Inoperable Tumors

Stage I/II Non–Small Cell Lung Cancer

The standard of care for a patient with operable early-stage lung cancer remains lobectomy or pneumonectomy with mediastinal lymph node dissection. However, a significant percentage of these patients cannot tolerate invasive procedures because of the comorbidities prevalent in patients with lung cancer, such as chronic obstructive pulmonary disease and poor cardiovascular health. Historically, the standard therapeutic approach for these patients has been conventionally fractionated definitive radiotherapy alone, with daily fractions delivered over a period of 6 to 8 weeks.¹⁶² More recently, a hypofractionated approach with delivery of a small number of large fractions over a short period of time has gained acceptance. This approach has most commonly been referred to as stereotactic body radiation therapy (SBRT), although recently there has been a move to rename this approach stereotactic ablative radiotherapy (SABR) to emphasize its distinct radiobiology.¹⁶³

Conventionally Fractionated External-Beam Radiotherapy

The RTOG performed a multi-institutional dose escalation study for inoperable NSCLC using three-dimensional conformal radiotherapy (3D-CRT). Patients with small, early-stage tumors were escalated to doses as high as 83.8Gy with acceptable toxicity. The 1-year local control rate for patients treated to this dose was 76%.¹⁶⁴ Hayman et al.¹⁶⁵ performed an adaptive dose escalation trial allowing safe delivery of doses up to 102.9 Gy to small peripheral tumors.¹⁶⁵ However, the OS rates for patients with medically inoperable early-stage NSCLC remain poor when compared to surgery. The 5-year survival for patients treated with definitive radiotherapy range from 10% to 30% and are approximately one-half that reported in surgical series^166–169 (Table 51.6). Several possible explanations exist for this disparity in outcomes, including the poorer overall health of the medically inoperable patient and the fact that most of these patients are clinically, rather than surgically, staged. An additional limitation is the maximum dose that can be delivered to the tumor through conventionally fractionated external-beam radiotherapy (EBRT) utilizing currently available techniques. Based on fundamental radiobiologic principles, Fletcher¹⁷⁰predicted that using conventional fraction sizes of 1.8 to 2 Gy, doses of 100 Gy or higher might be required for the sterilization of most NSCLC tumors. These doses are not routinely achievable with conventionally fractionated radiotherapy in the medically inoperable patient without excessive toxicity.

TABLE 51.6. Outcome by Radiation Therapy Dose and Treatment Volume for Patients with Early-Stage Non–Small Cell Lung Cancer

Stereotactic Body Radiotherapy

SBRT refers to the delivery of large doses of radiation to a small treatment volume, usually employing multiple beams, using a small number of fractions (usually five fractions or less). It has been known for quite some time that this approach is remarkably effective at tumor sterilization, presumably due to greater radiobiologic efficacy.¹⁷¹ This treatment approach was initially put to clinical use over a half-century ago by a Swedish neurosurgeon, Lars Leksell, for the treatment of intracranial metastases.¹⁷²However, unlike the cranial vault, the lung is a highly mobile structure. Thus, application of SBRT in lung cancer was impractical until advanced imaging treatment delivery techniques were developed (Fig. 51.4).

FIGURE 51.4. Stereotactic body radiation therapy (SBRT) in stage I non–small cell lung carcinoma (NSCLC).

The patient was diagnosed as having T1N0M0 right upper lobe NSCLC and was treated with SBRT. A: Pretreatment tumor volume. B: Treatment plan with dose color-wash C: CT showing response 6 weeks after treatment.

A phase I dose escalation trial enrolled patients with T1–2 N0 NSCLC, stratified into three dose escalation groups based on T-stage and size (T1, T2 <5 cm, and T2 5–7 cm). This trial reported a maximally tolerated dose for T2 tumors >5 cm of 22 Gy × 3 and was not reached at 20 Gy × 3 for T1 tumors or at 22 Gy × 3 for T2 tumors <5 cm.¹⁷³ There was a loose association between total delivered dose and likelihood of local failure, with 9 of 10 local failures observed in patients treated to the lower dose levels (<16 Gy × 3). Based on these results, this group moved forward with a phase II trial, utilizing the dose levels identified in the phase I trial. They were able to duplicate the excellent local control results in this expanded cohort of 70 patients. With a median follow-up of 17.5 months, the local control rate was 95%. However, with such large fraction sizes (of approximately 20 Gy), the group also identified an association between tumor location and toxicity, with severe toxicity occurring at a median of 10.5 months in 17% of those patients with peripheral lesions versus 46% with central lesions.¹⁷⁴ Preliminary data from other institutions suggest that early, central lesions can be treated safely and effectively using a lower dose per fraction (e.g., 7 to 12 Gy).¹⁷⁵ To this end, the RTOG has recently opened a phase I dose escalation trial for patients with centrally located, medically inoperable stage I NSCLC.

Several other institutions have published their experience applying SBRT to early (primarily peripheral) lung cancer with a variety of dose fractionation and prescription schemes (Table 51.7). The initial data appear promising with 80% to 100% local control, 40% to 100% 2- to 3-year survival, and 0% to 4% grade 3 toxicity, although in general the median follow-up for these studies is relatively short.^176–182Timmerman et al.¹⁷⁴ reported the results of RTOG 0236, a phase II trial of SBRT in medically inoperable patients with T1 or T2 tumors treated to 54 Gy in three 18-Gy fractions. In this study, 59 patients were enrolled, with 55 patients having evaluable disease. At a median follow-up of 34 months, they reported a 3-year primary tumor control rate of 97.6% and a 3-year primary tumor and involved lobe (local) control rate of 90.6%. Two patients experienced regional failure; the locoregional control rate was 87.2%. Eleven patients experienced distant recurrence with a 3-year rate of distant failure of 22.1%. The rates for disease-free survival and OS at 3 years were 48.3% and 55.8%, respectively. The median OS was 48.1 months. Protocol-specific treatment-related grade 3 adverse events were reported in 7 patients; grade 4 adverse events were reported in 2 patients. No grade 5 adverse events were reported. The RTOG (RTOG 0618) initiated a phase II study of SBRT in operable patients with early-stage NSCLC, and, together with the ACOSOG, a randomized trial of SBRT versus sublobar resection for high-risk early-stage NSCLC. SBRT, with its advantage of patient convenience and promising local control results, has largely replaced conventionally fractionated radiotherapy as the standard approach in the medically inoperable patient.

TABLE 51.7. Outcome for Patients with Early-Stage Non–Small Cell Lung Cancer Receiving Stereotactic Body Radiation Therapy

Stage III Non–Small Cell Lung Cancer

Definitive Radiotherapy

The majority of patients with inoperable locally advanced NSCLC will receive definitive thoracic radiotherapy as a part of their treatment strategy. The rationale for definitive radiotherapy in patients with inoperable NSCLC is to provide intrathoracic control of disease. Kubota et al.¹⁸³ performed a prospective randomized trial in 63 patients with stage III NSCLC comparing chemotherapy alone to chemotherapy plus thoracic radiotherapy. The survival rate in the thoracic radiotherapy group was 58% at 1 year, 36% at 2 years, and 29% at 3 years, compared with 66%, 9%, and 3% at 1, 2, and 3 years, respectively, in the chemotherapy-alone group. The investigators concluded that thoracic radiotherapy “significantly increases the number of long-term survivors as compared with chemotherapy alone and that radiotherapy to bulky disease in the thorax is an important part of combined modality therapy, and a necessary part of further studies in locally advanced disease.” At present, definitive thoracic radiotherapy is part of the standard therapeutic approach for patients with unresectable locally advanced NSCLC. However, because of high local failure rates and the significant toxicity associated with this treatment, the optimal dose, treatment volume, and optimal integration scheme with chemotherapy remain to be defined.

Dose and Fractionation with Radiotherapy Alone

The RTOG launched a prospective randomized trial in 1973 to determine the most effective dose and fractionation schedule in patients with inoperable NSCLC. In the initial report of RTOG 7301, 365 patients with T1-3, N0-2, M0 unresectable NSCLC were randomized to one of four treatment regimens: 40 Gy given in a split course of 20 Gy in five fractions in 1 week, a 2-week rest, and then an additional 20 Gy in 1 week; or 40 Gy, 50 Gy, or 60 Gy given in 2 Gy per fraction continuous course 5 days per week. The split-course group had the poorest survival: 10% at 2 years.¹⁸⁴ The incidence of tumor recurrence in the irradiated volume was 58% for the patients receiving 40 Gy continuous course, 53% for those treated with 40 Gy split course, 49% with 50 Gy continuous irradiation, and 35% in the patients receiving 60 Gy.¹⁸⁵ There were no differences in 5-year survival rates between the four arms. However, based on the differences in local tumor control and short-term survival, this study established 60 Gy as the standard of care.

Motivated by these results, the RTOG moved to explore methods of escalating radiation dose while maintaining the therapeutic ratio through altered fractionation schedules or improved treatment delivery techniques. RTOG 8311 was a randomized phase I/II trial that delivered thoracic radiation at a dose of 1.2 Gy with twice daily fractions escalating from a starting point of 60.0 Gy to 79.2 Gy. A total of 848 patients were enrolled and analyzed for outcome. No significant differences in the risks of acute or late effects in normal tissues were found in the five arms. In a subset analysis of good performance status patients (stage III, Karnofsky performance scale [KPS] ≥70, <6% weight loss), there was a dose response identified for survival with 69.6 Gy yielding improved survival over the lower-dose arms (p = .02). There were no differences in survival among the three high-dose arms; therefore, 69.6 Gy became the standard altered fractionation regimen for subsequent RTOG trials.¹⁸⁶

The development of 3D-CRT in the early 1990s allowed the radiation oncologist to increase the dose distribution to the tumor while restricting the dose to surrounding critical normal structures.¹⁸⁷ This approach had immediate applications in the treatment of NSCLC, and preliminary data suggested that 3D-CRT might allow for safe escalation of dose to the tumor bed.¹⁸⁸ However, it is unclear whether this approach to dose escalation can be broadly applied to all lung cancer patients. Bradley et al.¹⁸⁹ examined 207 patients with inoperable NSCLC and demonstrated by multivariate analysis that GTV was strongly predictive of overall and cause-specific survival, suggesting that large-volume disease might require escalated doses of radiotherapy, if feasible without significantly increased toxicity risk.¹⁸⁹ Rengan et al.¹⁹⁰examined the value of dose escalation in patients with large-volume stage III disease and found that even in patients with large tumor volumes, local failure rates were significantly reduced when treated to ≥64 Gy. Taken together, these data suggest that dose escalation can be achieved safely in locally advanced NSCLC via novel fractionation or treatment delivery approaches.

Volume of Radiation with Definitive Radiotherapy: Involved-Field Versus Elective Nodal Irradiation in Inoperable Stage III Non–Small Cell Lung Cancer

In the era of two-dimensional (2D) radiation therapy for NSCLC, it was customary to include the elective nodal basin in the radiation portals for any patient receiving curative intent radiotherapy, regardless of stage. There is ample evidence that the elective nodal basins can be safely omitted in stage I NSCLC, as there is low risk of nodal failure after IFRT either with conventionally fractionated radiotherapy or SBRT in this setting in patients who have undergone modern clinical staging.^191,192 The rationale for IFRT in locally advanced disease is to allow for safe dose escalation. Although there are limited data to suggest that escalating radiation dose could improve local control and that this approach would be feasible in locally advanced NSCLC, this increased dose is associated with an increased risk of radiation toxicity when larger treatment volumes are employed.¹⁹⁰ One technique for facilitating dose escalation while maintaining the therapeutic ratio is to utilize IFRT; this approach has been widely adopted. However, there is clear evidence to suggest that the untreated nodal basin may harbor occult disease. Surgical studies report that 10% to 35% of patients with clinically node negative NSCLC have evidence of occult mediastinal metastasis on lymph node dissection.¹⁹³ Additionally, although ¹⁸FDG-PET/CT has become an indispensible tool for noninvasive staging of the mediastinum, studies have shown that FDG-PET may carry up to a 25% false-negative rate in lymph nodes <1 cm in the short axis.⁶⁹ Therefore, some have argued that while IFRT may allow for dose escalation, this may come at the expense of clinical outcome in this disease.¹⁹⁴

Motivated by this concern, several studies have examined the rate of elective nodal failure in patients treated with IFRT and have shown this to be a relatively rare event.¹⁹⁵ In a study of 524 inoperable patients treated with IFRT, Rosenzweig et al.¹⁹⁶ reported a 2-year elective nodal control rate of 92.4%. Kepka et al.¹⁹⁷ studied 207 unresectable patients, staged without ¹⁸FDG-PET and treated with elective nodal irradiation (ENI). This study reported a 2-year elective nodal control rate of 88%. In a separate study, Kepka et al.¹⁹⁸ performed a comparative analysis of IFRT, limited ENI, and extended ENI and reported that substantial incidental radiation dose was delivered to the elective nodal basins even with IFRT; the median dose delivered to these areas ranged from 18 Gy to 45 Gy, depending on the location of the primary tumor and involved nodes as well as the technique employed. Further, there was no significant difference in dose delivered to much of the elective nodal basin between extended and limited ENI. In the only prospective study of ENI versus IFRT, Yuan et al.¹⁹⁹ demonstrated an increase in local control with IFRT of 8% and 15% at 2 and 5 years, respectively. This increase, however, was only statistically significant at the 5-year time point. Additionally, Yuan et al.¹⁹⁹ demonstrated an improved OS rate at 2 years with IFRT (39.4% vs. 25.6%, p = .048) and significantly higher pneumonitis rates in patients treated with ENI (29% vs. 17%, p = .044). Although interesting, this study has been criticized for the imbalances in several factors, including the radiation dose delivered (68 to 74 Gy for IFRT vs. 60 to 64 Gy for ENI) and V₂₀ between the two arms, making attribution of the results observed solely to IFRT or ENI problematic. In a recently published single-institution retrospective cohort comparison of patients receiving definitive 3D-CRT for locally advanced NSCLC, Fernandes et al.²⁰⁰ analyzed 108 consecutive patients treated with either ENI or IFRT. The median follow-up time for survivors was 18.9 months. The median dose for patients treated with IFRT was 69.9 Gy versus 63.6 Gy for ENI. In a multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high-grade esophagitis (odds ratio 0.31, p = .036). There was a suggestion of improved 2-year local control with IFRT (59.6% IFRT vs. 39.2% ENI); however, this was not significant (p = .23). There were no significant differences in elective nodal control (84.3% vs. 84.3%), distant control (52.7 IFRT vs. 47.7% ENI), and OS (43.7% IFRT vs. 40.1% ENI) rates between ENI and IFRT. The authors concluded that IFRT had a favorable therapeutic ratio compared with ENI owing to reduced acute toxicity. Taken together, these data suggest that IFRT can be employed in patients with locally advanced NSCLC without risk of significant compromise in clinical outcome.

Combined Modality Therapy for Inoperable Stage III Non–Small Cell Lung Cancer

Sequential Chemoradiotherapy

Although dose escalation was achievable and appeared to be associated with improvements in local control in locally advanced NSCLC, the dominant pattern of failure in these patients is through distant dissemination in about 75% to 80% of patients.¹⁸⁵ To address the issue of systemic disease in locally advanced cases, the CALGB initiated a phase III randomized trial of 155 patients with unresectable stage III NSCLC with excellent performance status and minimal weight loss to either radiotherapy alone to 60 Gy or to induction chemotherapy with cisplatin (100 mg/m² given intravenously on days 1 and 29) and vinblastine (5 mg/m² given intravenously on days 1, 8, 15, 22, and 29) followed by radiotherapy to 60 Gy. Median survival was improved with induction chemotherapy to 13.7 months versus 9.6 months with radiotherapy alone (p = .0066). The 5-year survival was improved from 6% to 17% with induction chemotherapy.²⁰¹ A subsequent intergroup trial was launched randomizing 490 patients with inoperable locally advanced NSCLC to one of the following regimens: (a) standard radiation therapy to 60 Gy, (b) induction chemotherapy followed by standard radiation therapy to 60 Gy, and (c) twice-daily radiation therapy to 69.6 Gy as 1.2 Gy given twice daily. Median survival was improved to 13.8 months with induction chemotherapy compared to 11.4 months with standard radiotherapy and 12.3 months with hyperfractionated radiotherapy (p = .03).²⁰² A third prospective randomized trial reported by Le Chevalier et al.¹³⁶ examined a total of 325 patients with unresectable locally advanced NSCLC who were randomized to either radiotherapy alone to 65 Gy delivered in a split course in 26 fractions over 45 days or 3 monthly cycles of VCPC therapy: vindesine, 1.5 mg/m² on days 1 and 2; lomustine, 50 mg/m² on day 2 and 25 mg/m² on day 3; cisplatin, 100 mg/m² on day 2; and cyclophosphamide, 200 mg/m² on days 2 through 4 followed by radiotherapy to 65 Gy in 26 fractions delivered in a split-course fashion over 45 days starting 2 to 3 weeks after the third cycle of chemotherapy. The 2-year survival rate was 14% in patients receiving radiotherapy alone and 21% in the chemoradiotherapy group (P = .08). The distant metastasis rate was significantly lower in patients receiving induction chemotherapy, with the relative risk of metastasis twofold higher in the radiotherapy-alone arm compared to the chemoradiotherapy group (p<.001). Overall, these trials established the role of chemotherapy, in addition to radiation, in the management of inoperable stage III NSCLC (Table 51.8).

TABLE 51.8. Sequential Chemotherapy Versus Radiation Therapy Alone for Locally Advanced Non–Small Cell Lung Cancer

Concurrent Chemoradiotherapy

The EORTC performed a phase III randomized trial comparing concurrent cisplatin-based chemoradiation to radiotherapy alone and demonstrated a clear survival benefit to this approach.¹³⁸ Of note, there was no difference in rate of distant metastases; thus, the authors concluded that the benefit in OS was attributable to an improvement in local control secondary to enhanced radiosensitization of the tumor by low-dose cisplatin. A meta-analysis performed in 2010 to examine the value of concurrent chemotherapy in definitive management of NSCLC by O'Rourke et al.²⁰³ included 19 randomized studies with a total of 2,728 patients with NSCLC (stages I through III), who were randomized to receive either concurrent chemoradiotherapy or radiotherapy alone. Concurrent chemotherapy significantly reduced overall risk of death (HR 0.71) and improved overall PFS at any site (HR 0.69). However, this clinical benefit came at the expense of increased acute toxicity, especially severe esophagitis with concurrent treatment (RR 4.96).

Concurrent Versus Sequential Chemoradiotherapy

Initial phase II trials suggested that concurrent chemoradiotherapy might be an even more effective treatment than sequential chemoradiotherapy.²⁰⁴ Therefore, Furuse et al.²⁰⁵ performed a phase III randomized trial comparing concurrent chemoradiotherapy with mitomycin, vindesine, and cisplatin (MVP) to sequential chemotherapy and radiation therapy. They demonstrated a statistically significant survival advantage to the concurrent approach (median survival of 16.5 months vs. 13.3 months and 5-year survival of 15.8% vs. 8.9%). RTOG 9410 compared two different concurrent regimens (cisplatin and vinblastine with conventional radiotherapy, arm 1, or cisplatin and oral etoposide with hyperfractionated radiotherapy, arm 2) with a “standard” sequential regimen of cisplatin followed by conventional radiotherapy (arm 3). Comparing arm 1 to arm 3 (as per the study design), median survival times improved significantly (17 vs. 14.6 months), as did 5-year survival (15% vs. 10%) with an increase in acute grade 3 through grade 5 nonhematologic toxicities.^206,207 The survival in arm 2 was not significantly better than arm 1, although this intensive regimen was associated with much higher esophageal toxicity. Fournel et al.²⁰⁸ reported the results of a smaller randomized trial that did not show a statistically significant survival advantage for concurrent chemoradiotherapy, with a median survival of 14 months with sequential chemoradiotherapy versus 16 months with concurrent chemoradiotherapy (p = .24). Nevertheless, a consistent trend favoring concurrent chemoradiotherapy in median, 2-, 3-, and 4-year survival rates was observed.²⁰⁸ More recently, a meta-analysis performed by Auperin et al.²⁰⁹analyzed data from six clinical trials involving 1,205 patients. The median follow-up was 6 years. They observed a significant benefit favoring concurrent over sequential chemotherapy and radiotherapy with respect to OS (HR 0.84, p = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. PFS was also improved with concurrent chemoradiotherapy (HR 0.90, p = .07). Concurrent chemoradiotherapy decreased locoregional progression (HR 0.77, p = .01), although not distant progression. Again, this improvement in locoregional control came at the expense of greater acute toxicity for the patient receiving concurrent chemoradiotherapy, with an increase in acute esophageal toxicity (grades 3 and 4) from 4% to 18% with a relative risk of 4.9 (p <.001).²⁰⁹

Because of the increased toxicity with concurrent chemoradiation, especially acute esophagitis, there are often treatment delays that are potentially detrimental in terms of radiobiologic efficacy. Cox et al.²¹⁰examined the impact of prolonged treatment time in stage III NSCLC treated with radiotherapy alone and documented an association with decreased locoregional control and 5-year survival (15% vs. 0%). To determine whether treatment time had a similar impact in the setting of concurrent chemoradiation, Machtay et al.²¹¹ performed a retrospective study of three prospective RTOG trials (RTOG 9106, 9204, and 9410), all of which included good performance status stage III NSCLC patients treated with cisplatin-based concurrent chemoradiotherapy. The authors defined “short” treatment time as finishing treatment within 5 days of the projected end date. They found that “long” treatment time was significantly associated with acute esophagitis. They also found a nonsignificant trend toward improvement in median survival in the “short” (19.5 months) versus “long” treatment time (14.8 months). This study, although retrospective, indicated that even with concurrent chemoradiation, there could be a detrimental effect on survival with delayed treatment time.²¹¹ Thus, appropriate patient selection and maneuvers to minimize toxicity are increasingly important to minimize the likelihood of treatment delays that can compromise the efficacy of concurrent therapy.

In summary, these data strongly support concurrent chemoradiotherapy as the standard approach for patients with good performance status and minimal weight loss. This therapeutic strategy results in improved OS, likely driven by an improvement in locoregional control in patients with locally advanced NSCLC. Of note, this comes at the expense of greater toxicity to the patient, and therefore patient selection is critical when using this approach.

Cytotoxic Platforms for Concurrent Chemoradiotherapy in Locally Advanced Non–Small Cell Lung Cancer

The management of patients with locally advanced NSCLC remains a therapeutic challenge. The era of combined modality therapy was ushered in by Dillman et al.²⁰¹ when the CALGB demonstrated superior survival for chemotherapy with vinblastine and cisplatin followed by definitive radiation (XRT) versus radiation alone. The benefits of sequential chemotherapy followed by radiation were reinforced by subsequent trials by the RTOG and in France.^{212–213,214} In fit patients with minimal weight loss (<5% to 10% from baseline) and intact performance status (ECOG performance status 0 to 1), concurrent chemoradiation with a platinum-based combination has demonstrated clear superiority to radiation alone and to sequential chemotherapy followed by radiation.^{138,205,207,208,215,216} A meta-analysis by Auperin²¹⁷reinforced this observation, demonstrating a 5% absolute increase in long-term survival. Multiple studies in this arena have confirmed 4- to 5-year survival rates of 10% to 20%, which are clearly better than the 5% to 7% observed with XRT alone in this setting^{205,207,208,217,218–219,220,221} (Table 51.9). In the absence of significant comorbidity, hearing loss, or renal compromise in patients who can readily tolerate an acute fluid load, cisplatin-based therapy is considered the standard of care. Most North American clinicians have opted for the EP combination. Unlike limited SCLC, where cisplatin is dosed at 60 mg/m²every 3 weeks and etoposide at 80 to 120 mg/m² daily × 3 both during and after radiation, an alternative dose and schedule is generally used.²²² There are abundant data from the SWOG and RTOG for a schedule that was ultimately phase III tested in RTOG 9309 and later by the Hoosier Oncology Group: cisplatin 50 mg/m² days 1 and 8, 29 and 36; and etoposide 50 mg/m² intravenously days 1 through 5 and days 19 through 33.^{139,140,223,224} This schedule, while inconvenient, is tried and tested and usually safe. Ideally, radiation to a minimum total dose of 60 Gy is given concurrently day 1 with chemotherapy.

TABLE 51.9. Concurrent Chemoradiotherapy for Stage III Non–Small Cell Lung Cancer

In frailer patients or older patients, and in those with significant comorbidity including renal insufficiency (creatinines of 1.5 to 3.0), hearing loss, congestive heart failure, or severe COPD, a carboplatin combination is clearly better tolerated compared to cisplatin, and paclitaxel is often substituted for etoposide. Pilot trials by Belani²²⁵ and Choy²²⁶ clearly demonstrated the safety and efficacy of carboplatin (area under the concentration-time curve [AUC] 2 weekly) and paclitaxel (45 to 50 mg/m² weekly) both initiated day 1 of thoracic radiation, followed by two cycles of full-dose “consolidative” chemotherapy once radiation is completed.^227,228 Conventionally, during the consolidation phase, carboplatin AUC 6 and paclitaxel 200 mg/m² are administered for two cycles at 3-week intervals. This regimen has become the platform for multiple cooperative group phase II and phase III trials, most notably RTOG 0617.

Many have argued that carboplatin-based therapy is inferior to cisplatin in the treatment of locally advanced NSCLC. However, recent data from Japan in a combined modality trial (West Japan Oncology Group Trial WJTOG 0105) evaluating various concurrent chemoradiation regimens failed to show superiority for cisplatin over carboplatin in the context of concurrent chemoradiation.²²¹ Investigators led by Nobuyuki Yamamoto compared their erstwhile standard of MVP to weekly carboplatin in combination with either irinotecan or paclitaxel during XRT; in each arm, those without disease progression or untoward toxicity went on to receive two cycles of full-dose chemotherapy during the “consolidation” period using the same agents administered during XRT. The paclitaxel-carboplatin regimen resulted in less toxicity, fewer dose reductions or omissions, and equivalent if not superior survival at 5 years: 19.5% versus 17.5% for MVP and 17.8% for irinotecan-carboplatin. In fairness, this study also compared second-generation to third-generation chemotherapy; to date, this study is the only phase III trial to attempt to address the platinum question, which arises continually in the clinic.

    Updated by Ramesh Rengan (11/22/2013) There is also recent data to suggest that the toxicity profile with carboplatin-paclitaxel may be distinct from that observed with EP. Palma et al. performed an individual patient meta-analysis to identify predictors for radiation pneumonitis after concurrent chemoradiotherapy and found that elderly patients receiving carboplatin-paclitaxel chemotherapy were at highest risk. (Palma DA, Senan S, Tsujino K, et al., Int J Radiat Oncol Biol Phys. 2013 Feb 1;85:444-50 [PMID: 22682812])

There are additional data to suggest that third-generation regimens are superior to second-generation therapy. Segawa et al.²¹⁸ form the Okayama Lung Cancer Study Group in Japan that demonstrated therapeutic superiority for docetaxel in combination with cisplatin compared with MVP in combination with XRT. An ongoing, pharmaceutical-based, randomized phase III trial in the context of chemoradiation is comparing pemetrexed-cisplatin (another third-generation regimen) followed by single-agent pemetrexed during the consolidation period to EP during XRT followed by investigator's choice during the consolidation period.²²⁹

In patients with baseline V20s (percentage of normal lung that will receive >20 Gy) >35% or in those with borderline pulmonary function or other comorbidities, many clinicians consider administration of chemotherapy first for two or even three cycles, followed by radiation alone or concurrent chemoradiation if there has been sufficient tumor shrinkage to allow a more reasonable radiotherapy treatment field. In those with minimal or no tumor shrinkage using this approach, some investigators omit concurrent chemotherapy during XRT to avoid untoward toxicity, proceeding with XRT alone. These patients are often much more symptomatic than those with smaller-volume tumors, with postobstructive symptoms including wheezing, pneumonitis, and hypoxia, and often have compromised performance status. However, the one study to isolate the role of induction therapy prior to concurrent chemoradiation with paclitaxel and carboplatin failed to show a survival advantage compared to concurrent chemoradiation alone.²²⁰

Toxicity mitigation is another major challenge that has been inadequately addressed. Both acute esophagitis and long-term pneumonitis and pulmonary fibrosis are common complications of combined-modality therapy. A recent meta-analysis by Auperin et al.²¹⁷ demonstrated a sixfold increase in short-term esophagitis, grade 3 or worse (18% vs. 3%) in those receiving concurrent chemoradiation as opposed to asynchronous or sequential chemotherapy and radiation. A phase III study evaluating amifostine as an esophageal protectant failed to show a significant reduction in esophagitis rates, as determined by objective measures, compared to a control arm that did not feature this agent²⁶; however, a subsequent analysis based on patient-reported outcomes suggested a modest benefit with reduction in pain and weight loss.^114,230 There is continued interest in evaluating mucosal protectants, including palifermin and other agents, although to date, no prospective randomized phase III trial has demonstrated a palliative benefit. Consequently, the approach to in-field toxicity has generally been reactive rather than pre-emptive. Newer technologies including proton beam may help to reduce the severity and duration of acute and late esophageal and pulmonary effects. This is currently under investigation.

Consolidative Chemotherapy

Consolidative chemotherapy remains highly controversial. A SWOG trial using the EP/XRT regimen as a platform investigated the role of consolidation docetaxel in stage IIIB patients, yielding a 5-year survival rate of nearly 30%, which is virtually unprecedented in the realm of locally advanced NSCLC.¹³⁹ However, in a phase III randomized Hoosier Oncology Group trial, docetaxel consolidation failed to yield a survival advantage compared to standard “observation” in patients who had completed concurrent chemoradiation with EP, in part because the reference arm “outperformed” its historic controls.²²⁴ These results were disappointing. However, there was a borderline significant imbalance in baseline pulmonary function favoring the control arm: nearly 60% of patients on the arm featuring no consolidation had an FEV1 ≥2 L, compared to slightly >40% in the investigational arm. Similarly, empiric use of gefitinib as maintenance therapy in a SWOG trial led to a paradoxical survival decrement compared to placebo after completion of docetaxel consolidation.²³¹ Hence, based on these trials, there is no proven role for consolidative chemotherapy in patients who have already received systemically dosed chemotherapy during thoracic XRT. In those who receive a radiosensitizing schedule of chemotherapy during XRT, the general consensus favors at least two cycles of full-dose chemotherapy after chemoradiation is completed. Despite the disappointments with docetaxel and empiric gefitinib in this setting, the role of consolidation or maintenance therapy after chemoradiation remains an open question.

Targeted Agents in Locally Advanced Disease

There are no data as yet to support the empiric use of EGFRs, TKIs, EGFR monoclonal antibodies (MAbs), or angiogenesis inhibitors either during or after chemoradiation. The CALGB mounted a randomized phase II trial of concurrent radiation and chemotherapy with carboplatin and pemetrexed followed by “consolidative” pemetrexed with or without cetuximab.²³² The latter did not appear to exacerbate typical in-field toxicities, nor did it yield a significant improvement in long-term survival. The RTOG separately spearheaded a phase II study evaluating cetuximab in combination with standard thoracic radiotherapy and weekly paclitaxel-carboplatin, demonstrating feasibility as well a promising median survival approaching 2 years.²³³ The phase III trial comparing higher dose XRT (74 Gy) to standard dose (60 Gy) was amended early on to address the role of cetuximab in a 2 × 2 design. Although the component of the trial testing higher versus standard dose XRT was closed because of futility, the C225 question remains open and RTOG 0617 continues to accrue; enrollment completed in November of 2011 and results are eagerly awaited. In higher-risk patients with >5% weight loss or compromised performance status, the CALGB is evaluating induction therapy with nab-paclitaxel and carboplatin followed by concurrent XRT and erlotinib. A previous, analogous phase II CALGB study in higher-risk patients evaluating induction carboplatin and paclitaxel followed by concurrent XRT and gefitinib yielded a median OS of 19 months.²³⁴ Attempts to integrate bevacizumab into the combined-modality approach have been unsuccessful, with adverse events including tracheoesophageal fistulas and pulmonary hemorrhages.^235,236

Dose Escalation with Concurrent Chemoradiotherapy

Although concurrent chemoradiotherapy has emerged as the standard therapeutic approach for fit patients with unresectable locally advanced disease, this has come at the cost of increased toxicity to the patient. It is therefore unclear whether dose escalation in the setting of concurrent chemotherapy will provide meaningful clinical benefit. The Lineberger Comprehensive Cancer Center group reported the results of a single-institution phase I dose escalation study with concurrent chemoradiation. They performed a stepwise escalation of thoracic radiation dose from 60 to 74 Gy in conjunction with paclitaxel-carboplatin without a clinically significant increase in toxicity.²³⁷ The median survival of 24 months and 5-year survival of 25% in this study were promising, although patient numbers are small. In 2006, the RTOG opened a 2 × 2 phase III randomized trial to simultaneously examine the question of 60 Gy versus 74 Gy and concurrent chemoradiotherapy with or without cetuximab for patients with inoperable stage III NSCLC. After a planned interim analysis, the high-dose radiation therapy (74 Gy) arms of RTOG 0617 were closed to accrual effective June 17, 2011. In a communication to all RTOG trial investigators, Bradley²³⁸ stated that the “high dose arms crossed a futility boundary, meaning that high dose radiation therapy cannot result in a survival benefit with further accrual or follow up of patients on these 2 arms.” At the 2011 American Society of Therapeutic Radiology and Oncology (ASTRO) annual meeting, the initial results of this trial were presented, actually demonstrating a statistically significant detriment to survival with 74 Gy (p = .02). The interim analysis did not identify patient safety concerns and gave no indication of a statistical difference in high-grade toxicity between arms, nor any clear explanation for the observed decrement in survival. Regardless, the 74-Gy arm for this trial has been closed and 60 Gy remains the standard dose in all RTOG lung cancer trials going forward.²³⁹

Superior Sulcus Tumors and Pancoast's Syndrome

SSTs were first described in 1838 and the characteristic accompanying neurologic symptoms in 1932 by Dr. Henry Pancoast.²⁴⁰ The most common tumors of the superior sulcus are bronchogenic, primarily squamous cell, followed by adenocarcinoma, and less likely small cell. SSTs account for <5% of all lung cancer.²⁴¹

Signs and Symptoms

The most common symptom among patients with SST is pain in the shoulder, which may radiate down the arm. This can be attributable to direct tumor invasion of the parietal pleura, vertebral body, ribs one through three, or the brachial plexus (Fig. 51.5). Pain radiating down the ulnar aspect of the arm past the elbow indicates involvement of the T1 nerve root, whereas extension to the fourth and fifth digits indicates involvement of the C8 nerve root or more distally the ulnar nerve. There may be weakness or atrophy of the intrinsic muscles of the hand. SSTs that invade the neural foramina may cause spinal cord compression, which can ultimately occur in up to 25% of patients. Involvement of the stellate ganglion may manifest as Horner's syndrome: the triad of ptosis, papillary miosis, and facial anhidrosis. Irritation or compression of the adjacent sympathetic chain may cause ipsilateral flushing and sweating of the face or reflex sympathetic dystrophy, a regional syndrome of burning neuropathic pain. Pancoast's syndrome is a constellation of signs and symptoms including shoulder/arm pain, Horner's syndrome, and unilateral upper extremity weakness.

FIGURE 51.5. A 51-year-old former smoker presented with right shoulder pain and right-sided Horner's syndrome and was found to have an adenocarcinoma in the right superior sulcus.

A: Coronal view with gross tumor volume (GTV) contoured. B:An axial view with GTV contoured. A 4-cm tumor is seen invading the mediastinum with displacement of the trachea. He underwent a staging evaluation including mediastinoscopy and was staged as T4N0M0. C: Sagittal view with GTV contoured showing vertebral body impingement. The patient was treated with radiotherapy with concurrent cisplatin and etoposide to 50 Gy and underwent resection with negative margins.

Diagnosis and Staging

SSTs are staged in the same way that SCLC and NSCLC are staged elsewhere in the thorax. For patients without metastatic disease, it is important to assess resectability. Surgery typically involves lobectomy with en bloc resection of the chest wall, which may be accompanied by resection of portions of the parasympathetic chain, stellate ganglion, lower trunks of the brachial plexus, subclavian artery, and portions of vertebral bodies.

Management

Determining the feasibility of resection is a critical decision point in the management of NSCLC SSTs. Because of the apical location of the tumor, invasion of the brachial plexus, vertebral bodies, and subclavian vessels is not uncommon and may eliminate surgical resection as an option, depending on the extent of invasion. In addition to CT, PET, and bone scan, MRI is useful in documenting the extent of involvement of the brachial plexus, spinal nerve roots, vertebral bodies, and subclavian vessels and is more sensitive than CT for this purpose.²⁴² Small cell SSTs in patient with good performance status are treated with concurrent chemoradiotherapy for limited-stage disease or chemotherapy for extensive-stage disease.

Multimodality Therapy for Superior Sulcus Tumors

Several large retrospective series and prospective trials have investigated outcomes of multimodality treatment of SSTs. SWOG 9416/Intergroup 0160 included 110 patients with T3-4, N0-1 SSTs. All patients were treated with two cycles of EP with radiotherapy (45 Gy in 25 fractions), followed by surgery within 3 to 5 weeks, and then two further cycles of chemotherapy.²⁴³ The study included patients with apical tumors and Pancoast's syndrome, or SSTs with chest wall invasion, or involvement of the vertebrae or subclavian vessels. In this study, 88 patients (80%) underwent surgery, and 83 (76%) had complete resection. The 5-year OS was 44%. As well, 61 resected patients (56%) had a pathologic complete response to induction therapy, and their 5-year survival was significantly better at 54%. A Japan Clinical Oncology Group (JCOG) study enrolled 76 patients and used induction mitomycin, vindesine, and cisplatin with 45 Gy in 27 fractions (split course) followed by surgery.²⁴⁴ The study included patients with SSTs, staged T3-4, N0-1, and nonbulky N2 disease; 76% of patients underwent resection, and 68% had complete resection. The 5-year OS was 56%. A single-institution French study enrolled 107 patients with SSTs in a prospective trial of induction chemoradiotherapy.²⁴⁵ The study excluded those with bulky N2 or N3 disease. All patients received EP concurrently with radiotherapy to 45 Gy; 72 patients underwent resection; unresectable patients received an additional 25 Gy. The 3-year OS was 40%.

In patients who are resectable at diagnosis, surgery may be offered as initial therapy. A prospective trial at the University of Texas MD Anderson Cancer Center enrolled 32 patients with resectable or marginally resectable SSTs.²⁴⁶ All patients had gross total resection initially; 28% had microscopic residual disease. Postoperatively, patients were treated with radiotherapy to 60 Gy in 1.2-Gy fractions (for negative margins) or 64.8 Gy in 1.2-Gy fractions (for positive margins) with concurrent EP. The 5-year locoregional control was 76%, and 5-year OS was 50%.

    Updated by Ramesh Rengan (11/22/2013) The long-term results of this trial were recently updated showing the 10-year locoregional control to remain excellent at 76% and the 10-year OS to be 45%. (Gomez DR, Cox JD, Roth JA, et al., Cancer. 2012 Jan 15;118:444-51 [PMID: 21713767])

Chemoradiotherapy

Retrospective evidence suggests that patients who undergo surgery have better local control and survival than those treated with radiation therapy, although such data is subject to significant selection bias.²⁴⁷Patients with unresectable localized SSTs and those with stage III disease and bulky N2 (or N3) lymph nodes should be treated with definitive chemotherapy and radiation. Early studies of radiotherapy alone for SSTs show acceptable local control and survival. In a series of 32 patients treated with definitive radiation, 91% of patients with pain reported relief, and 75% of patients with Horner's syndrome had symptomatic improvement.²⁴⁸ The addition of concurrent chemotherapy improves local control and survival in patients with stage III NSCLC—an observation that has led to the widespread use of concurrent therapy in SSTs. Small series in patients with SSTs appear to support this. A retrospective analysis from the Netherlands examined the outcome of patients treated with chemoradiotherapy.²⁴⁹ In this study, 49 patients with stage II or III SST received 66 Gy with daily cisplatin (6 mg/m²); 19 patients had sufficient response to undergo resection, and in these patients there was a 53% pathologic complete response rate. The 5-year OS was 18% in patients who received chemoradiotherapy and 33% in patients who were able to undergo surgery.