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.
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).
Table 85-1Summary Of Prospective Phase II Clinical Studies and Notable Retrospective Series Studying Stereotactic Body Radiotherapy (Sbrt) for Stage I Non–Small Cell Lung Cancer ||Download (.pdf) Table 85-1Summary Of Prospective Phase II Clinical Studies and Notable Retrospective Series Studying Stereotactic Body Radiotherapy (Sbrt) for Stage I Non–Small Cell Lung Cancer
|INSTITUTION ||NUMBER ||MEDIAN F/U (months) ||DOSE (Gy/# fractions) ||LC (Year) ||OS (Year) ||GRADE 3 TOXICITY (%) ||REFERENCES |
|Indiana || 70 ||50.2 ||60/3 ||88.1% |
|16 ||36 |
|Karolinska || 57 ||35 ||45/3 ||92% |
|30 ||37 |
|RTOG 0236 || 59 ||34.4 ||60/3 ||97.6% |
|16.3 ||34 |
|Kyoto || 45 ||30 ||48/4 ||98% |
|IA: 83% |
|0 ||38 |
|VUMC ||206 ||12 ||60/3, 60/5, 60/8 ||93% |
|5 ||39 |
|Cleveland Clinic Foundation || 94 ||15.3 ||50/5, 60/3 ||95% |
|0 ||40 |
|Princess Margaret ||108 ||19.1 ||50/10, 60/8, 48/4, 54/3, 60/3 ||89% |
|6 ||41 |
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).
Table 85-2Summary of Selected Prospective Clinical Studies Using Chemoradiotherapy for Stage III Non–Small Cell Lung Cancer ||Download (.pdf) Table 85-2Summary of Selected Prospective Clinical Studies Using Chemoradiotherapy for Stage III Non–Small Cell Lung Cancer
|TRIAL ||NUMBER ||CHEMOTHERAPY ||RADIATION THERAPY ||LC (Year) ||OS (Year) ||REFERENCES |
|EORTC—Schaake-Koning ||107 ||Daily cisplatin ||55 Gy, split- |
|31% (2) ||16% |
|Jeremic et al. ||65 ||Daily carboplatin, etoposide ||69.6 Gy, BID ||42% (4) ||23% |
|WJLCG ||147 ||Cisplatin, vindesine, mitomycin ||56 Gy ||67% |
|GLOT-GFPC ||100 ||Cisplatin, etoposide ||66 Gy ||69% |
|CALGB 39801 ||182 ||Carboplatin, paclitaxel ||66 Gy ||64% |
|RTOG Summarya ||1,356 ||Variable ||Variable, >60 |
|48% (5) ||15% |
|Auperin meta-analysis ||603 ||Variable ||Variable ||65% (5) ||15.1% |
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.
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.
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.