Original Article
Clinical Prognostic Factors in Patients With Locally Advanced (Stage III) Nonsmall Cell Lung Cancer Treated With Hyperfractionated Radiation Therapy With and Without Concurrent Chemotherapy Single-Institution Experience in 600 Patients ´ , MD, PhD; Biljana Milic ˇ ic ´, MD, PhD; and Slobodan Milisavljevic, MD, PhD Branislav Jeremic
BACKGROUND: Influence of potential clinical prognostic factors on overall survival (OS), local progression-free survival (PFS), and distant metastasis-free survival (MFS) in patients with locally advanced nonsmall cell lung cancer treated with hyperfractionated radiation therapy (HFX RT) with or without concurrent chemotherapy was investigated. METHODS: Three phase 3 and 2 phase 2 studies have been designed and executed with a total of 600 patients. HFX RT alone was given in 127 and HFX RT-chemotherapy was given in 473 patients. HFX RT doses were either 64.8 grays (Gy) or 69.6 Gy using 1.2 Gy twice daily, or 67.6 Gy using 1.3 Gy twice daily. Chemotherapy consisted of concurrent carboplatin and etoposide in 409 patients and concurrent carboplatin and paclitaxel in 64 patients. Sex, age, Karnofsky performance score (KPS), weight loss (>5%), stage, histology, interfraction interval, and treatment (the addition of concurrent chemotherapy) were investigated as potential prognostic factors. RESULTS: The median OS, median local PFS, and median distant MFS times were 19, 21, and 23 months, respectively. Five-year OS, local PFS, and distant MFS rates were 19%, 29%, and 35%, respectively. Univariate and multivariate analysis showed that only age did not influence OS and local PFS, whereas female sex, lower KPS, less pronounced weight loss, lower stage, squamous histology, shorter interfraction interval, and treatment independently predicted better OS and local PFS. Only age and treatment did not influence distant MFS, whereas histology was of borderline significance. CONCLUSIONS: This study identified independent prognosticators of treatment outcome. These results may have implicaC 2011 American Cancer Society. tions for future studies in this disease. Cancer 2011;117:2995-3003. V KEYWORDS: locally advanced nonsmall cell lung cancer, radiation therapy, chemotherapy, prognostic factors.
Lung cancer is among the major health problems worldwide. The majority of patients have nonsmall cell lung cancer (NSCLC), and of them, the vast majority are diagnosed as locally advanced (stage III) and metastatic (stage IV) disease. For such patients, radiation therapy (RT) and chemotherapy have mostly been used in the past. Nowadays, only a minority of patients with stage III disease are treated with a combined modality approach incorporating surgery. The remaining majority is treated with either RT alone, chemotherapy alone, or with increasing frequency in the past 2 decades, with combined RT-chemotherapy as the dominant approach in a curative setting. Although induction chemotherapy followed by a radical RT1-3 has been shown to be an improvement for a combined regimen, concurrent RT-chemotherapy has also been shown to be superior to RT alone in clinical trials,4 including recent a meta-analysis.5 Finally, the data from 2 more recent meta-analyses6,7 clearly showed the superiority of concurrent RT-chemotherapy over induction chemotherapy followed by radical RT. To optimize treatment approach in stage III NSCLC, we have performed a series of prospective studies8-12 exploring various aspects of concurrent RT-chemotherapy regarding total RT dose and dose per fraction, as well as timing and dose Corresponding author: Branislav Jeremic´, MD, PhD, Institute of Pulmonary Diseases; Institutski put 4, 21204 Sremska Kamenica, Serbia;
[email protected] Department of Oncology, University Hospital, Kragujevac, Serbia DOI: 10.1002/cncr.25910, Received: August 20, 2010; Revised: September 29, 2010; Accepted: December 6, 2010, Published online January 10, 2011 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
July 1, 2011
2995
Original Article
of concurrent chemotherapy given during the course of radical RT. Our results have helped establish concurrent RT-chemotherapy as the standard treatment approach in this disease. In addition to investigation of various treatment approaches to optimize outcome, identification of prognostic factors should be attempted because of their key role in the treatment decision-making process, as the current therapeutic approach uses a risk stratification paradigm. Prognostic factors facilitate risk assessment and guide decisions on whether to initiate therapy, including also the influence they exert on the choice of therapy to administer. The use of 1 or more of these factors, however, has become confusing, producing conflicting results. In addition, some of prognostic factors may be significant by random chance alone, as their importance is rather difficult to evaluate without verification in multiple studies. It was shown in various studies that the characteristics of patients can influence their clinical course,13,14 and it is observed that the magnitude of differences in outcome for categories of the strongest prognostic factors can be larger than those for the type of therapy used in various studies.15 Therefore, we underwent current analysis to identify prognostic factors influencing outcome of patients with stage III NSCLC treated with hyperfractionated (HFX) RT with or without concurrent chemotherapy. We have focused on clinical prognostic factors because they are easy to observe and note. They can also be collected early in the course of the disease/diagnosis, before we decide upon the optimal treatment approach in this disease, as well as easily monitored during the latter part of the course of the disease.
MATERIALS AND METHODS Over a period of 10 years (1988-1998), a total of 600 patients were treated according to 5 prospective study protocols. Three prospective phase 3 and 2 prospective phase 2 studies8-12 were performed in adults with confirmed stage III NSCLC, a Karnofsky performance score (KPS) score of at least 50%, and no previous therapy. Exclusion criteria included postoperative thoracic recurrence or a history of any prior or concurrent cancer (except that of the skin), unless the patient had shown no evidence of disease for >5 years; patients with malignant pleural effusion were excluded as well. Uniform diagnostic and staging procedures (medical history, physical examination, complete blood count, biochemical screening tests, chest radi-
2996
ography, and computed tomography [CT] of the thorax and upper abdomen were used; brain CT scanning and pulmonary function tests were performed whenever possible), including follow-up schedules and procedures. Exceptions to this were Study 1,8 where CT scans of the thorax and brain and pulmonary function tests were performed when possible, whereas abdominal CT scan was not a part of the initial evaluation and was performed only in patients with recurrence, and Study 5,12 where eligibility criteria included KPS of 70%, and weight loss of
