A Phase II Study of Erlotinib (Tarceva) and Hypofractionated Thoracic Radiotherapy for Patients With Advanced or Inoperable Non-Small-Cell Lung Cancer

Hypothesis/Rationale: Lung cancer is the number one cause of cancer-related mortality in both men and women in the United States, with over 170,000 cases diagnosed annually. The overall 5-year survival rate remains 14% despite decades of clinical research. Thoracic RT is the standard treatment for locally advanced (Stage III) NSCLC, in combination with chemotherapy in favorable patients. Metastatic lung cancer (Stage IV) is treated with systemic chemotherapy, with the addition of RT for palliation of tumor symptoms. Most lung cancers present as large tumors, measuring 2 to 7 cm in largest dimension. It is therefore not difficult to understand that only 16% of patients experience a complete resolution of their irradiated tumors within 3 months following a course of standard fractionated (2.0 Gy daily) RT and chemotherapy.

From basic principles advocated by Fletcher, it is thought that standard fractionated RT doses up to 100.0 Gy may be necessary to sterilize tumors of the size frequently encountered in clinical practice. Tumor control probability for bronchogenic carcinoma can be estimated to be 10% for tumors of greater than 4 cm at a dose of 80.0 Gy, with an assumption, that an average-size lung cancer may require doses beyond 100.0 Gy standard fractionated to have a 50% to 80% probability of controlling the tumor. This has been demonstrated in the "stereotactic radioablation" approach to patients with the medically inoperable Stage I NSCLC, in whom 20 Gy per fraction to a total of 60 Gy (a BED equivalent of >100 Gy) resulted in an excellent local control of >90% (Timmerman R et al, 2006; Onishi H et al, 2007).

Hypofractionated RT: It is generally accepted that the presence of chronically hypoxic cells within tumors may be an important cause of radioresistance and resultant local failure in radiotherapy, particularly in large solid tumors such as locoregionally advanced NSCLC. In-vitro experiments indicated that the dose needed to kill severely hypoxic cells is on the order of 2 or 3 times the dose needed for oxic cells. Therefore, delivering a higher RT dose to the tumor may result in higher tumor cell kill and improved local control. One of the approaches to increase RT dose is to use hypofractionated RT, which not only increases the dose, but also reduces the overall treatment time. The radiobiological rationale for hypofractionated RT was described by Mehta et al (Mehta et al, 2001). Based on these theoretical assumptions, University of Wisconsin has recently completed a dose escalation study of progressively increasing fraction sizes in thoracic RT for lung cancer. Such larger RT fraction sizes may require "tighter" radiation fields (to achieve reliable normal-tissue sparing) and improved precision of RT delivery, something that is afforded by the SBF (Stereotactic Body Frame) immobilization and daily CT scan based image verification of tumor position. More experiences have been reported in the literature on hypofractionated regimens for lung cancer. Japanese investigators (Nagata Y et al, 2002) treated 40 patients with T1-T3N0 tumors or lung metastases with 10-12 Gy per fraction to a total of 40-48 Gy. No pulmonary (or other) complications >Grade 2 were observed and the local control was 100% in the subgroup of primary lung tumors. Another group from Japan (Onimaru R et al, 2003) reported on 45 patients with primary lung tumors up to 6cm receiving 7.5 Gy per fraction to 60 Gy (lesions <3cm) or 6 Gy per fractions to 48 Gy (lesions 3-6cm). One patient with a central tumor died of a radiation-induced ulcer in the esophagus. One patient with a peripheral lesion experienced Grade 2 chest wall pain. The 3-year local control rate was 80%. No adverse respiratory events were noted.

The "ultimate" hypofractionated RT regimen of 60 Gy given in 3 fractions of 20 Gy each has been demonstrated to be feasible and highly effective in patients with medically inoperable Stage I NSCLC tumors measuring up to 7 cm and located outside the central airways (Timmerman et al, 2006). However, the same regimen was associated with a high incidence of severe toxicity if applied to central airway. Since most tumors in patients with Stage III and IV NSCLC are located centrally, a novel hypofractionated regimen needs to be developed specifically for them.

In our institution we have completed a Phase I/II investigator-initiated trial of dose-escalated hypofractionated RT given concurrently with Gefitinib (Iressa) with Gefitinib continued after RT completion until progression or toxicity. Three RT dose levels are applied: 4.2 Gy in 10 fractions to 42 Gy; 4.2 Gy in 12 fractions 50.4 Gy and 4.2 Gy in 15 fractions to 63 Gy. Eligible pts are those with either Stage III or IV NSCLC who needed thoracic RT and could not receive chemotherapy. No selection by the EGFR receptor status has been applied. A total of 12 patients have been enrolled. Main toxicities were pulmonary (1 grade 2 pneumonitis; 1 grade 3 infectious pneumonia; 1 grade 4 pneumonitis). There was 1 grade 3 abdominal pain. One patient (with thoracic tumor controlled) died due to the late radiation-esophageal toxicity (tracheo-esophageal fistula in a setting of pre-existing esophageal diverticula) at 12 months from RT. Only one patient experienced local progression of the irradiated tumor, which is very encouraging and may support the hypothesis of the radiosensitizing effect of the EGFR inhibitors. As of now, median survival time for all 12 enrolled patients is 9 months (range: 1-26 mo) from the time of initiating Gefitinib, which is an encouraging result in mostly pretreated patients, many with metastatic disease (Werner-Wasik et al, oral presentation, First ESMO/IASLC European Meeting on Lung Cancer, Geneva, Switzerland, April 2008).