Combined chemo-radiotherapy for locally advanced non-small cell lung cancer: Current status and future development

Critical Reviews in Oncology/Hematology 68 (2008) 222–232

Combined chemo-radiotherapy for locally advanced non-small cell lung cancer: Current status and future development Cesare Guida a , Paolo Maione b , Antonio Rossi b , Marianna Bareschino b , Clorinda Schettino b , Domenico Barzaghi a , Massimo Elmo a , Cesare Gridelli b,∗ b

a Division of Radiotherapy, S.G. Moscati Hospital, Avellino, Italy Division of Medical Oncology, S.G. Moscati Hospital, Contrada Amoretta 83100 Avellino, Italy

Accepted 28 May 2008

Contents 1. 2.

3. 4.

5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sequential versus concurrent chemoradiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Sequential chemo-radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Concurrent chemo-radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Induction and consolidation chemotherapy in addition to concurrent chemoradiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combination of chemoradiotherapy with molecularly targeted therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Epidermal growth factor receptor inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Angiogenesis inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemo-radiotherapy in elderly patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recent innovations in the radiotherapy of NSCLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

223 223 223 224 226 227 227 228 229 229 230 230 230 230 232

Abstract Currently, combinations of chemotherapy and radiotherapy are the standard treatment approach for locally advanced NSCLC patients. Concomitant chemo-radiotherapy, although associated with increased acute toxicity, has demonstrated to be the better strategy over sequential chemoradiotherapy, and it is to be considered a standard approach in patients with good performance status (0–1). However, the approach to locally advanced NSCLC and to chemo-radiotherapy regimens remains heterogeneous among oncologists, and clinical outcomes are yet disappointing. Thus, the search of new strategies is mandatory. The main fields of research aiming at improving the survival of locally advanced NSCLC patients are: the addition of further combination chemotherapy as induction or consolidation to concurrent chemo-radiotherapy, and the integration of molecularly targeted therapies into conventional chemo-radiotherapy regimens. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Locally advanced NSCLC; Combined chemo-radiotherapy; EGFR inhibitors; Angiogenesis inhibitors

∗

Corresponding author. Tel.: +39 0825 203574; fax: +39 0825 203556. E-mail address: [email protected] (C. Gridelli).

1040-8428/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2008.05.007

C. Guida et al. / Critical Reviews in Oncology/Hematology 68 (2008) 222–232

1. Introduction Locally advanced Non Small Cell Lung Cancer (NSCLC) patients, accounting for more than 40,000 cases annually in the United States, represent an heterogeneous group of patients and several clinically distinct sub-stages. Patients with unresectable stage IIIA or IIIB NSCLC have traditionally been treated with radiotherapy alone. Since all known macroscopic disease is confined to the chest, therapy was given in theory with curative intent. However, only 5–10% of patients survived beyond 5 years. This was frequently owing to distant disease progression (outside the radiation field), which occurred in up to 70% of patients and reflects the presence of systemic micrometastases at the time of initial therapy. Disease in a large proportion of patients also progressed within the irradiated volume, reflecting the inability of radiotherapy to eliminate all macroscopic disease. Efforts to increase cure rates have, therefore, attempted to increase both loco-regional and systemic control. In practice, sequential chemo-radiotherapy or concomitant chemo-radiotherapy have been studied to achieve these goals. A number of randomised clinical trials and meta-analyses support the conclusion that combined modality approaches using cisplatin-based chemotherapy improve survival compared with radiotherapy alone in patients with surgically unresectable stage III disease. Currently, in unresectable stage III disease, combinations of chemotherapy and radiotherapy are the standard treatment approach for patients with good performance status (PS), and concomitant chemo-radiotherapy has demonstrated to be the better strategy. However, clinical outcomes are yet disappointing and the search of new strategies is mandatory. The main fields of research aiming at improving the survival of locally advanced NSCLC patients are: the addition of further combination chemotherapy as induction or consolidation to concurrent chemoradiotherapy, and the integration of molecularly targeted therapies into conventional chemoradiotherapy regimens.

2. Sequential versus concurrent chemoradiotherapy In the past, radiation therapy was considered the standard therapy for patients with stage IIIA or IIIB disease. Longterm survival was poor, in the range of 5–10%, with poor local control and early development of distant metastatic disease. The dominant pattern of failure in curatively resected or radically irradiated patients is distant metastatic failure. Thus, the rationale for chemotherapy given to potentially cure patients with NSCLC is prevention of distant relapse. Indeed, it is reported that at least 80% of patients treated with local modalities alone will have micrometastases and will, therefore, relapse [1,2]. Depending on the strategy used, chemotherapy may play a cytotoxic role by eradicating distant micrometastases, a radiosensitizing role by improving local control, or both. It has been shown that chemo-radiotherapy is more

223

efficient than either chemotherapy alone or radiation alone, for the therapeutic management of localized unresectable NSCLC [3]. In the Cambridge metanalysis, aimed at evaluating the efficacy of cytotoxic chemotherapy on survival in NSCLC patients, 9387 patients enrolled on 52 randomized studies were distributed in 4 broad categories as a function of stage of disease. One of these categories consisted in the comparison between radiotherapy and radiotherapy plus chemotherapy. The combination of radiotherapy and cisplatin-based chemotherapy significantly reduced the risk of death by 13% (hazard ratio 0.87; P = 0.005). The 2-year survival rate was 15% and 19% in the radiotherapy group and the radiotherapy plus chemotherapy group, respectively; the 5-year survival rate was 5% and 7% in the radiotherapy group and the radiotherapy plus chemotherapy group, respectively [3]. Several randomized trials have compared thoracic irradiation alone with chemo-radiation therapy in patients with stage III NSCLC. Some of them employed sequential chemo-radiation therapy and others concurrent chemo-radiation therapy. 2.1. Sequential chemo-radiotherapy The benefit of induction chemotherapy before radiotherapy in stage III NSCLC was established by the Cancer and Leukemia Group B (CALGB) 8433 [4] and subsequently verified by the RTOG 8808 randomized phase III studies [5]. In the CALGB 8433 trial, induction chemotherapy consisted of cisplatin, 100 mg/m2 on days 1 and 29, plus vinblastine, 5 mg/m2 weekly for 5 weeks. Standard irradiation consisted of 60 Gy given in 30 fractions beginning on day 1 in the standard radiotherapy arm and on day 50 in the chemoradiotherapy arm. After more than 7 years’ follow-up in 155 initially evaluable patients, median survival times in the chemo-radiotherapy arm and the radiotherapy-only arm were 13.7 and 9.6 months, respectively (P = 0.012). The rate of tumor response was 56% for the chemo-radiotherapy arm and 43% for the radiotherapy arm (P = 0.092). The authors concluded that although the 4.1-month increase in median survival favoring sequential chemo-radiotherapy over radiotherapy alone, about 80–85% of the patients enrolled onto this trial died within 5 years, with treatment failure occurring both in the irradiated field and at distant sites [4]. Further improvement in both local and systemic treatment of disease was necessary. In the RTOG 8808 trial, patients were randomised to three treatment arms: sequential chemoradiotherapy, standard radiotherapy, and hyperfractionated radiotherapy. The sequential chemo-radiotherapy arm and the standard radiotherapy arm consisted in the same regimens used in the CALGB 8433 trial. In the third treatment arm patients received hyperfractionated irradiation at 1.2 Gy twice daily to a total of 69.6 Gy. In this study, with 458 initially evaluable patients, overall survival was statistically superior for the patients receiving chemotherapy and radiation versus the other two radiotherapy-only arms of the study (P = 0.04). Median survival times after 5 years were

224

C. Guida et al. / Critical Reviews in Oncology/Hematology 68 (2008) 222–232

11.4 months with standard irradiation, 13.2 months with chemo-radiotherapy, and 12 months with hyperfractionated irradiation. The respective 5-years survivals were 5% for standard radiation therapy, 8% for chemotherapy followed by radiation therapy, and 6% for hyperfractionated irradiation. The twice-daily radiation therapy arm, although better, was not statistically superior in survival compared with standard radiation arm [5]. 2.2. Concurrent chemo-radiotherapy The first approach to be tested as concurrent chemoradiotherapy was the combination of radiotherapy with radiosensitizing low-dose chemotherapy. One of the first trials evaluating concurrent chemo-radiation therapy versus radiation alone, the European Organization for Research and Treatment of Cancer (EORTC) trial 08844, compared radiotherapy alone with radiotherapy and concomitant (daily or weekly) low-dose cisplatin therapy [6]. This study demonstrated a significant survival advantage for daily cisplatin and radiotherapy compared with radiotherapy alone (3-year survival rates, 16% vs. 2%); the weekly cisplatin/radiation therapy arm produced intermediate results (3-year survival rate, 13%) (Table 1). Another phase III concurrent chemo-radiation therapy trial, showed that the combination of hyperfractionated radiation therapy and low-dose daily chemotherapy (carboplatin plus etoposide) was superior to hyperfractionated radiation therapy alone (to 69.6 Gy), with 4-year survival rates of 23% versus 9% (P = 0.02) [7]. Sequential approaches to chemo-radiotherapy, in which platinum-based chemotherapy precedes thoracic radiation, have generally improved outcome by reducing distant failure rates. In contrast, concurrent chemo-radiotherapy using low-dose cisplatin was reported to improve survival by reducing local recurrence, without an effect on distant metastases. In view of these observations, concurrent chemo-radiotherapy approaches integrating both radiosensitizing agents and dose levels of chemotherapy effective against micrometastases have been the most studied strategies. After several randomized trials comparing sequential and concurrent chemo-radiotherapy to radiation alone and demonstrating the superiority of the combined approaches, the superiority of concurrent administration of chemotherapy and radiotherapy over sequential therapy has been supported by two influential studies: RTOG 9410 [8] and a

study from West Japan, Lung Cancer Group [9]. The RTOG 9410 study assessed 597 patients with stage II–III NSCLC. Cisplatin 100 mg/m2 on days 1 and 29, with vinblastine, 5 mg/m2 weekly for 5 weeks, and with radiotherapy, started on day 50 and administered to a total dose of 60 Gy, was compared with the same chemotherapy regimen plus radiotherapy started on day 1. A third group received concomitant chemo-radiotherapy involving cisplatin/oral etoposide and hyperfractionated radiotherapy (total dose, 69.6 Gy). Median survival times for the three respective treatment groups were 14.6, 17.0, and 15.6 months. The 4-year survival rates with concurrent cisplatin/vinblastine and once-daily irradiation was 21% versus 12% with sequential treatment (P = 0.04). The third treatment arm (concurrent cisplatin/oral etoposide and hyperfractionated irradiation) was intermediate with a 4-year survival of 17%. These data show a strong trend favoring concurrent chemotherapy with standard radiation therapy over sequential or hyperfractionated treatment groups. The rates of acute grade 3–4 non-hematological toxicity were reported to be higher with concurrent than sequential therapy, but late toxicity rates were similar [8]. Movsas et al. reported the results of a quality-adjusted time without symptoms of toxicity (QTWiST) analysis of RTOG 94-10. Despite the increase in reversible non-hematologic toxicities in the concurrent arms, the overall mean toxicity was highest in the sequential arm, which involved the longest treatment time. The concurrent once-daily arm had the optimal QTWiST, further supporting concurrent chemo-radiation therapy as a new treatment paradigm [10]. Thus, delivering hyperfractionated radiation with concurrent chemotherapy produced higher toxicity rates with no increase in survival over once daily radiation concurrent with chemotherapy. The West Japan Lung Cancer Group studied 314 evaluable patients with unresectable stage III NSCLC and showed a 3.2-month median survival advantage (median survival 16.5 vs. 13.3 months, 5-year survival rates 15.8% vs. 8.9%, P = 0.04) when irradiation was administered in what is currently considered an outdated schedule, with 28 Gy in 14 fractions at five fractions per week administered twice in a split-course regimen (total dose 56 Gy) concurrently with cisplatin, vindesine, and mitomycin rather than sequentially after the completion of chemotherapy at five fractions weekly to a total of 56 Gy [9]. Despite the disadvantages of split-course techniques, which allow not only the repair of normal tissues but also proliferation of tumor clones during the break, the 5-year survival rate significantly favored the concurrent approach.

Table 1 Main phase III randomized trials on combined chemo-radiotherapy vs. radiotherapy Author

Regimens

Efficacy (MST or 3-year survival rate)

Dillman (1996) [4] Sause (2000) [5] Schaake-Koning (1992) [6]

Cisplatin/vinblastine + SRT vs. RT Cisplatin/vinblastine + SRT vs. RT Daily cisplatin + CRT vs. RT

13.7 m* 9.6 m 13.2 m* 11.4 m 16%* 2%

MST: Median survival time; m: months; RT: radiotherapy; CRT: concurrent radiotherapy; SRT: sequential radiotherapy; gr: grade; *: statistically significant vs. sequential treatments.

C. Guida et al. / Critical Reviews in Oncology/Hematology 68 (2008) 222–232

225

Table 2 Main phase III randomized trials on concurrent vs. sequential chemo-radiotherapy Author

Regimens

Efficacy (MST)

Toxicity

Furuse et al. (1999) [9]

Cisplatin/vindesine/mitomycin + CRT vs. Cisplatin/vindesine/mitomycin + SRT Cisplatin/vinblastine + CRT vs. Cisplatin/vinblastine + SRT vs. Cisplatin/oral etoposide + CHRT

16.5 m* 13.3 m

Myelosuppression significantly greater in the concurrent arm

17.0 m* 14.6 m 15.6 m

Acute gr 3/4 non-hematologic toxicity rates higher in the concurrent arms

Curran et al. (2003) [8]

MST: Median survival time; m: months; CRT: concurrent radiotherapy; SRT: sequential radiotherapy; gr: grade; *: statistically significant vs. sequential treatments.

The authors also reported the patterns of failure, which demonstrated a benefit of concurrent chemo-radiotherapy in improving the local relapse-free survival (P = 0.04) but not the distant relapse-free survival (P = 0.6). Myelosuppression was reported to be significantly greater among patients on the concurrent arm than on the sequential arm (P = 0.0001) (Table 2). After these two phase III studies, several other trials including new generation chemotherapy drugs confirmed that survival outcomes are superior with concurrent therapy. The GLOT-GFPC study NPC 95-01 randomly assigned 212 patients to sequential versus concurrent chemo-radiotherapy [11]. However, the chemotherapy differed in the two arms. In the sequential arm, cisplatin 120 mg/m2 days 1, 29, and 57 and vinorelbine 30 mg/m2 weekly for 12 doses was followed by thoracic irradiation to 66 Gy in 33 fractions. In the concurrent arm, cisplatin and etoposide for two cycles was given with the same radiation dose. Patients received consolidation chemotherapy with cisplatin 80 mg/m2 on days 78 and 106, plus vinorelbine 30 mg/m2 weekly for eight cycles. The concurrent arm had a higher rate of grade 3/4 esophagitis (26.1% vs. 0%) and dysphagia (19.3% vs. 1%). The median survival was 13.8 months for the sequential and 15 months for the concurrent arm (not significant). The 2-year survival showed a trend in favor of concurrent chemo-radiotherapy (35% vs. 23% for sequential). Furthermore, the 4-year overall and progression-free survival rates were higher in the concurrent arm (20.7% and 15%) than in the sequential arm (14.2% and 8.8%, respectively). The benefit is maintained in the long-term. The difference in overall survival between the two strategies, 6.2% at 3 years and of 6.5% at 4 years, is apparently constant. The lack of a significant survival difference between sequential and concurrent therapy in this study might be related to a lack of statistical power, or alternatively, to the excess of early deaths in the concurrent arm (25 vs. 17, respectively), particularly toxic deaths (10 vs. 3, respectively). In a phase III Czech Republic study [12] one-hundred two patients were randomly assigned to a concurrent chemoradiotherapy group (with radiotherapy started concurrently with the second cycle of chemotherapy) or to a sequential chemo-radiotherapy arm (started 2 weeks after the end of chemotherapy). The chemotherapy regimen consisted in cisplatin (80 mg/m2 day 1) every 4 weeks and vinorelbine (25 or

12.5 mg/m2 days 1, 8, 15) for up to four cycles. Radiotherapy consisted in the classic regimen of 60 Gy in 6 weeks. The concurrent arm was superior (P < 0.023) with median survival of 16.6 months versus 12.9 months, and 3-year survival of 18.6% versus 9.5%. Obviously more toxicity was registered in the concomitant arm. However, there were no treatment related deaths. The most recent randomised phase III study on this topic has been performed by Belderbos et al. (EORTC 08962) [13]. The Authors have compared sequential and concurrent chemo-radiotherapy in 158 NSCLC patients, randomised to receive two courses of gemcitabine (1250 mg/m2 days 1, 8) and cisplatin (75 mg/m2 day 2) prior to, or daily low-dose cisplatin (6 mg/m2 ) concurrent with radiotherapy, consisting of 24 fractions of 2.75 Gy in 32 days, with a total dose of 66 Gy. Because of the poor power of the study no significant differences in median survival, overall survival and progression-free survival was detected. For sequential and concurrent arm, median survival was, respectively, 16.2 and 16.5 months, 2-year overall survival was 34% and 39%, 3-year overall survival was 22% and 34%, but acute haematological toxicity, and oesophagitis grade 3/4 were more frequent, respectively, in the sequential and in the concurrent arm (21% vs. 5% and 5% vs. 14%). However, even in a metanalysis, the Rowell’s Cocrane review [14], the superiority of concurrent versus sequential chemoradiotherapy (RR 0.86; 95% CI 0.78–0.95; P = 0.003) was underlined. As supported by clinical trials, the Patterns of Care Study (PCS) for lung cancer, aimed at determining the national patterns of radiation therapy practice in patients treated for non-metastatic lung cancer in 1998–1999, demonstrated that patients with clinical stage III NSCLC received chemotherapy plus radiation therapy more than radiotherapy alone (P < 0.0001). Factors correlating with increased use of chemotherapy included lower age (P < 0.0001), histology (SCLC more than NSCLC, P < 0.0001), increasing clinical stage (P < 0.0001), increasing Karnofsky performance status (P < 0.0001), and lack of comorbidities (P = 0.0002), but not academic versus nonacademic facilities (P = 0.81). Of all patients receiving chemotherapy, approximately three-quarters received it concurrently with radiotherapy. Only 3% of all patients were treated on Institutional Review Board-approved trials, demonstrating the need for improved accrual to clinical trials [15].

226

C. Guida et al. / Critical Reviews in Oncology/Hematology 68 (2008) 222–232

3. Induction and consolidation chemotherapy in addition to concurrent chemoradiotherapy In order to improve the outcomes obtained with concurrent chemoradiotherapy clinical research is focusing on additional combination chemotherapy administered in the induction or consolidation phase in addition to concurrent chemoradiotherapy. A phase III study (CALGB 39801) [16] randomly assigned 366 patients with locally advanced NSCLC to two cycles of induction chemotherapy with paclitaxel (200 mg/m2 ) and carboplatin administered every 3 weeks followed by weekly paclitaxel (50 mg/m2 ) and carboplatin (AUC = 2) with thoracic radiation or the same regimen without induction chemotherapy. The median survival time was 12 months without the induction regimen and only 14 months with the induction regimen. Perhaps, the poor results obtained in both the arms can be explained by the fact that weight loss of more than 5% was not a specific exclusion criterion in this study. However, in the subset of patients with weight loss of more than 5%, induction therapy followed by concurrent chemoradiotherapy resulted in a better overall 3-year survival rate than concurrent chemoradiotherapy alone (23% vs. 10%, respectively). The American College of Radiology (ACR) 427 Locally Advanced Multimodality Protocol (LAMP) [17] was a randomized phase II trial by Choi et al. It evaluated the optimal sequence of chemotherapy with paclitaxel (200 mg/m2 ) plus carboplatin (AUC 6) and radiotherapy in three arms: chemotherapy for two cycles followed by radiotherapy to 63 Gy (sequential arm); same chemotherapy followed by concurrent chemo-radiotherapy to 63 Gy with weekly paclitaxel (45 mg/m2 ) and carboplatin (AUC 2) (induction/concurrent arm); and concurrent chemo-radiotherapy as in the previous arm followed by two cycles of consolidation chemotherapy (concurrent/consolidation arm). With a median follow-up of 26 months, the concurrent/consolidation arm reported a non-significant improvement in the median survival (16 months) when compared with the other two arms (11 and 12.5 months). Vokes et al. [18], within CALGB, performed a phase II randomized trial of three different induction regimens consisting of cisplatin (80 mg/m2 days 1 and 22) combined with either gemcitabine (1250 mg/m2 days 1, 8, 22, and 29), paclitaxel (225 mg/m2 day 1 and 22), or vinorelbine (25 mg/m2 days 1, 8, 15, 22, and 29). This was followed by radiotherapy to 66 Gy concurrent with two more cycles of the same chemotherapy, but with dose reduction of the second agent. Tolerance, in general, was good. The three arms had similar median survival of 17 months, but 2–3-year survival rates were not an improvement over those reported in second generation trials. A German phase III trial (Huber et al.) [19] randomly assigned 303 patients with stage IIIA/B disease. All patients received induction paclitaxel (200 mg/m2 ) and carboplatin (AUC 6) for two cycles, followed by either radiotherapy alone (60 Gy) or the same radiotherapy concurrently with weekly paclitaxel (60 mg/m2 ). Concurrent chemoradiotherapy yielded a median survival of 19.2 months versus

14.6 months, but the difference did not reach statistical significance. In a very recent paper by Huang et al. [20], with a retrospective review of the outcome of patients treated with induction/concurrent chemo-radiotherapy versus exclusive chemo-radiotherapy it was demonstrated a survival advantage from adding induction chemotherapy to concurrent chemoradiation applied only to patients with adenocarcinoma or large-cell carcinoma. Interestingly, a similar finding was reported in an analysis of outcomes from the RTOG 8808/Eastern Cooperative Oncology Group 4588 trial [21] by histologic cell type. Gandara [22] et al. presented intriguing results from a Southwest Oncology Group (SWOG) phase II trial (SWOG 49504) of concurrent chemo-radiotherapy followed by maintenance chemotherapy. In this trial, stage III patients received cisplatin 50 mg/m2 on days 1, 8, 29, and 36 plus etoposide 50 mg/m2 on days 1–5 and 29–33 with 61 Gy concurrent radiotherapy, followed by consolidation with docetaxel 75 mg/m2 on days 71 and 75 or 100 mg/m2 on days 92 and 113. The hypothesis was to intensify the chemotherapy effect using a different and non-cross-resistant agent after the initial regimen. The investigators presented very impressive 1-, 2- and 3-year survival rates (76%, 54%, and 37%, respectively). Based on these data, a definitive phase III trial incorporating this regimen and subsequently randomizing patients to maintenance gefitinib or placebo is just ended up, showing the negative effect of gefinitib. Unfortunately Hanna [23] reported the Hoosier Oncology Group LUN 01-24/USO-023 trial results from a randomized, prospective phase III trial comparing concomitant etoposide plus platinum and radiotherapy with or without consolidation docetaxel in 203 patients. The median survival for all patients was 21.15 months; for docetaxel patients was 21.6 months versus 24.2 months for observation ones. Docetaxel treatment was associated with significant increase in grade 3/4 toxicities and with a 5.5% of toxic deaths. Thus, authors concluded that consolidation docetaxel does not further improve survival, is associated with significant toxicity including an increased rate of hospitalization and premature death. Another recent randomized phase III trial conducted by Kim et al. [24] compared induction chemotherapy followed by concurrent chemo-radiotherapy versus immediate chemo-radiotherapy. Induction chemotherapy consisted of two cycles of gemcitabine (1000 mg/m2 days 1.8) and cisplatin (70 mg/m2 day 1) q 21 days. Chemotherapy during chemo-radiotherapy consisted of 6 cycles of weekly paclitaxel (50 mg/m2 ) and cisplatin (20 mg/m2 ). Radiation therapy was performed with hypofractionated scheme (2.2 Gy/fraction, once a day) and total dose was 66 Gy. Grade 3/4 toxicities during induction chemo-radiotherapy consisted mainly of neutropenia (11%/3%). The grade 3 esophagitis rate was, unexpectedly, quite similar, but median survival was 12.6 months on arm with induction chemotherapy versus 18.2 months on the other arm. Thus, authors concluded that the addition of induction chemotherapy to concomitant chemo-radiotherapy failed to increase the survival of unresectable stage III NSCLC over concomitant chemo-radiotherapy (Table 3). These recent data

C. Guida et al. / Critical Reviews in Oncology/Hematology 68 (2008) 222–232

227

Table 3 Induction and consolidation chemotherapy in addition to concurrent chemoradiotherapy Author

Phase

Regimen

Conclusions

Vokes et al. (2007) [16]

III

Induction chemotherapy followed by concurrent chemo-radiotherapy vs. concurrent chemoradiotherapy

Negative results, however, in the subset of patients with weight loss of more than 5%, induction therapy resulted in a better overall 3-year survival rate

Choy et al. (2002) [17]

II (randomized)

Non significant median survival advantage for the concurrent/consolidation arm

Hanna et al. (2007) [23]

III

Sequential chemo-radiotherapy vs. induction chemotherapy followed by concurrent chemo-radiotherapy vs. concurrent chemo-radiotherapy followed by consolidation chemotherapy Concomitant etoposide plus platinum and radiotherapy with or without consolidation docetaxel

Kim et al. (2007) [24]

III

Induction chemotherapy followed by concurrent chemo-radiotherapy vs. immediate chemo-radiotherapy

The addition of induction chemotherapy to concomitant chemo-radiotherapy failed to increase the survival

emphasize the importance of giving multidisciplinary care and tailoring treatment strategies to individual patients. For patients with an unresectable squamous cell carcinoma with a greater risk for locoregional invasion, induction chemotherapy may not provide any significant advantages; instead, this subset of patients may benefit from pursuing other strategies, such as more efficient locoregional treatment. For patients with adenocarcinoma or large-cell carcinoma, induction chemotherapy followed by concurrent chemoradiation may provide a small but significant survival benefit by allowing the earliest possible treatment of micrometastases using full systemic doses of chemotherapy. This approach is reasonable considering that adenocarcinoma have an higher propensity for lymphatic spread and hematogenous metastases as compared to squamous cell carcinoma [19,25].

4. Combination of chemoradiotherapy with molecularly targeted therapies Although some progress has been made in the treatment of locally advanced NSCLC by combining chemotherapy with radiotherapy, treatment outcomes in this clinical setting are still to be considered disappointing. Thus, clinical research of new treatment strategies is warranted. Advances in the knowledge of tumor biology and mechanisms of oncogenesis has granted the singling out of several molecular targets for NSCLC treatment. A large amount of pre-clinical in vivo and in vitro data have been gathered on the antitumor properties of a number of new biological agents, both as single agents and combined with other conventional treatment modalities such as chemotherapy and radiotherapy. Consequently, several targeted agents have been introduced into clinical trials in NSCLC. However, to date, clinically meaningful advances with targeted therapies have been achieved only in advanced NSCLC [26–29]. The targeted therapies with the major implications in locally advanced NSCLC treatment are epidermal

Consolidation docetaxel does not improve survival, and it is associated with significant toxicity including an increased rate of hospitalization and premature death

growth factor receptor family inhibitors, and angiogenesis inhibitors. 4.1. Epidermal growth factor receptor inhibitors The pathways associated with activation of the epidermal growth factor receptor (EGFR) have been identified as pivotal for the unregulated growth of many epithelial cancers including lung cancer. EGFR overexpression occurs in 50–80% of NSCLCs and 81–93% of NSCLCs express the EGFR ligand, transforming growth factor-alpha (TGF-␣) [30]. The EGFR pathway can be upregulated by radiation resulting in radioresistance [31,32] and interference of this pathway has been to shown to amplify radiation cytotoxicity in a variety of human tumor models [33,34]. Clinically, agents that target the extracellular binding domain of the EGFR such as cetuximab (ErbituxTM ), a monoclonal antibody, or the intracellular tyrosine kinase domain such as gefitinib (IressaTM ) or erlotinib (TarcevaTM ), two small molecules, are well tolerated with chronic administration. Encouraging preclinical data employing anti-EGFR agents alone or in combination with radiation has led to incorporation of anti-EGFR compounds with radiation in human clinical trials. In a phase I study, the combination of gefitinib (250 mg daily), carboplatin (AUC = 2 weekly), and paclitaxel (45 mg/m2 weekly) was found to be tolerable in combination with radiation therapy [35]. In this phase I trial Rischin et al. have reported the preliminary toxicity and response data in patients with stage III NSCLC. Patients with ECOG performance status of 0–1 and no prior radiation were eligible for this Phase I trial. Patients received fixed dose radiation to 60 Gy/30 fx/6 weeks to the primary site and involved regional nodes. Concurrent oral gefitinib 250 mg/day and carboplatin AUC 2, weekly were administered with radiation on dose level 1, and weekly paclitaxel was added at 25, 35, and 45 mg/m2 at dose levels 2, 3, and 4, respectively. Initially patients continued on maintenance gefitinib; however, this was stopped after the first

228

C. Guida et al. / Critical Reviews in Oncology/Hematology 68 (2008) 222–232

6 patients due to concerns of the development of interstitial pneumonitis. Dose escalation up to dose level 4 has been completed with 15 patients enrolled. No dose limiting toxicities were observed. Treatment was well tolerated: with 3 patients experiencing grade 3 esophagitis and no reported grade 3 pneumonitis (grade 2, n = 5; 4 of which occurred in patients who continued gefitinib after chemo-radiation). Interestingly, PET analysis indicated a complete response rate in 11 evaluable patients of 55. The chemotherapy complete response rate was 27% and partial response rate was 64%, for an overall response rate of 91%. The CALGB 30106 study is a phase II trial that stratified locally advanced NSCLC patients into two groups, stratum 1 (PS of 2 or PS of 0 or 1 with weight loss exceeding 5%) and stratum 2 (PS of 0 or 1) [36]. In fact, the investigators hypothesized that the addition of gefitinib as a single agent to radiotherapy would result in more tolerable toxicities than those associated with traditional concomitant chemo-radiotherapy, and thus, might define a feasible approach to the treatment of patients with a PS of 2 or pretreatment weight loss exceeding 5%. All enrolled patients received two cycles of paclitaxel (200 mg/m2 ) and carboplatin (AUC = 6) administered every 3 weeks along with gefitinib 250 mg once a day. After induction chemotherapy with gefitinib, patients in stratum 1 received gefitinib and thoracic radiation (66 Gy), and patients in stratum 2 received gefitinib along with thoracic radiation and weekly paclitaxel (50 mg/m2 ) and carboplatin (AUC = 2). Among the 59 eligible patients analyzed, there were no increased acute toxicities with the addition of gefitinib. The median failure-free survival time for the poor-risk patients (stratum 1, n = 20) was 11.5 months, and the median overall survival time was 19 months. However, the median failure-free survival time for the good-risk patients (stratum 2, n = 39) was a disappointing 9.2 months, and the median survival was 12 months. Although the small sample size limits the interpretation of the efficacy data, this trial has demonstrated the feasibility of the combination of gefitinib with standard doses of radiotherapy. A phase I study conducted by the University of Chicago Consortium reported no significant increase in the in-field toxicities when erlotinib was added to chemoradiotherapy. In this study, patients received either the combination of cisplatin and etoposide or paclitaxel and carboplatin along with erlotinib and thoracic radiation [37]. SWOG conducted a phase III study comparing maintenance gefitinib (250 mg daily) with placebo after concurrent chemoradiotherapy and consolidation docetaxel therapy (SWOG 0023) [38]. SWOG 0023 was discontinued after a planned interim analysis when the Data and Safety Monitoring Committee concluded that the hypothesis of an improvement in survival with gefitinib was untenable. The median survival time favored the placebo group (35 months vs. 23 months, respectively; P = 0.01). The primary cause of death in this study was disease progression and not drug-related toxicities. The RTOG conducted a phase II study of cetuximab in combination with weekly paclitaxel, carboplatin, and thoracic radiation (RTOG 0324) [39]. After completion of chemoradiotherapy, patients received two

additional cycles of paclitaxel and carboplatin administered at systemically active doses along with weekly cetuximab. Although the efficacy data are not available, the addition of cetuximab did not increase the toxicites of chemoradiotherapy. An ongoing CALGB study (CALGB 30407) is randomly assigning patients with locally advanced NSCLC to receive thoracic radiation along with either pemetrexed and carboplatin or the same chemotherapy with cetuximab [40]. In conclusion, the above mentioned studies confirm that the addition of EGFR inhibitors (both small molecules and monoclonal antibodies) to chemoradiotherapy in the treatment of locally advanced NSCLC is feasible and safe. However, the efficacy of this approach is yet to be demonstrated. 4.2. Angiogenesis inhibitors In exploring novel approaches to treating NSCLC it is known that irradiation up-regulates vascular endothelial factor (VEGF) production in tumor cells, which stimulates tumor angiogenesis [41]. Teicher’s work in the 1990s was instrumental in demonstrating that inhibiting angiogenesis enhanced radiation cytotoxicity [42]. Interfering with vascular endothelial growth factor receptor (VEGFR) signaling is under investigation in pre-clinical studies with radiation. Bevacizumab is an anti-VEGF monoclonal antibody, and represents the most studied antiangiogenetic agent in oncology and specifically in lung cancer treatment. The very promising results achieved in the advanced disease [27,28], suggest that the approach of combining bevacizumab with chemotherapy is worth to be tested also in the treatment of locally advanced NSCLC. However, safety concerns about the integration of bevacizumab in the chemoradiotherapy regimens, mainly regarding the risk of respiratory bleeding associated with this agent, renders the clinical development of bevacizumab in this clinical setting slow and very careful. In fact, 2 of 29 patients with limited-stage small-cell lung cancer enrolled onto a nonrandomized study of bevacizumab in combination with cisplatin, etoposide and radiation developed tracheoesophageal fistula, and one additional patient died of severe hemorrhage suspected to be secondary to tracheoesophageal fistula [43]. In lung cancer models, promising pre-clinical data has been reported using orally bio-available small molecule VEGFR-tyrosine kinase inhibitors. ZD6474 is an example of this class of molecules currently under investigation in human clinical trials in patients with advanced NSCLC. ZD6474 appears to have dual inhibitory action against both VEGFR and EGFR signaling. In pre-clinical studies using an orthotopic lung cancer model, combinations of ZD6474 and radiation were superior to paclitaxel and radiation in preventing pleural effusions due to tumor as well as reducing tumor burden and preventing metastasis. Enhanced apoptosis and decreased microvessel density was observed in the animals treated with ZD6474 and radiation [44]. ZD6474 is to be considered a promising agent to test in combination with chemo-radiotherapy in the treatment of locally advanced

C. Guida et al. / Critical Reviews in Oncology/Hematology 68 (2008) 222–232

NSCLC. Moreover, the role of the multikinase inhibitors (inhibiting also VEGFR) sorafenib and sunitinib [45] in combination with chemoradiotherapy is being studied in early phase I studies.

5. Chemo-radiotherapy in elderly patients Relatively limited elderly-specific prospective data are available regarding the role combined chemo-radiotherapy in the treatment of locally advanced NSCLC. In this context, phase II studies are particularly informative since alternative schedules and doses may be more appropriate for elderly patients; relevant trials have investigated low-dose chemotherapy as well as non-cisplatin regimens, which have been demonstrated to be active and feasible in the elderly population [46,47]. Atagi et al. performed a phase III trial in elderly (>70 years) patients with stage III NSCLC [48]. Patients were randomly assigned to either radiotherapy or radiotherapy and concurrent daily carboplatin (JCOG 9812). This trial was terminated early because of 4 deaths due to treatment toxicity (one on the radiotherapy alone arm and three on the radiotherapy + carboplatin arm). The investigators concluded that the efficacy of concurrent carboplatin + radiotherapy remains unclear because of the early termination of this study. In addition, retrospective analyses of randomized trials of chemo-radiotherapy have compared treatment outcomes between elderly patients and their younger counterparts [49–53]. Results are inconsistent with some analyses showing an excess of toxicity and the lack of survival benefit in the elderly subgroup [49–51], others confirming both feasibility and efficacy for combined modality treatment in this population, including the more toxic, concurrent schedule [52], and others demonstrating increased toxicity, but survival rates equivalent to younger individuals [53]. In particular, the North Central Cancer Treatment Group performed a secondary analysis examining the relationship between patient age and outcome in a phase III trial evaluating two different schedules of radiation therapy (bid vs. daily) with concurrent chemotherapy for stage III NSCLC. This analysis compared the outcomes of patients aged ≥70 years with those of younger individuals. The 2-year and 5year survival rates were 39% and 18% in patients younger than 70 years, compared to 36% and 13% in elderly patients (P = 0.4). Toxicity ≥ grade 4 occurred in 62% of patients younger than 70 years compared with 81% of elderly patients (P = 0.007). Hematologic toxicity ≥ grade 4 occurred in 56% of patients younger than 70 years, compared with 78% of elderly patients (P = 0.003). Pneumonitis ≥ grade 4 occurred in 1% of those younger than 70 years, compared with 6% of elderly patients (P = 0.02). Despite increased toxicity, elderly patients treated with concurrent chemo-radiotherapy had survival rates equivalent to younger individuals. Therefore, the authors concluded that fit, elderly patients with

229

locally advanced NSCLC should be encouraged to receive combined-modality therapy, but preferably on clinical trials with cautious, judicious monitoring [53]. In conclusion, since data coming from retrospective analyses suffer from inherent uncontrolled biases, only specifically designed prospective studies can define the value of combined chemo-radiotherapy for the broader population of elderly patients with locally advanced NSCLC [54].

6. Recent innovations in the radiotherapy of NSCLC A detailed discussion of the new techniques of irradiation is beyond the scope of this review. However, here we give a brief summary of the most relevant and recent innovations in the radiotherapy of NSCLC. The new strategies include altered radiotherapy fractionation, dose escalation and improved tumor targeting (3-dimensional planning and intensity-modulated radiotherapy, image-guided radiation therapy) [55]. About altered radiotherapy fractionation, randomized prospective studies have failed to demonstrate an advantage for twice-daily radiotherapy compared with once-daily radiotherapy [56,57]. On the contrary, three-times-per-day radiotherapy appears to be a promising technique for unresectable NSCLC based on a randomized trial versus once-daily radiotherapy, and on a pilot trial where it was administered concurrently with escalating doses of cisplatin [58,59]. Investigators have performed dose-escalation studies using three-dimensional treatment planning [60]. Threedimensional planning systems allow one to create beams from any angle to treat a tumor. Complex treatment plans with carefully chosen fields can be used to deliver greater than standard doses while respecting the tolerance of the normal tissues. Up to 90 Gy can be administered, but significant concerns exist on the chronic toxicity of such approaches. Intensity-modulated radiotherapy (IMRT) uses multiple beamlets of varying intensity within each radiation field. Planning is generally performed with inverse planning systems and delivered with dynamic multileaf collimators that vary the field shape actively during radiotherapy. The multileaf collimators are computer-guided motorized metal blades that extend into the radiation field and act as blocks. They move costantly during the IMRT to modulate the intensity of the beam. Inverse planning is performed with sophisticated computer algorithms that allow the user to prescribe specific radiation dose parameters for individual structures. Then the computer creates the beams to accomplish these goals. IMRT is an advanced treatment delivery technique that can improve the therapeutic dose ratio. Compared with three-dimensional plans, IMRT plans are potentially associated with better tumor coverage and sparing of normal tissues. IMRT has already resulted in promising outcomes for inoperable NSCLC [61], but further studies are needed

230

C. Guida et al. / Critical Reviews in Oncology/Hematology 68 (2008) 222–232

to define whether this technology can deliver higher than standard doses of radiotherapy safely. Image-guided radiotherapy is also known as helical tomotherapy. This technique includes IMRT delivered as the linear accelerator rotates around the patient in acontinuos helix. This is performed with a linear accelerator mounted in a manner analogous to a computed tomographic scanner. Tomotherapy, compared with conventional threedimensional field techniques, has the potential to further decrease the dose administered to the normal tissues and could allow the safe delivery of a greater dose to the tumor volume. One additional advantage of this unit is the ability to image the patient during therapy and evaluate the location of the tumor to prevent geographic misses. Recent developments in image-guided radiotherapy include the positron emission tomography/computed tomography tomotherapy [62]. The functional imaging has the potential to further improve clinical outcomes. However clinical studies are needed to evaluate the real potential of helical tomotherapy. Stereotactic radiotherapy has been used to treat NSCLC with favorable preliminary results (in terms of local failure, survival and safety) compared with historical data using conventional radiotherapy [63,64]. In contrast to conventional radiotherapy, stereotactic techniques include fixation, ultraprecise treatment planning, radiotherapy directed to known disease alone, and high dose per fraction.

7. Conclusions Over the past 20 years, the outcome of patients with locally advanced NSCLC has improved slowly, but significantly. These results are mainly the reflection of a multidisciplinary approach to the treatment. To date, concurrent chemoradiotherapy is to be considered the standard treatment in this clinical setting for PS 0–1 patients. For PS 2 and for elderly patients sequential chemo-radiotherapy is a valid treatment option. However, the approach to locally advanced NSCLC and to chemo-radiotherapy regimens remains heterogeneous among oncologists. In fact, the results by 2 recently published surveys about the pattern of care, respectively in central and east Europe and in USA, were opposite. In the European countries [65], sequential chemo-radiotherapy was the most common approach to radical management of NSCLC (57% of patients), followed by radiotherapy alone (30%) and concomitant chemo-radiotherapy (10%). On the contrary, 77% of American radiation oncologists [66] respondents, submitted patients to concurrent chemo-radiotherapy followed by adjuvant chemotherapy, and only 11–16% to sequential followed by concurrent chemo-radiotherapy for patients with good performance status. Because distant metastases remain the major site of failure, it is likely that more effective chemotherapy or other systemic antitumor agents as moleculary targeted therapies will be required to further improve the current level of response and survival of locally advanced NSCLC patients.

Reviewers Rafael Rosell, M.D., Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n E-08916 Badalona, Barcelona, Spain. Frederik Wenz, M.D., Professor and Chairman Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Theodor-Kutzer-ufer, 1-3 D-68167 Mannheim, Germany.

Conflict of interest The authors have no conflict of interest in writing this manuscript.

References [1] Rosell R. The integration of newer agents into neoadjuvant therapy. Semin Oncol 1998;25(Suppl. 8):24–7. [2] Gandara DR, Lara Jr PN, Goldberg Z, Roberts P, Lau DH. Neoadjuvant therapy for non-small cell lung cancer. Anticancer Drugs 2001;12(Suppl. 1):S5–9. [3] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 1995;311:899–909. [4] Dillman RO, Herndon J, Seagren SL, Eaton WL, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210–5. [5] Sause W, Kolesar P, Taylor IV S, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer. Radiation Therapy Oncology, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 2000;117:358–64. [6] Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 1992;326:524–30. [7] Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. J Clin Oncol 1996;14:1065–70. [8] Curran Jr WJ, Scott CB, Langer CJ, et al. Long-term benefit is observed in a phase III comparison of sequential vs. concurrent chemo-radiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 2003;22:621. [9] Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small cell lung cancer. J Clin Oncol 1999;17:2692–9. [10] Movsas B, Scott C, Curran W, Byhardt R, Langer C. A Quality-Adjusted Time Without Symptoms or Toxicity (QTWiST) analysis of Radiation Therapy Oncology Group (RTOG) 94-10. Proc Am Soc Clin Oncol 2001;20:313a. [11] Fournel P, Robinet G, Thomas P, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d’Oncologie Thoracique-Groupe Francaisde Pneumo-Cancerologie NPC 95-01 Study. J Clin Oncol 2005;23(25):5910–7. [12] Zatloukal P, Petruzelka L, Zemanova M, et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally

C. Guida et al. / Critical Reviews in Oncology/Hematology 68 (2008) 222–232

[13]

[14] [15] [16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26] [27]

[28]

[29]

advanced non-small cell lung cancer: a randomized study. Lung Cancer 2004;46:87–98. Belderbos J, Uitterhoeve L, van Zandwijk N, et al., EORTC LCG and RT Group. Randomised trial of sequential versus concurrent chemoradiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972-22973). Eur J Cancer 2007;43(1):114–21. Rowell NP, O’rourke NP. Concurrent chemoradiotherapy in non-smallcell lung cancer. Cochrane Database Syst Rev 2004;4:CD002140. Movsas V, Moughan J, Komaki R, et al. Radiotherapy (RT) Patterns of Care Study (PCS) in lung carcinoma. J Clin Oncol 2003;21:4553–9. Vokes EE, Herndon JE, Crawford J, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 2007;25:1698–704. Choy H, Curran WJ, Scott CB, et al. Preliminary report of locally advanced multimodality protocol (LAMP): ACR 427: a randomized phase II study of three chemo-radiation regimens with paclitaxel, carboplatin, and thoracic radiation (TRT) for patients with locally advanced non small cell lung cancer (LA-NSCLC) (Abstract). Proc Am Soc Clin Oncol 2002;21, 291◦ . Vokes EE, Herndon II JE, Crawford J, et al. Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: Cancer and Leukemia Group B study 9431. J Clin Oncol 2002;20:4191–8. Huber RM, Schmidt M, Flentje M, et al. Induction chemotherapy and following simultaneous radio/chemotherapy versus induction chemotherapy and radiotherapy alone in inoperable NSCLC (stage IIIA/IIIB). Proc Am Soc Clin Oncol 2003;22 [abstract #622]. Huang E, Zhongxing L, Guerrero TM, et al. Comparison of outcomes for patients with unresectable, Locally advanced non–small-cell lung cancer treated with Induction chemotherapy followed by concurrent Chemoradiation vs. Concurrent chemoradiation alone. Int J Radiation Oncology Biol Phys 2007;68/3:779–85. Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary Results of a Phase III Trial in Regionally Advanced, Unresectable Non-Small-Cell Lung Cancer. J Natl Cancer Institute 1995;87/3:198–205. Gandara D, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-smallcell lung cancer: phase-II Southwest Oncology Group Study S9504. J Clin Oncol 2003;21:2004–10. Hanna H, Neubauer M, Ansari R, et al. Phase III trial of cisplatin plus etoposide plus concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small cell lung cancer (NSCLC): HOG LUN 01-24/USO-023. J Clin Oncol 2007;25/18S:7512. Kim S, Kim M, Choi E, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone for unresectable stage III non-small cell lung cancer (NSCLC): Randomized phase III trial. J Clin Oncol 2007;25/18S:7528. Vokes EE, Crawford J, Bogart J, Socinski MA, Clamon G, Green MR. Concurrent Chemoradiotherapy for Unresectable Stage III Non–Small Cell Lung Cancer. Clin Cancer Res 2005;11:5045s–50s. Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated non small cell lung cancer. New Engl J Med 2005;353:123–32. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. New Engl J Med 2006;355:2542–50. Manegold C, von Pawel J, Zatloukal P, et al. Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704. J Clin Oncol 2007;25/18S:LBA7514. Douillard JY, Hirsh E, Mok V, et al. Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small-cell

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

231

lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label phase III study (INTEREST). J Thorac Oncol 2007;2/8(Suppl. 4):S305. Raymond R, Faivre S, Armand J. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs 2000;60(Suppl. 1):15–23. Dent P, Reardon D, Park J, et al. Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell 1999;10:2493–506. Akimoto T, Hunter NR, Buchmiller L, Masou K, Ang KK, Milas L. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res 1999;5:437–43. Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 1999;59:1935–40. Bianco C, Tortora G, Bianco R, et al. Enhancement of Antitumor Activity of Ionizing Radiation by Combined Treatment with the Selective Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor ZD1839 (Iressa). Clin Cancer Res 2002;8:3250–8. Rischin D, Burmeister B, Mitchell P, et al. Phase I trial of gefitinib (ZD1839) in combination with concurrent carboplatin, paclitaxel and radiation therapy in patients with stage III non-small cell lung cancer. J Clin Oncol 2004;22/14S:7077. Ready N, Janne P, Herndon J, et al. Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer: a CALGB stratified phase II trial. J Clin Oncol 2006;24:375s [abstract 7046]. Hoffman PC, Mauer AM, Haraf DC, Lester EP, Szeto LL, Vokes EE. A phase I study of erlotinib in combination with chemoradiation for unresectable, locally advanced non-small cell lung cancer. J Clin Oncol 2005;23/16S:648s [abstr. 7113]. Kelly K, Chansky K, Gaspar LE, et al. Updated analysis of SWOG 0023: a randomized phase III trial of gefitinib versus placebo maintenance after definitive chemoradiation followed by docetaxel in patients with locally advanced stage III non-small cell lung cancer. J Clin Oncol 2007;25:388s [abstr. 7513]. Werner-Wasik M, Swan S, Curran W, et al. A phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small cell lung cancer: an interim overall toxicity report of the RTOG 0324 trial. J Clin Oncol 2005;23/16S:654s [abstr. 7135]. Bogart JA, Govindan R. A randomized phase II study radiation therapy, pemetrexed, and carboplatin with or without cetuximab in stage III non-small-cell lung cancer. Clin Lung Cancer 2006;7:285–7. Steinauer KK, Gibbs I, Ning S, French JN, Armstrong J, Knox SJ. Radiation induces upregulation of cyclooxygenase-2 (COX-2) protein in PC-3 cells. Int J Rad Oncol Biol Phys 2000;48:325–8. Teicher BA, Depuis NP, Kusumoto T, et al. Anti-angiogenic agents can increase tumor oxygenation and response to radiation therapy. Radiat Oncol Invest 1995;2:269–76. Food and Drug Administration: Important drug warning regarding Avastin (bevacizumab). http://www.fda.gov/medwatch/safety/2007/ Avastin DHCP TEF Final April2007.pdf. Keiko S, Komaki R, Wenjuan W, et al. Targeted therapy against VEGF and EGF signaling with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic mouse model of human non-small cell lung cancer. In: Proceedings of the 46th annual meeting of american society of therapeutic radiology and oncology. 2004 [Abst #35]. Gridelli C, Maione P, Del Gaizo F, et al. Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist 2007;12/2:191–200. Atagi S, Kawahara M, Ogawara M, et al. Phase II trial of daily lowdose carboplatin and thoracic radiotherapy in elderly patients with locally advanced non-small cell lung cancer. Jpn J Clin Oncol 2000;30: 59–64.

232

C. Guida et al. / Critical Reviews in Oncology/Hematology 68 (2008) 222–232

[47] D’Angelillo RM, Trodella L, Ramella S, et al. Neoadjuvant chemoradiotherapy followed by surgery in elderly patients with locally advanced Non-Small Cell lung Cancer: analysis of feasibility, toxicity and factors predicting surgical resection and survival. Proc Am Soc Clin Oncol 2004;23:654. [48] Atagi S, Kawahara M, Tamura T, et al. Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer: a phase III trial of the Japan Clinical Oncology Group (JCOG9812). Jpn J Clin Oncol 2005;35:195–201. [49] Movsas B, Scott C, Sause W, et al. The benefit of treatment intensification is age and histology-dependent in patients with locally advanced non-small cell lung cancer (NSCLC): a quality-adjusted survival analysis of radiation therapy oncology group (RTOG) chemoradiation studies. Int J Radiat Oncol Biol Phys 1999;45:1143–9. [50] Werner-Wasik M, Scott C, Cox JD, et al. Recursive partitioning analysis of 1999 Radiation Therapy Oncology Group (RTOG) patients with locally-advanced non-small-cell lung cancer (LA-NSCLC): identification of five groups with different survival. Int J Radiat Oncol Biol Phys 2000;48:1475–82. [51] Langer C, Scott C, Byhardt R, et al. Effect of advanced age on outcome in Radiation Therapy Oncology Group studies of locally advanced NSCLC. Lung Cancer 2000;29(Suppl. 1):119. [52] Langer CJ, Hsu C, Curran WJ, et al. Elderly patients with locally advanced non-small cell lung cancer benefit from combined modality therapy: secondary analysis of Radiation Therapy Oncology Group (RTOG) 94-10. Proc Am Soc Clin Oncol 2002;21:299a. [53] Schild SE, Stella PJ, Geyer SM, et al., North Central Cancer Treatment Group. The outcome of combined-modality therapy for stage III nonsmall-cell lung cancer in the elderly. J Clin Oncol 2003;21:3201–6. [54] Perrone F, Gallo C, Gridelli C. Re: Cisplatin-based therapy for elderly patients with advanced non-small cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 2002;94:1029–31. [55] Schild SE, Bogart JA. Innovations in the radiotherapy of non-small cell lung cancer. J Thor Oncol 2006;1/1:85–90. [56] Schild SE, Stella PJ, Geyer SM, et al. Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002;54:370–8. [57] Komaki R, Seiferheld W. Sequential vs. concurrent chemotherapy and radiation therapy for inoperable non-small cell lung cancer (NSCLC): analysis of failures in a phase III study (RTOG 9410). Int J Radiat Oncol Biol Phys 2000;48:113. [58] Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial: CHART Steering committee. Radiother Oncol 1999;52:137–48.

[59] Schild SE, Wong WW, Vora SA, et al. The long-term results of a pilot study of three times a day radiotherapy and escalating dosesof daily cisplatin for locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2006;62:1432–7. [60] Socinski MA, Morris DE, Halle JS, et al. Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a doseescalation phase I trial. J Clin Oncol 2004;22:4341–50. [61] Sura S, Gupta V, Yorke E, Jackson A, Amols H, Rosenzweig KE. Intensity-modulated radiation therapy (IMRT) for inoperable nonsmall cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol 2008;87:17–23. [62] Chang JY, Dong L, Liu H, et al. Image-guided radiation therapy for non-small cell lung cancer. J Thorac Oncol 2008;3:177–86. [63] Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 2003;124:1946–55. [64] Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated highdose irradiation for stage I non small cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer 2004;101:1623–31. [65] Kepka L, Danilova V, Saghatelyan T, et al. Resources and management strategies for the use of radiotherapy in the treatment of lung cancer in Central and Eastern European countries: results of an International Atomic Energy Agency (IAEA) survey. Lung Cancer 2007;56/2:235–45. [66] Kong F, West B, Bonner J, Choy H, Gaspar LE, Komaki R. Patterns of practice in radiation therapy for non-small cell lung cancer among members of American Society of Therapeutic Radiology and Oncology. J Clin Oncol 2007;25/18S:7693.

Biography Cesare Gridelli, M.D., is currently Chief of Division of Medical Oncology and Director of Department of Oncology/Hematology at the “S.G. Moscati” Hospital of Avellino (Italy). His areas of expertise are lung cancer, cancer in the elderly, antiemetics. He is involved in the clinical development of new anticancer agents. He is member of Advisory Board of scientific journals and of several expert panels. Dr. Gridelli has been invited speaker of international conferences and educational activities of oncology societies (ASCO, ESMO). He is author or co-author of about 500 papers, of which about 200 extended papers published on international indexed journals, and several chapters of books.