatic patients are treated with both local and systemic therapy, and there is an increasing interest in the integration of all three modalities. Radiation oncology has experienced dramatic technologic innovations over this time, which has allowed for reduced toxicity and consequent improvements in the therapeutic ratio, and in the notable case of stage I NSCLC, significantly higher cure rates.

The purpose of this chapter is to summarize the state of contemporary thoracic radiotherapy as it is used in the management of nonmetastatic, inoperable NSCLC. Inherent to this discussion are the relevant improvements in radiation therapy planning and delivery, which will be outlined in the beginning of this chapter. The remarkably improved efficacy of stereotactic body radiotherapy (SBRT) for stage I NSCLC will then be described, and this discussion will conclude with a focus on locally advanced lung cancer, highlighting three key and controversial issues that are central to the development of a treatment plan: use of chemotherapy, total radiotherapy dose, and the volume of tissue irradiated.

Brief History of Radiation Therapy

In the early era of radiotherapy, radiation planning was based on external anatomic landmarks and simple measurements of patient thickness.¹ These plans were obviously crude, but the large field size presumably made up for inaccuracies in treatment planning. By the 1960s, fluoroscopic simulators, which emulated treatment machine geometry, were developed commercially, allowing radiation oncologists to design fields based on bony anatomy. Radiation planning was performed in two dimensions following the fluoroscopic simulation, in which plain radiographs were taken in the treatment position. The external contour of the patient was modeled at the isocenter of the field, and relevant internal structures were drawn on the contour by the physician, including the target and critical normal organs. The appropriate location of these structures was determined by their anatomic relationship with bony anatomy. Although the visualization of bony anatomy allowed radiation fields to become more complex, they were still fundamentally limited by an inability to know the three-dimensional (3D) location of the tumor and surrounding normal structures.

The 1970s witnessed the dawn of axial imaging, as computed tomography (CT) and magnetic resonance imaging (MRI) were developed and introduced into medical care.¹ As soon as CT was developed, it became obvious to radiation oncologists and physicists that the technology could revolutionize radiation planning.² First, the anatomic detail dramatically improved the physician's knowledge of tumor extent, and theoretically this information would lead to better target coverage. Second, the 3D dataset would allow the radiation planner to create a substantially more sophisticated beam arrangement, using computerized dosimetry and a “beam's eye-view” to optimally cover the tumor and avoid normal structures.³ Multiple research groups attempted to merge CT technology with radiotherapy planning, and by 1996, several commercial 3D planning systems became available, bringing conformal radiotherapy (CRT) into general practice.⁴ Radiotherapy plans created by these systems are termed 3D-conformal radiotherapy (3D-CRT), in contrast to the plans calculated from fluoroscopic simulators, simply termed 2D.⁵

Simulation and Target Delineation

As detailed earlier, the bedrock of modern thoracic radiotherapy is the CT simulation, in which patients are first immobilized and then CT is performed, ideally with intravenous contrast. The immobilization is often performed using a thick plastic bag with beads inside, and a vacuum is created within the bag once the patient is in the appropriate position; the bag is thus held in position once the vacuum is applied. The CT is typically obtained in 2.5- to 3-mm thick slices, though thinner or thicker slices may be used depending on the indication.

Although one of the most obvious benefits of CT simulation is the improvement in target delineation, the information contained in the 3D dataset also has provided tremendous insight into predictors of radiation pneumonitis (RP). Treatment planning software can calculate a dose–volume histogram (DVH), which describes the percent of lung that receives a certain dose, as well as additional statistics such as the mean, maximum, and minimum dose. For example, the percent volume of lung receiving more than 20 Gray (Gy) is called the V20, and similarly the percent volume of lung receiving more than 5 Gy is the V5. Although much work needs to be performed to better predict the risk of this severe complication – particularly in the molecular arena – rough predictors of RP have been devised, such as the V5, V20, and mean lung dose (MLD), and these help guide radiation oncologists as they determine the safety of a given radiotherapy plan.^6,7

The salient benefit of CT-based planning is the improved delineation of the target. This process has been particularly advanced by the development of four-dimensional CT (4D-CT) simulation, in which the purported fourth “dimension” is time.⁸ In brief, during 4D-CT, an external marker is placed on the patient, which is ultimately used to mark the different phases of the respiratory cycle. The scan is performed multiple times at the same couch position, and thus several axial slices are obtained at a given position; these slices are reformatted according to the respiratory cycle at which they are taken, and a “movie” of the tumor during the respiratory cycle is visible. Multiple studies have confirmed that lower lobe primary masses and lymph nodes, particularly in the hilar and subcarinal stations, often move more than 1 cm in the superior to inferior direction.^9,10 Without this patient-specific knowledge, margins around the tumor could be either too small or too large; in comparison, simulation with 4D-CT allows for the optimal margin and improves the therapeutic ratio.

Furthermore, the use of positron emission tomography (PET) and PET-CT has also improved the delineation of primary and lymph node targets. Although a more complete discussion of PET imaging is beyond the scope of this chapter, several studies have shown that PET and/or PET-CT aids the radiation oncologist in distinguishing primary tumor from atelectasis, and malignant from benign adenopathy.¹¹ For example, DeRuysscher showed that PET-CT radiotherapy planning could increase the total radiation dose by over 20% and keep the toxicity risk the same by virtue of shrinking down the treatment volume based on the metabolic imaging.¹² Similarly, RTOG 0515 prospectively recorded the treatment volumes contoured by the radiation oncologist on CT and PET-CT and found that the gross tumor volumes (GTV) were significantly smaller on PET-CT volumes, and the nodal volumes were changed in 51% of patients.¹³ Although not mandatory, the integration of PET-CT information with the CT simulation images has become a standard practice in treatment planning.

Treatment Delivery

Once 3D information became available and treatment planning software developed the computing power and algorithms to calculate dose throughout the treatment volume, beam arrangements became more complex, and physicians were able to maximize dose to the tumor while reducing the dose to the organs-at-risk. Today, the majority of patients are treated with 3D-CRT, although intensity modulated radiation therapy (IMRT) has also been employed in the past several years.

IMRT introduced two new concepts in radiation planning and delivery. The first is termed “inverse planning,” in which the physician specifies the dose to tumor volumes and normal structures (e.g., esophagus, spinal cord), and the physicist instructs a computer algorithm to design a plan to meet those constraints. This process is distinctly different than traditional “forward planning,” in which the physician first creates the fields and the physicist or dosimetrist then determines the dose distribution. The benefit of the inverse planning algorithm is the ability to carve dose away from multiple normal structures while ensuring a radical dose to the planning target volume (PTV), and it is simply too difficult to accomplish this feat without a sophisticated cost function.

The second main component of IMRT is, as the name implies, intensity modulation. By definition, intensity is the total energy per unit area per unit time.¹⁴ In standard radiotherapy, the intensity across a given beam is basically constant; there is no variation across the field. If a particular beam delivers 100 cGy to a 10 × 10 cm² area at a certain depth, that 100 cm² region is essentially all receiving 100 cGy. In contrast, for a given IMRT field, the intensity throughout the field may vary substantially, a dosimetric feat which is typically accomplished through the use of multileaf collimators (MLC), narrow moveable leaves in the head of the linear accelerator.² In IMRT, each radiation beam is split into multiple subfields, each with a different arrangement of the MLCs, such that the final delivered dose – the summation of each subfield – is highly variable across its area.

Planning studies have suggested that IMRT can reduce the volume of normal lung receiving radiotherapy, which may lead to a lower risk of pneumonitis and allow for dose-escalation.¹⁵ Moreover, by definition, IMRT is able to push dose away from important normal structures such as the spinal cord, brachial plexus, and esophagus. However, IMRT faces at least three fundamental obstacles for its routine use in thoracic radiotherapy: potential geographic miss due to tumor motion (i.e., “interplay effect”), increased spread of low-dose irradiation to the normal lung, and cost. With respect to the interaction of tumor motion and the treatment beam, consider that the open area of the beam is constantly changing throughout the treatment, and the tumor is constantly moving; thus, if the tumor is moving during respiration to an area where the MLCs are closed, no dose will be delivered for a period of time; that underdosing can build up over the course of treatment, and the tumor may theoretically receive a subtherapeutic dose.¹⁶

The second concern with IMRT is the increase in low-dose spillage in the lung. Although there are typically four to five beams in a standard 3D-CRT plan, IMRT may utilize seven to nine beams, and consequently there may be a higher V5 (i.e., percent of the lung receiving 5 Gy or more), which could lead to an increased risk of pneumonitis.¹⁷ Although some data refute the hypothesis that IMRT increases the pneumonitis rate and argue that IMRT decreases it, other reports have supported the notion of a higher rate of severe toxicity.^18,19 The final issue with IMRT is cost, as the planning and delivery of the treatment are more complex, time-consuming, and thus expensive. Thus, whether a patient is better served by 3D-CRT of IMRT is patient-specific.

Despite these advances, in some situations, highly mobile tumors require large treatment ports and thus intolerable dose to the normal lung tissue. Although one solution to this dilemma is prescribing a lower dose of radiotherapy, this approach is clearly suboptimal. Thus, additional techniques have been developed to “gate” a mobile tumor; that is, turn on the irradiation only during certain parts of the respiratory cycle (e.g., end inspiration). There are three fundamental approaches to achieve this gating: attach the patient to a respirator-type device and only turn on the beam when a specified volume of air is inhaled (i.e., Active Breathing Control™), use external markers on the patient (or even surface anatomy) that acts as a surrogate for diaphragmatic motion, and only treat when that marker is at a position that represents a given phase of respiration, and insert an internal radio-opaque fiducial into the patient's tumor that is visible on fluoroscopy and use that fiducial as a marker to verify the external marker.^20–22 Whether or not these tools are implemented for a given patient is a function of tumor motion, risk of lung complications, patient tolerance of the gating method, and available technology.

On-Treatment Imaging

A highly precise radiotherapy plan is ultimately useless if the patient is not reproducibly set up each day for the treatment. Patients typically receive permanent small tattoos at simulation, and these tattoos serve as markers for the radiation therapist to place the patient at the isocenter (i.e., the middle of the treatment position) for each treatment. However, skin marks are highly unreliable from a day-to-day standpoint, particularly as patients lose weight during treatment, and thus additional isocenter verification is important, especially as the radiotherapy plan becomes more complex. For many years, the megavoltage beam from the treatment machine itself was used as an imager (“port film”), and radiographs were taken at the isocenter at least one time per week. However, megavoltage radiographs have very poor resolution, and although they are an improvement over simple setup to skin, they still needed improvement.

Over the past 10 years, linear accelerators became equipped with kilovoltage imagers perpendicular to the head of the gantry. This arrangement allowed physicians to obtain diagnostic quality x-rays before each fraction of treatment without adding to the total radiation dose. As a consequence, daily setup was more precise. This concept of using higher-resolution, daily imaging was termed image-guided radiotherapy, or IGRT; in contrast to the acronym IMRT, which defines a very specific type of treatment planning and delivery, IGRT refers to the paradigm of using daily imaging to reduce the treatment margins (and even shrink them over the course of therapy).²³ Image-guided radiotherapy is thus agnostic to the actual radiotherapy delivery technique.

Although daily orthogonal kilovoltage imaging was an improvement over daily megavoltage port films, the real advance in IGRT was the development of cone-beam computed tomography (CBCT), which is a CT scan performed on the linear accelerator, in the treatment position. In comparison to diagnostic CT scans which have multiple rows of detectors, CBCT uses the attached kilovoltage imager (or even the treatment beam as a megavoltage imager) to sweep around the patient, and the data are reformatted at the treatment console into a CT image. Although the quality of the image is far from diagnostic-level, it provides a remarkable improvement over orthogonal imaging, and the key structures (e.g., tumor, spinal cord) are easily visible; the accuracy of patient setup is therefore significantly improved, which allows for the possibility of decreased margins and either a higher total radiation dose or lower lung toxicity.

Stereotactic Body Radiotherapy

The concept of stereotactic radiation treatment was initially devised in the 1960s by neurosurgeon Lars Leksell and physicists Kurt Liden and Borje Larsson, who developed intracranial stereotactic radiosurgery (SRS).²⁴ Despite minimal to nonexistent axial imaging, SRS was feasible because the highly precise stereotactic frame was screwed into the patient's head, and thus the degree of accuracy of the stereotactic system translated to an equivalent level of accuracy of tumor localization.

However, prior to the very recent development of IGRT, obtaining the same level of setup accuracy in the extracranial body was much more difficult. One of the earliest reports of SBRT to the spine involved surgically fixating the vertebra to the stereotactic coordinate system, but this is not a viable solution for routine practice, and for almost any other body site, a frame cannot be screwed into the body.²⁵ Thus, as opposed to intracranial SRS, there was no straightforward, highly accurate system of setting the patient up at isocenter. Moreover, the complexities of treatment planning mandated the use of 3D-CRT, as delivering 54 Gy in 3 fractions with SBRT rather than 60 Gy in 30 fractions has a higher risk of significant side effects.

By the 1990s, CT simulation and 3D-CRT became feasible, and extracranial stereotactic frames were designed that allowed for rigid immobilization and stereotactic localization without surgical intervention.²⁶ Some centers also developed fluoroscopic systems that could image internal fiducial markers in lung tumors to ensure the treatment beam was turned on when the lesion was in the field.²⁷ These highly precise setup devices finally allowed for high-dose, SBRT, (Fig. 85-1) which is typically delivered using multiple (8–12) noncoplanar beams that converge on the target, leading to a high dose in the tumor margin with sharp falloff dose into the normal lung. Some physicians now promote calling this technique SABR or stereotactic ablative radiotherapy.

Many technological advances have been developed since the original linear accelerators were used to treat thoracic SBRT. For example, treatment planning software has become remarkably more sophisticated, IGRT enables highly accurate setup without requiring an external coordinate system, and other systems such as respiratory gating have been introduced as well. Linear accelerators have been specifically designed for SBRT (e.g., CyberKnife™, Accuray, Sunnydale, CA; Novalis TX™, Varian Medical Systems, Palo Alto, CA), which include unique IGRT systems for improved setup and delivery accuracy.²⁸ Although there are technical differences between these platforms, such as the typical need for internal gold fiducials for treatment with the CyberKnife, essentially any lesion that can be treated with one system can be treated by another; the key to a successful treatment is physician expertise rather than a particular linear accelerator.²⁸

As detailed in other chapters, the standard-of-care in the management of stage I NSCLC is lobectomy and lymph node dissection. However, given the general medical compromise of this patient population, a nontrivial percentage of individuals are not candidates for this procedure. Although there is controversy surrounding the relative benefits of segmentectomy and wedge resection, until recently there was no viable nonsurgical alternative.

Conventional Results

Indeed, until the mid-2000s, the standard approach for the treatment of medically inoperable stage I NSCLC was conventionally fractionated radiotherapy to 60 to 70 Gy in 30 to 35 fractions. Given the relatively small field, the treatment was tolerable, but it was also associated with unacceptably poor local control. For example, Bradley²⁹ reported on the outcomes of patients at Washington University in St. Louis with medically inoperable stage I NSCLC treated with RT alone to a median dose of 70 Gy. Although patients with tumors 2 cm or smaller experienced a 2-year local control probability of 83%, the tumors between 2 and 3 cm had a local control probability of only 62%, and that fell to 50% for tumors between 3 and 5 cm. Such poor local control rates are not compatible with long-term survival in this population. Similarly, in the University of Michigan dose-escalation trial of node-negative patients, 10 out of 35 patients (29%) developed an in-field recurrence, despite a median total dose of 84 Gy.³⁰ In a Cochrane review of medically inoperable NSCLC, local recurrence rates ranged from 6% to 70%, with most ranging between 40% and 60%.³¹ Nevertheless, it is clear that conventionally radiotherapy is inadequate for treating stage I disease, poor outcomes that are compounded by the inconvenient requirement of 6 to 8 weeks of daily treatment in these regimens.

Stereotactic Body Radiotherapy

The development of SBRT has significantly improved the local control and likely overall survival outcomes in patients with medically inoperable NSCLC, as the very high doses of radiotherapy are thought to overwhelm any underlying radioresistance of the tumor. Several of the earlier series come from Japan, where patients were initially treated using dosing schemes that were lower than the 54 to 60 Gy in three fractions as is typically done now. The outcomes, such as reported in 2004 by Onishi et al.³² were promising. In a series that totaled 245 patients, the total local progression probability was only 14.5%. There was a volume–response relationship, though, as the local failure probability for T1 tumors was 9.7% versus 20% for T2 malignancies. Although many other retrospective series showed comparable outcomes, only one phase I dose-escalation trial has been performed.

In this trial, investigators at University of Indiana escalated the total dose from 24 Gy in 3 fractions to 60 Gy in 3 fractions for T1 tumors with any dose-limiting toxicity, and the maximally tolerated dose for T2 tumors was 66 Gy; an unacceptable rate of lung toxicity was seen at 72 Gy.³³ Of note, only 1 local failure was seen in the patients who received over 16 Gy per fraction. The investigators continued to the phase II component of the trial, which found continued excellent local control (95% at 2 years) but a risk of treatment-related mortality in six patients whose lesions were centrally located. Four of these patients died from pneumonia, one from a pericardial effusion, and one from hemoptysis in the context of recurrent tumor. Although the true etiology of these toxicities – that is, unique to SBRT treatment or a stochastic process – are debatable, the Indiana experience has defined the Radiation Therapy Oncology Group (RTOG) eligibility criteria for SBRT, which is at least 2 cm beyond the proximal bronchial tree.

On the heels of this single-institution study, RTOG 0236 was a multi-institutional, phase II study of SBRT for medically inoperable patients with peripheral, stage I NSCLC.³⁴ The prescription dose was 60 Gy in 3 fractions, comparable to the Indiana experience. This trial showed that SBRT was feasible and highly efficacious in a multi-institutional setting, as the 3-year in-field, in-lobe, and locoregional control probabilities after treatment were 98%, 91%, and 87%, respectively. The 3-year overall survival was an impressive 56%, particularly notable given the underlying severe comorbidities in the cohort. It is important to note that the dose in this trial was 20 Gy × 3, but that this dose was calculated without “heterogeneity corrections,” which adjust for the air density of the lungs. As a consequence, the peripheral dose in RTOG 0236 was in effect 54 Gy, and thus 18 Gy × 3 has been essentially adopted as the standard regimen for peripheral lesions.³⁵ (Table 85-1) displays reported prospective and notable retrospective trials using SBRT. The results have been so promising that a national trial has been activated comparing SBRT with sublobar resection in medically compromised patients (ACOSOG Z4099/RTOG 1021).

The most well-known toxicity following SBRT, toxic death after treatment of central lung tumors as seen in the Indiana study, is quite rare, although Song et al.¹⁹ do describe a 33% (3/9 patients) risk of severe bronchial stenosis with subsequent pneumonia and/or death (n = 1) and an 88% (8/9 patients) risk of any bronchial stenosis in patients treated with SBRT near the proximal tree. Thus, although it is questionable whether SBRT is associated with lethal side effects in the proximal lesions, at the very least it appears to be more morbid than irradiation of peripherally located lesions. Some single-institutional experiences have successfully treated central lesions with a more gentle fractionation regimen (e.g., 4 to 5 fractions to approximately 50 Gy), without severe lung toxicity.^42,39 RTOG 0819 is currently enrolling patients in a phase I/II dose-escalation trial for patients with centrally based lesions. This study is actively accruing and will define the optimal dose and associated efficacy when using SBRT for central tumors.

Especially, given the fragile population typically treated with SBRT, other lung toxicities such as pneumonitis and pulmonary function test (PFT) decline are generally mild, but they do occur. In busy, experienced radiotherapy clinics, the treatment of peripheral lesions is associated with a risk of grade 2 to 3 pneumonitis between 2% and 11%.^{39,–43–45} Indeed, physicians at the Cleveland Clinic Foundation reported no change in the mean PFTs among 92 patients treated with SBRT, although 20% of patients experienced at least a 12.7% decrease of predicted FEV₁, and 20% of patients developed a decline in diffusion capacity of at least 18% of predicted.⁴³ Interestingly, the risk of these side effects appears to be higher in multi-institutional trials, as the probabilities of grade 2 or 3 to 4 pneumonitis probabilities were 24% and 16%, respectively, in RTOG 0236. This difference may be a function of older planning techniques, as most modern series started treating patients in the mid-2000s.

More recently it has become clear that chest wall toxicity is another potential complication of SBRT, in which patients with peripheral lesions can develop chronic chest wall pain and/or rib fracture. This complication usually occurs between 6 months and 1 year after finishing treatment. It is typically transient, but as shown by Stephans et al.⁴⁶ and Dunlap et al.⁴⁷, it can occur in 7% to 28% of patients, which can significantly decrease quality-of-life until it resolves. That being said, with careful monitoring of the chest wall dose during planning, the risk of this complication can be significantly decreased, and it is likely that future series which observed this constraint will show a lower risk of chest wall complications.

Locally Advanced Lung Cancer

Locally advanced lung cancer, defined here as stage IIIA or IIIB, comprises over half of the patients who present with nonmetastatic disease, yet further progress in improving overall survival has been relatively stagnant. As described later, the main advance over the past 20 years has been the integration of chemotherapy with radiation treatment, first as induction therapy, and then concurrent treatment, but further investigation into the relative benefit of more intensive radiotherapy has thus far been disappointing.

Integration with Chemotherapy

In the 1980s and early 1990s, locoregional control and overall survival outcomes after radiotherapy alone for locally advanced lung cancer were dismal. Meaningful radiation dose escalation was not feasible due to technical constraints, and with the recognition that lung cancer is typically a systemic disease at presentation, the main strategies to improve survival focused on combination therapy (Table 85-2).

The landmark Dillman⁵⁵ trial, published in 1993, compared cisplatin-based induction chemotherapy and radiotherapy with radiotherapy alone, and the results were practice-changing, as the treatment approach was associated with an overall survival benefit of 24% versus 10% at 3 years, and 17% versus 6% at 5 years. This finding was further supported by RTOG 8808/ECOG 4588, which randomized patients between daily RT, BID RT, and cisplatin-based induction chemotherapy followed by daily radiotherapy.⁵⁶ Patients in the chemotherapy arm benefitted from significantly superior survival versus the radiotherapy alone arms (median survival 13.8 vs. 12.3 vs. 11.4 months, for the induction, daily RT, and BID RT arms, respectively).

Although induction chemotherapy was associated with a survival benefit, in principle, the use of concurrent chemotherapy may optimize its radiosensitizing properties. Indeed, Schaake-Koning et al.⁴⁸ showed that the use of concurrent chemoradiotherapy versus radiotherapy alone was associated with a locoregional control and survival benefit; patients receiving split-course radiotherapy with daily cisplatin experienced superior 2-year locoregional control (31% vs. 19%) and survival (26% vs. 13%) versus radiotherapy alone. Similar results were found by Jeremic et al.⁴⁹ using a hyperfractionated radiotherapy regimen, in which patients were randomized to receive 69.6 Gy to radiation alone or radiotherapy with concurrent, daily carboplatin and etoposide, finding a significant 14% absolute difference in overall survival at 4 years in patients who received concurrent treatment.

Given the superiority of induction chemotherapy and radiotherapy over radiotherapy alone, and concurrent chemoradiotherapy over radiotherapy alone, the next logical question is the optimal combination of chemotherapy and radiotherapy: induction, concurrent, or both. RTOG 9410 compared induction chemotherapy and radiotherapy alone with two concurrent radiotherapy arms, one with hyperfractionated radiotherapy (69.6 Gy in 34 1.2 Gy BID fractions) and one with conventional radiotherapy.⁵⁷ Although this study has yet to be published, preliminary results have shown a survival benefit with the concurrent chemoradiotherapy arms. Similarly, Furuse et al.⁵⁰ randomized 320 patients between induction chemotherapy (cisplatin, vindesine, and mitomycin) followed by daily radiotherapy to 56 Gy, versus the same chemotherapy with concurrent split-course radiation treatment Despite the mandated break during radiotherapy, patients receiving concurrent treatment experienced superior survival (median 16.5 vs. 13.3 months), though curiously there was no demonstrable difference in failure-free recurrence between the two arms. Several other studies have further supported the benefit of concurrent versus induction chemotherapy, and a recent meta-analysis of these studies by Auperin et al. not only showed an absolute benefit of 5.7% with concurrent therapy, but also that the main benefit of concurrent treatment was improved locoregional control (HR 0.77).

Two recent trials attempted to determine the optimal timing of chemotherapy and radiotherapy. Belani et al. performed a phase II randomized trial (Locally Advanced Multimodality Protocol [LAMP]) comparing induction chemotherapy with paclitaxel and carboplatin followed by radiotherapy alone versus induction chemotherapy followed by chemoradiotherapy with weekly paclitaxel and carboplatin versus chemoradiotherapy followed by adjuvant chemotherapy. There were no survival differences between the arms, although the upfront chemoradiotherapy arm appeared to have the highest median survival (16.3 months vs. 13.0 and 12.7 in the induction arms).⁵⁸ In CALGB 39801, Vokes et al.⁵² compared chemoradiotherapy using 66 Gy with weekly carboplatin and paclitaxel to induction chemotherapy followed by the same chemoradiotherapy. There was no difference in overall survival between the two arms, despite the use of induction chemotherapy; as expected, induction chemotherapy was associated with more grade 4 toxicity. It is notable that 53 patients (15% of entire cohort) never received radiotherapy, which may have influenced the results. Given these two trials, induction chemotherapy prior to chemoradiotherapy is not a common practice unless investigated on clinical trials.

Since chemotherapy clearly extends survival in resected NSCLC and these trials of induction therapy do not, it is possible that the competing risk of locoregional failure after chemoradiotherapy obviates any systemic disease benefit from neoadjuvant or adjuvant chemotherapy, though this question will hopefully be reopened over time as control rates improve with nonoperative therapies.

Radiotherapy Dose

In the radiotherapy community, one of the most controversial issues is the total dose used in the treatment of inoperable NSCLC. Unfortunately, there are few randomized data to address this question. The classic dose-escalation randomized trial, RTOG 7301, randomized patients between 40 Gy delivered as split-course, 40 Gy continuous course, 50 Gy continuous course, and 60 Gy continuous course.⁵⁹ No chemotherapy was given, and thus the competing risk of distant recurrence significantly reduces the power to see a survival difference from improved local control. Indeed, although there were no differences in overall survival, there was a significant difference in intrathoracic recurrences with higher-dose radiotherapy: 52% after 40 Gy, 41% after 50 Gy, and 30% after 60 Gy. When the recurrence risks were stratified by tumor size, local relapse rates were higher in the 40 Gy arms in comparison to the higher-dose arms for tumors between 1 and 3 cm, and 4 and 6 cm but not in larger tumors. This trial, published in 1982, essentially established the standard radiotherapy dose for conventionally fractionated radiotherapy that has remained until today.

RTOG 9311 was a more recent dose-escalation study for stage I–III NSCLC, in which the radiation dose was escalated to over 90 Gy using daily fractionation.⁶⁰ Despite these high doses, there was no relationship between dose and response, progression-free survival, or overall survival in the 161 patients treated. On the other hand, there was a strong relationship between tumor size and overall survival and progression-free survival on multivariable analysis. RTOG 9311 did not include chemotherapy in the treatment regimen, and thus competing risk of distant metastasis may have eliminated any local control benefit of dose escalation.

Recently, Machtay et al.⁵³ performed a combined analysis of 7 RTOG chemoradiotherapy trials to analyze whether biologically effective dose (BED), a formula that considers the total dose and dose per fraction, was associated with local control and overall survival. The authors used the patient-specific data on the actual dose received rather than the protocol-specified dose. With a sample size that numbered over 1300 patients, the authors showed that the risk of locoregional failure and overall mortality decreased by 3% and 4%, respectively, for every increase of 1 Gy in the received BED. Although this study is limited by potential confounding between radiation dose and performance status/disease progression (i.e., worse comorbid disease leads to both shortened radiation treatment and life expectancy) the data do suggest that dose is associated with locoregional control and survival.

Several retrospective studies have more recently analyzed the relationship between local control and total radiation dose. For example, Rengan et al.⁶¹ evaluated the Memorial Sloan-Kettering experience with bulky stage III patients and found that compared with patients treated to a lower dose, those irradiated to 64 Gy or higher experienced higher 2-year local control (53% vs. 24%, p = 0.024) and a borderline improvement in overall survival (median 20 months vs. 15 months, p = 0.068). This group also found a significant relationship between GTV volume and local failure, as doubling the GTV resulted in a 46% increased risk of local failure. Investigators at the Washington University in St. Louis arrived at similar conclusions in analyzing their dataset of 207 patients with inoperable NSCLC; of note, 73% of the population had stage III disease, and almost half of the entire cohort received chemotherapy.⁶² Patients who received 70 Gy or more had significantly improved local control and cause-specific survival (absolute benefit of 3 years approximately 20%), but not overall survival. However, GTV volume was much more influential in overall survival and local control, as this variable was significant on multivariable analysis for both outcomes, whereas radiotherapy dose was not.

A more recent randomized controlled trial of 200 patients nominally compared the use of smaller versus larger radiotherapy fields, but in actuality compared 60 to 64 Gy to 68 to 74 Gy, depending on whether a limited or extensive nodal field was delivered.⁶³ In obvious contrast to RTOG 7301, patients received chemotherapy in both arms, and 3D-CRT was mandated. Local control was significantly greater at 5 years in the high-dose arm (51% vs. 36%). Although there was a visible but nonsignificant trend for improved survival in the high-dose arm (p = 0.2), only the survival percentage at 2 years was significantly different (39.4% vs. 25.6%). It is important to note that this study used nonstandard chemotherapy (1 cycle of induction, followed by chemoradiotherapy with 4 to 6 cycles in total) and needs additional follow-up, as the median follow-up at the time of its publication was 27 months. Nevertheless, although this study was not presented as a dose-escalation trial, in fact that is exactly what this paper describes, and for the first time since RTOG 7301, it shows a significant local control benefit to higher dose of radiotherapy in a randomized trial, which may have translated into a survival advantage had the study been appropriately powered.

In summary, it is difficult to abstract any firm conclusions on the relationship between radiotherapy dose and local control and survival. RTOG 7301 was performed in an earlier era using antiquated radiotherapy techniques and staging studies, and patients were treated without chemotherapy. Retrospective studies are limited by selection bias, and although several of the presented analyses suggest a relationship between dose and survival, the fact that GTV volume is consistently related to outcome argues that deliverable dose was more a function of the size of the tumor, and in actuality, any benefit from dose-escalation was a result of confounding; in other words, smaller tumors have a more favorable prognosis, and since the volume is smaller, it is safer to treat them to a higher dose, which is why higher dose appears to confer a more favorable prognosis.

In all likelihood, RTOG 0617 will provide the final word on the optimal radiotherapy dose, as patients are randomized between 60 and 74 Gy of chemoradiotherapy. The study has targeted accrual at 500 (currently standing at 464), which will provide for a power of 80% to see a 7-month median survival improvement with higher-dose radiotherapy. It is arguably the most important trial in locally advanced NSCLC accruing today, with the results expected in several years. Until that is published, doses between 60 and 74 Gy are considered within the standard-of-care, though doses in excess of 70 Gy are best reserved for clinical trials.

Radiotherapy Volume

The vast majority of published clinical trials utilizing thoracic radiotherapy have utilized large treatment fields that treated regional nodal basins that did not contain gross disease; this practice is called “elective nodal irradiation,” or ENI, and it is the standard practice in many disease sites in radiation oncology.⁶⁴ In principle, lymph nodes with a reasonable chance at harboring occult metastases are treated to a lower but theoretically sterilizing dose (e.g., 50 Gy). In the lung, performing ENI implies irradiating the supraclavicular fossa, bilateral mediastinum and in some situations, bilateral hila. This treatment field significantly increases the dose that the normal lung receives, which can meaningfully increase lung and esophageal toxicity and further, prevent dose-escalation to the primary tumor.

An alternative treatment planning approach is to only treat the known tumor and involved lymph nodes, which is called involved-field radiation therapy (IFRT). Because less normal lung and esophagus are irradiated, the benefits of this strategy include safer dose-escalation to the known gross disease as well as less esophageal toxicity.⁶⁵ The obvious risk of this strategy is that occult disease in the lymph nodes is missed in the treatment field, which could lead to regional recurrence, and multiple surgical series have shown the risks of microscopic nodal disease, even in stage I disease, can exceed 35%.⁶⁶ Nevertheless, multiple retrospective series and prospective trials, accounting for hundreds if not thousands of patients, have shown that the risk of isolated elective nodal failure – in other words, regional recurrence that could have been prevented with a higher, elective dose to that region – is less than 10%. As detailed earlier, the single randomized trial of ENI versus IFRT, in which dose was escalated in the IFRT arm, favored IFRT in local control, perhaps survival, and toxicity (significantly less pneumonitis, 29% vs. 17%, p = 0.044); yet this trial was primarily a question of dose, and whether ENI improves locoregional control when dose is held constant (if technically possible) was not the hypothesis of the trial.⁶³

These data showing a low risk of isolated elective nodal failure following radiotherapy conflict with known patterns of microscopic disease in NSCLC. There are several explanations for this finding. It is theoretically possible that the tumors in patients treated with primary RT have a different biology than those patients treated with surgical resection, but this scenario is unlikely.⁶⁷ A second possibility is that elective nodes receive a sterilizing dose through incidental radiation to the involved field: “nonelective” elective nodal irradiation. Several investigators have shown that over 50% of nontargeted proximal nodal stations (e.g., subcarina treating a primary tumor and hilum) receive a sterilizing dose of radiotherapy through incidental radiotherapy from IFRT. However, as radiation planning becomes more conformal with IMRT, IGRT, and smaller margins, lower incidental doses are delivered to these elective regions, with the potential for a higher likelihood of elective nodal failure.

The third potential explanation to explain the discrepancy between the likelihood of occult nodal disease and low regional failure rate is the poor locoregional control of known gross disease following with radiotherapy or chemoradiotherapy. There is thus no opportunity to see an elective nodal failure because the patients are first progressing from their gross disease at presentation. In an interesting paper from the University of Pennsylvania, Fernandes et al.⁶⁸ showed that while the 2-year probability of isolated elective nodal failure after IFRT was only 4.5%, initially uninvolved nodes still recurred 21% of the time at some point in the treatment course. Such data reinforce the notion that occult nodal disease may actually present clinically if given enough time.

Nevertheless, as of 2011, to my knowledge every cooperative group trial involving NSCLC mandates involved-field radiotherapy and no longer allows ENI, and to the extent that active national studies define the standard-of-care, IFRT would thus be considered the appropriate radiotherapy fields. However, controversy still remains, and every radiation plan must be tailored to the individual patient, based on his own disease characteristics and the predicted likelihood of harboring nodal metastases in any given nodal station. Although the extensive fields that irradiated the thoracic inlet to 5 cm below the carina are no longer delivered, more tailored elective nodal treatment, such as treating an entire ipsilateral level 4 station if an inferior level 4 node is positive on imaging, may be indicated based on the clinical scenario. From a thoracic surgeon's perspective, the concept of involved-field radiotherapy highlights the importance of information obtained from the mediastinoscopy. The additional pathologic information may be very useful for designing the radiotherapy fields in the context of IFRT, even if the overall management paradigm does not change based on the results. Moreover, as systemic and local control improves over time, either with novel chemotherapeutic or radiotherapy advances, the relative benefit of elective nodal irradiation becomes more prominent, and the indications of ENI may need to be addressed again at a later point.

This chapter has summarized both the technical advances in thoracic radiotherapy as well as treatment innovations in inoperable NSCLC. With respect to early-stage disease, technical improvements in radiation therapy delivery have led to SBRT, which has dramatically improved local control, and presumably survival, in medically inoperable NSCLC.

In locally advanced patients, technical advances have led to better tumor delineation, more accurate patient setup, and more precise and conformal delivery of radiotherapy. These improvements have likely improved the therapeutic ratio, as higher doses of radiotherapy can be delivered with lower toxicity, but the relationship between survival and advanced techniques must still be analyzed. Although survival outcomes have slowly increased over time, this improvement is more a function of chemotherapy delivery rather than improved radiation treatment. Given the combined challenge of eradicating locoregional disease and distant metastases, further research must be performed on optimizing combined modality therapy, with more creative integration of all three core therapies in lung cancer—radiation therapy, chemotherapy, and thoracic surgery.

This excellent chapter has reviewed the state of the art in radiation therapy for NSCLC. Regarding early-stage disease, the comments concerning the use of SBRT for medically inoperable disease are quite correct. Depending on the results of the current trials for its use in resectable and central disease, one may be able to apply these conclusions to those populations as well. The author gives a very clear review of the status of using radiation therapy for locally advanced inoperable disease, clearly restating the case for concurrent chemoradiation therapy. The current study will finally put to rest questions related to high-dose (60 Gy) versus extra high-dose (70 Gy) radiation therapy. One final point not mentioned here is the role of chemoradiation as neoadjuvant therapy for potentially resectable stage IIIA NSCLC. Although there remains much argument regarding the role of pnuemonectomy in these patients, there is a developing consensus for the role of high-dose chemoradiation followed by surgery when lobectomy is feasible.