Radiotherapy for Locally Advanced Nonsmall Cell Lung Cancer Including Combined Modality

Dose

When radiotherapy alone is used to treat locally advanced NSCLC, the median survival is approximately 10 months and the 5-year survival rate is 5%. In the 1970s, the Radiation Therapy Oncology Group (RTOG) conducted a phase III trial (RTOG 73-01) to evaluate the effect of radiotherapy dosage on local control rates and overall survival. Patients were randomly assigned to treatment with 40 Gy, 50 Gy, or 60 Gy in 2-Gy daily fractions or to a split-course schedule. Local control rates were significantly better with the highest dose (52% vs. 62% vs. 73%, respectively; p = 0.02), although median survival rates were similar (10.6 months vs. 9.5 months vs. 10.8 months, respectively). The split-course schedule was associated with inferior local control and survival. This trial established 60 Gy in 30 fractions as the standard radiotherapy dose-fractionation scheme for decades.

Early radiotherapy portals were designed to cover the primary tumor, ipsilateral hilum, ipsilateral and contralateral mediastinum, and ipsilateral supraclavicular nodes, leading to a large irradiated volume. This approach was called elective nodal irradiation. As the toxicity of this approach and the relation between local failure occurring mainly at the level of the gross tumor volume and poor patient outcomes became more apparent, treatment planning shifted toward involved field radiation. Concern about the potential for nodal recurrence has slowed the adoption of involved field radiation; however, a prospective randomized trial from China showed promising results. Patients with locally advanced NSCLC were treated with 68 Gy to 74 Gy involved field radiation or 60 Gy to 64 Gy elective nodal irradiation. At 5 years, patients who received involved field radiation had significantly better overall response rates (90% vs. 79%, p = 0.032), local control (51% vs. 36%, p = 0.032), and fewer cases of pneumonitis (17% vs. 29%, p = 0.044).Treatment with involved field radiation significantly improved overall survival at 2 years (39.4% vs. 25.6%, p = 0.048). Despite several limitations of this study, the results are intriguing and suggest that involved field radiation is unlikely to compromise clinical outcomes. Furthermore, several studies have clearly demonstrated that the number of isolated nodal failures outside the involved field radiation remains very low.

Technologic advances have enabled researchers to determine the optimal volume and explore the role of dose escalation in improving local control rates. The introduction of positron emission tomography (PET)–computed tomography (CT) imaging has enhanced treatment planning. The addition of cone-beam CT on linear accelerators has led to new radiotherapy such as intensity-modulated radiotherapy (IMRT)—either static or rotational—and image-guided radiotherapy, which improves the accuracy of daily radiotherapy delivery. Because of these improvements, the classical safety margins can be decreased, allowing researchers to increase the total dose either physically or biologically.

In early phase I/II trials, increasing the radiotherapy dose to 74 Gy or more improved the median survival times to 24 months. Given the promising results of these trials and a pooled analysis of Cooperative Group studies, a phase III randomized trial (RTOG 06-17 trial) was designed to compare concurrent chemoradiotherapy and dose-escalated radiotherapy with standard radiotherapy dosage. There was a second randomization to evaluate the role of cetuximab. Patients with locally advanced NSCLC were randomized to a standard-dose radiotherapy (60 Gy in 30 daily fractions) or a high-dose radiotherapy (74 Gy in 37 fractions) concurrently with weekly paclitaxel and carboplatin followed by two cycles of consolidation and to cetuximab or not. The 2-year survival rates were 58% for the standard dose and 45% for the high radiation dose. The local failure rate was also higher in the experimental arm: 38.6% versus 30.7%, respectively, at 2 years. Planning target volumes were very similar between the two arms as well as the use of IMRT. However, although 10 patients died in the 74-Gy arms compared with two in the 60-Gy arms, the toxicity rates were not different between the two groups. Several explanations have been put forward to explain these worse outcomes in the higher dose arm, including heart toxicity and the loss of efficacy through longer overall treatment time and accelerated repopulation. It is important to note that the outcomes in the low-dose arm are among the best ever observed in a population with stage III NSCLC. A subsequent analysis examined the role of IMRT as patients were stratified according to the radiation technique: the planning target volume was larger for patients treated by IMRT compared with three-dimensional conformal radiation therapy (486 mL vs. 427 mL), but the outcomes were similar for the two techniques. Less grade 3 pneumonitis, lower heart dose, and less dose reduction for chemotherapy were observed for patients treated by IMRT. There was a concern that IMRT could result in very low doses of radiation to large volumes of normal lung with increased pneumonitis risk, but an increased incidence of radiation pneumonitis was not observed.

Hypofractionation

Hypofractionated radiotherapy is the delivery of fewer, larger (>2 Gy) doses of radiotherapy and is another potential strategy for improving dose intensity. This approach has become more feasible as a result of decreasing radiotherapy volumes, which allow for more conformal radiotherapy delivery and limit the dose delivered to normal tissue. Few studies have evaluated hypofractionation with modern radiotherapy techniques for locally advanced NSCLC. Two prospective phase II studies evaluating concurrent platinum-based chemotherapy with radiotherapy (2.4 Gy/d to 2.75 Gy/d) have reported an encouraging median survival of 20 months. In the sequential or concurrent cancer radiation (SOCCAR) trial, 55 Gy was delivered in 20 fractions over 4 weeks with sequential or concurrent chemotherapy (cisplatin [DDP]–vinorelbine). In this limited phase II trial, 2-year survival rates were similar (50% vs. 46%) with 8% experiencing grade 3 esophagitis. Additional studies using modern radiotherapy techniques are currently being conducted within a cooperative group setting as well as in single institutions. One study of interest is a phase III trial comparing a hypofractionated course of 60 Gy in 15 fractions over 3 weeks with conventional radiotherapy (60–66 Gy in 30–33 fractions over 6 weeks to 7 weeks) without concurrent chemotherapy for patients with stage II–III NSCLC and poor performance status (NCT01459497).

Ongoing research is examining isotoxic dose escalation based on normal tissue tolerance or using the stereotactic body irradiation therapy technique to increase the dose to ¹⁸ F-2-deoxy- d -glucose-avid portions of the tumor based on intratreatment PET–CT. Currently, a randomized trial is comparing a homogeneous dose distribution to the primary tumor or a heterogeneous dose distribution based on the metabolic image provided by a PET–CT ( Fig. 39.1 ). Last but not least, protons are under investigation in stage III NSCLC to take advantage of better dose distribution, especially allowing better sparing of the heart, but the results of a randomized trial were disappointing.

In summary, higher physical or biologic dose (altered fractionation) is associated with better local control and, in some trials, with better survival, but the optimal dose and fractionation are yet to be defined. Currently, 60 Gy to 66 Gy in daily fractions of 2 Gy remains the most common schedule.

Role of Chemotherapy

For patients with medically inoperable or technically unresectable locally advanced NSCLC, thoracic radiotherapy alone, which is potentially curative, was regarded as a standard therapy in the 1980s; however, the treatment results were unsatisfactory due to a high rate of relapse and distant metastases. It was thought that chemotherapy with radiosensitizing anticancer drugs might improve survival by controlling remote metastases and increasing tumor sensitivity to radiotherapy, and several trials tested this hypothesis. Results from meta-analyses showed that survival after sequential or concurrent chemoradiation therapy that included a platinum agent was better than survival after radiotherapy alone. The important role of chemotherapy was demonstrated with an absolute benefit of 3% at 2 years and 2% at 5 years. Furthermore, a third meta-analysis has clearly demonstrated the superiority of a concurrent to a sequential approach.

Nevertheless, these findings were still not satisfactory, and subsequent investigations aimed to establish the optimal timing and type of chemotherapy needed to control micrometastases, increase the effects of radiotherapy, and improve local control and survival.