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Phase II study of bi-weekly docetaxel and carboplatin with concurrent thoracic radiation therapy followed by consolidation chemotherapy with docetaxel plus carboplatin for stage III unresectable non-small cell lung cancer
Lung Cancer (2004) 43, 195—201
Phase II study of bi-weekly docetaxel and carboplatin with concurrent thoracic radiation therapy followed by consolidation chemotherapy with docetaxel plus carboplatin for stage III unresectable non-small cell lung cancer Hiroshi Sakai a,*, Shuichi Yoneda a , Kunihiko Kobayashi a , Hiroshi Komagata a , Seiji Kosaihira a , Tomoko Kazumoto b , Yoshihiro Saito b a
Division of Respiratory Disease, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan b Division of Radiation Oncology, Saitama Cancer Center, Saitama, Japan Received 24 April 2003 ; received in revised form 11 August 2003; accepted 22 August 2003
KEYWORDS Concurrent chemoradiotherapy; Docetaxel; Carboplatin; Non-small cell lung cancer
Summary Objective: Docetaxel and carboplatin (DC) have demonstrated activity as radiation sensitizers in pre-clinical studies. The aim of this phase II study was to evaluate the efficacy and toxicity of DC with concurrent thoracic radiation therapy (TRT) followed by consolidation chemotherapy with DC for stage III unresectable non-small cell lung cancer (NSCLC). Patients and methods: Thirty-three previously untreated patients with inoperable, locally advanced (LA) NSCLC received docetaxel 30 mg/m2 over 1 h and carboplatin at an AUC of 3 every 2 weeks for six courses–—four courses during concurrent chemoradiotherapy and two courses following completion of radiotherapy. Concurrent TRT was performed in 2-Gy daily fractions to a total dose of 60 Gy. Results: Among 32 evaluable patients, the overall response rate was 91%, with two complete responses (CR) and 27 partial responses (PR). Median survival time by intention-to-treat analysis was 27 months, with survival rates of 76% at 1 year and 61% at 2 years. Serious side effects were generally limited to grade 3 neutropenia in 6%, grades 3 and 4 pulmonary toxicity in 6 and 3%, respectively, and grade 3 esophagitis in 3% of patients. Conclusions: DC with concurrent TRT followed by consolidation chemotherapy was highly active with manageable toxicity in patients with stage III unresectable NSCLC. © 2003 Elsevier Ireland Ltd. All rights reserved.
1. Introduction * Corresponding
author. Tel.: +81-48-722-1111; fax: +81-48-723-5197. E-mail address: hiroshi [email protected] (H. Sakai).
Approximately 20—25% of non-small cell lung cancer (NSCLC) patients are initially diagnosed with stage III disease. This group of patients is of particular
0169-5002/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2003.08.021
196 interest, because results of several recent randomized studies indicate that such patients benefit from multimodality treatment with chemotherapy and radiotherapy. However, survival rates remain relatively low because local and distant treatment failures are common. Treatment goals in stage III NSCLC are to improve both locoregional and systemic control of disease. To further improve therapeutic efficacy and reduce toxicity, numerous issues remain to be investigated. For example, whether radiotherapy should be administered sequentially to, or concurrently with, chemotherapy is still unresolved, and the respective efficacies of induction chemotherapy given prior to chemoradiotherapy, and consolidation chemotherapy given after chemoradiotherapy, have not been determined. In this regard, results of trials conducted by the West Japan Lung Cancer Group, the Radiation Therapy Oncology Group (RTOG9410), and other phase III trials performed in the 1990s indicated that concurrent chemoradiotherapy was superior to sequential treatment [1,2]. This approach has become the accepted standard for unresectable stage III NSCLC. On the other hand, it is thought that adjuvant chemotherapy may increase or maintain the effects of primary chemoradiotherapy treatment; several clinical trials are evaluating this concept. Docetaxel has demonstrated activity as a radiation sensitizer in pre-clinical studies [3,4]. The mechanism of the radiation-enhancing effect is not well defined, although potential mechanisms include cell cycle synchronization, apoptosis and reoxygenation. Several in vitro studies using docetaxel with concurrent radiation have shown sensitizing enhancement ratios ranging from 1.45 to 2.33 in some cell lines [4]. Several pre-clinical studies have suggested that carboplatin also effectively modulates radiation cell damage [5]. The combination of docetaxel and radiotherapy has been studied in phases I and II clinical trials [6,7]. Optimal dosages were identified as 20—30 mg/m2 per week of docetaxel and 60 Gy of radiation. Response rates obtained in several phase II trials ranged from 34 to 80%, with 1 year survival rates of 48—59% [7]. In addition, concurrent combination therapy consisting of docetaxel + cisplatin (or carboplatin) + radiotherapy resulted in good response rates of 70—90%, 1 year survival rates of 55—74%, and 2 year survival rates of 41—43% [8,9]. A weekly administration schedule for chemotherapy in concurrent chemoradiotherapy regimens has been commonly reported. Choy et al. [10] used a weekly schedule in a study aimed at achieving a radiosensitizing effect in patients with locally advanced (LA) NSCLC. This chemoradiotherapy regimen resulted in a comparatively high incidence
H. Sakai et al. of esophagitis, which was dose-limiting. In this regard, we devised a novel bi-weekly administration schedule, and decided to use consolidation chemotherapy after chemoradiotherapy in attempts to improve both locoregional and systemic disease control. We previously reported results of a phase I study demonstrating the feasibility of bi-weekly docetaxel and carboplatin when administered with concurrent radiotherapy [11]. Doses recommended for use in the phase II setting were docetaxel 30 mg/m2 and carboplatin at an AUC of 3. Dose-limiting toxicity was neutropenia [11]. This paper reports results of a phase II study of the efficacy and toxicity of bi-weekly docetaxel and carboplatin with concurrent radiation therapy in patients with stages IIIA and IIIB NSCLC. Doses used were those recommended in our previous phase I trial.
2. Patients and methods 2.1. Patient selection Patients with histologically proven stage III NSCLC whose disease was not suitable for surgical treatment were enrolled in the study. Other eligibility criteria were: (i) no previous chemotherapy or radiotherapy; (ii) no malignant pleural effusion; (iii) presence of bidimensionally measurable lesion; (iv) age ≥18 and ≤75 years; (v) Eastern Cooperative Oncology Group (ECOG) performance status ≤1; (vi) adequate hematopoietic reserve: absolute neutrophil count ≥2000 mm−3 , platelet count ≥100,000 mm−3 ; (vii) adequate hepatic and renal functions: serum creatinine <1.5 times the upper normal limit (UNL), serum bilirubin, AST and ALT <1.5 times UNL; and (viii) arterial blood gases at PaO2 >70 mmHg. Other patient assessments performed before study entry were computed tomography (CT) scan and radiography of the chest, magnetic resonance imaging (MRI) of the brain, bone scan, and bronchoscopy. The institutional ethics committee approved the study protocol. Informed consent was obtained from all patients.
2.2. Treatment Patients received a 1 h infusion of docetaxel 30 mg/m2 followed by 1 h infusion of carboplatin at AUC = 3.0 every 2 weeks for six courses. All patients received prophylactic pre-medication with dexamethasone 4 mg intravenously (i.v.) on the day of chemotherapy. Antiemetics were administered as needed. Radiation therapy was administered
Phase II study of bi-weekly docetaxel and carboplatin with concurrent thoracic radiation therapy with 2.0 Gy daily fractions by a linear accelerator generating 10 MV photon. The initial radiotherapy target volume was primary tumor, ipsilateral hilar and mediastinal lymph nodes by antero-posterior parallel opposed fields with a 1—1.5 cm margin around the primary tumor and involved nodes. Ipsilateral supraclavicular fossa was included, when tumor existed in the upper lobe or the enlarged lymph nodes were seen. Paraesophageal nodes were included if the lesion was in the lower lobe. The contralateral hilum was excluded. A shrinking field technique was used. Mediastinal lymph nodes were irradiated up to 40 Gy for prophylaxis. Primary tumor, involved ipsilateral hilar and mediastinal lymph nodes were irradiated up to 60 Gy in 6 weeks without interruption. These doses were calculated at the central axis without the use of lung correction. Spinal cord was spared after 40—50 Gy. The first four chemotherapy courses were administered concurrently with radiotherapy, and the fifth and sixth courses were given after completion of radiotherapy. The use of granulocyte-colony stimulating factors (G-CSF) was not allowed during concurrent and consolidation phases, except for patients with febrile neutropenia, or WHO grade 4 leukopenia or neutropenia, according to investigator decision.
2.3. Dose adjustments Patients experiencing any toxicity ≥ grade 2 skipped chemotherapy. For patients with hematological toxicity ≥ grade 4 or non-hematological toxicity ≥ grade 2, radiotherapy was stopped until hematological effects recovered to ≤ grade 3 or non-hematological effects to ≤ grade 2, at which time radiotherapy was resumed. For patients with febrile neutropenia, or WHO grade 4 leukopenia or neutropenia, radiotherapy was stopped until hematological effects recovered to ≤ grade 3 with G-CSF.
2.4. Treatment evaluation A complete blood cell count and blood chemistry tests were performed weekly. Patients were assessed weekly for toxicity according to the National Cancer Institute-Common Toxicity Criteria. In addition, delayed radiation toxicities occurring more than 90 days after the start of radiotherapy were assessed according to the Late Radiation Morbidity Scoring Scheme of the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer (RTOG/EORTC). Response evaluation was based on World Health Organization (WHO) criteria. Tumor response was assessed by CT scan every 4 weeks. Responding patients
197
had a confirmatory CT scan at least 4 weeks after the initial determination of response. CT scan of the chest and upper abdomen and chest radiograph were repeated 1 month post-chemotherapy. Progression-free survival and overall survival were measured from the date of first treatment administration to the date of disease progression or death for the former and the date of death for the latter. The Kaplan—Meier method was employed to determine medians and 95% confidence intervals (CI) of the time-related parameters.
3. Results 3.1. Patient characteristics From May 2000 to July 2001, a total of 33 patients were enrolled in the study. Patient characteristics are shown in Table 1. Thirty-two men and one woman, with a median age of 64 years (range, 33—74), were treated. ECOG performance status was 0 for four patients (12%) and one for 29 patients (88%). Fifteen patients (45%) had adenocarcinoma, 16 (48%) had squamous cell carcinoma, and two had large cell carcinoma. Thirteen patients (39%) had stage IIIA disease and 20 (61%) had stage IIIB disease (T4N0/1: 5, T4N2: 5, any TN3: 10). Of 33 patients enrolled, 1 withdrew from the study Table 1 Patient characteristics Characteristic
Number of patients (%)
Treated/eligible
33/33
Age (years) Median Range
64 33—75
Gender Male Female
32 (97) 1 (3)
ECOG performance status 0 1
4 (12) 29 (88)
Histology Adenocarcinoma Squamous Large cell
15 (45) 16 (48) 2 (6)
Stage IIIA IIIB T4N0/1 T4N2 anyTN3
13 (39) 20 (61) 5 5 10
198
H. Sakai et al.
during the first week of treatment because of allergic reactions, leaving 32 patients evaluable for toxicity and response.
3.2. Dose administration The 32 evaluable patients received 99 cycles of bi-weekly docetaxel and carboplatin, or 77% of the planned chemotherapy doses during the concurrent phase. Twenty-eight of 32 patients received the planned 60 Gy of radiation. The mean duration of the radiation period was 41 days (range, 35—50 days). Fifty-one cycles of consolidation chemotherapy were administered, or 82% of the planned chemotherapy doses during the consolidation phase.
3.3. Response and survival Among 32 evaluable patients, two achieved a complete response (CR) and 27 a partial response (PR), for an overall response rate of 91% (95% confidence interval: 75—98). There were no differences in response rates between patients with squamous cell and non-squamous cell histologies (88% versus 94%). One patient had progressive disease and two had stable disease (Table 2). The median follow-up time was 19.3 months. Fig. 1 shows overall and progression-free survival curves for all 33 enrolled patients. Based on Kaplan—Meier analysis, 1 and 2 years overall estimated survival rates were 76 and 61%, respectively. Median overall survival time was 27 months. The 1 and 2 year progression-free survival rates were 52 and 39%, respectively, and median progression-free survival time was 12.1 months. Assessment of pattern of first failure in 19 patients showed that the first documented site of failure was within the irradiated field in 10 patients (31% of the total or 53% of the first failure) and outside of the irradiated field in nine (28% of the total or 47% of the first failure). The brain was the most common site of distant metastasis (9% of the total or 33% of the distant sites of first failure).
At the time of this report, 16 patients had died of cancer-related causes.
3.4. Toxicity Hematological and non-hematological toxicities are summarized in Table 3. The majority of toxicities were grade 1 or 2. Neutropenia was the most significant toxicity noted in the study, however, grade 3 or greater neutropenia occurred in only 6% of patients. Esophagitis rated as grade 3 was seen in one patient, grade 2 in one patient, and grade 1 in 29 patients. Fewer cases of serious esophagitis were noted in this trial than in other studies of concurrent chemoradiotherapy. Three patients (9%) had pulmonary toxicity of grade 3 or greater, of whom two had acute and one had late pulmonary toxicity. Most cases of pneumonitis improved rapidly in response to corticosteroid treatment.
3.5. Post-treatment No criteria were set with regard to treatment after completion of the study regimen. However, surgery was judged feasible based on down staging of disease in three patients (two stage IIIA patients, and one stage IIIB patient). The two stage IIIA patients gave informed consent and underwent surgery, and both achieved pathological CR. The stage IIIB patient refused surgery.
4. Discussion Chemoradiotherapy is currently being investigated as induction therapy and as consolidation therapy. At the 2002 meeting of the American Society of Clinical Oncology (ASCO), Choy et al. [12] reported interim results from the Locally Advanced Multimodality Protocol (LAMP) study, which compared three chemoradiotherapy schedules in patients with stages IIIA/IIIB NSCLC. Patients in a sequential administration group received chemotherapy (paclitaxel + carboplatin [PC]) followed by
Table 2 Efficacy Response Overall response Complete response Partial response Stable disease Progressive disease
No. of patients (%) Total
Squamous
Non-squamous
29 2 27 2 1
14 2 12 2 0
15 0 15 0 1
(91) (6) (84) (6) (3)
(88) (6) (75) (6) (0)
(94) (0) (94) (0) (3)
Phase II study of bi-weekly docetaxel and carboplatin with concurrent thoracic radiation therapy
199
100 90
Survival (%)
80 70 60 50 40 30 20 10 0 0
0.5
1
1.5
2
2.5
Time (year) Fig. 1 Kaplan—Meier curves showing overall (solid line) and progression-free (dotted line) survival in 33 enrolled patients in phase II study of bi-weekly docetaxel and carboplatin with concurrent radiation therapy followed by consolidation therapy with docetaxel and carboplatin for stage III unresectable non-small cell lung cancer. Intention-to-treat analysis.
radiotherapy; a second patient group received induction chemotherapy (PC) and then chemoradiotherapy (PC); and the third patient group received chemoradiotherapy (PC) followed by consolidation chemotherapy (PC). Median survival times in the three groups were 12.5, 11, and 16.1 months, respectively. Thus, concurrent chemoradiotherapy followed by consolidation chemotherapy, the administration schedule used in the present study, produced the best results. The addition of consolidation chemotherapy may therefore have improved
the control of distant metastasis, which was reflected by the prolongation of survival time. Two approaches for consolidation chemotherapy include using a different chemotherapy regimen from that used during chemoradiotherapy (i.e. SWOG 9504) [13], and using the same regimen, as in our present study. In SWOG 9504, patients with pathologically confirmed stage IIIB NSCLC received consolidation chemotherapy with docetaxel after having received chemoradiotherapy using cisplatin and etopside. Median survival time was 26 months,
Table 3 Hematological and non-hematological toxicity per patient (worst of any course, n = 32) Grade, n (%)
Percentage ≥ grade 3
1
2
3
4
Neutropenia Anemia Thrombocytopenia
3 (9) 23 (72) 13 (41)
16 (50) 5 (16) 1 (3)
2 (6) 0 0
0 0 0
6 0 0
Nausea/vomiting Esophagitis Pneumonitis Allergy Asthenia
0 29 (91) 13 (41) 0 4 (12)
0 1 (3) 2 (6) 0 0
0 0 1 (3) 0 0
0 0 9 0 0
1 1 2 1 0
(3) (3) (6) (3)
200 and 1, 2, and 3 year survival rates were 76, 54, and 37%, respectively [13]. Various reasons for these excellent results were discussed, including the avoidance of development of resistance to the induction chemotherapy and potential molecular mechanisms of p53-independent apoptosis. On the other hand, in the current trial in which the same chemotherapy regimen was used for both concurrent and consolidation therapy, median survival time was 27 months–—even when considering only the stage IIIB patients. These findings were thus similar to those obtained in the SWOG 9504 study. The efficacy of the carboplatin and docetaxel regimen in controlling systemic NSCLC diseases is known from one phase III randomized trial (TAX 326), which was reported at ASCO in 2001 [14]. Both drugs were administered on day 1 every 3 weeks, with docetaxel at a high dose of 75 mg/m2 . However, no randomized studies on the efficacy of the bi-weekly regimen have been published. The regimen used in TAX 326 is a candidate as a consolidation chemotherapy regimen, but concurrent chemoradiotherapy is often followed immediately by worsening of the performance status and treatment-induced myelosuppression. Accordingly, it is possible that consolidation chemotherapy cannot be completed at the full drug doses. In fact, in SWOG 9504, only 78% of patients were able to advance to the consolidation phase, and a mere 41% completed the treatment according to the protocol. It is difficult to assess the contribution of the bi-weekly consolidation regimen to the encouraging results of our present study, however, further study is needed to develop an optimal regimen for consolidation chemotherapy. In the present trial, the severity of esophagitis tended to be milder than with other chemoradiotherapy regimens. This effect was of short duration, with no late-phase adverse reactions requiring surgery to dilate the esophagus. Hematological toxicities were comparatively mild, and it was concluded that this regimen was feasible. Similar patterns of disease recurrence were observed in the SWOG 9504 study and the present study. The brain was the most common site of distant metastasis, indicating that brain metastasis is extremely difficult to control even with the addition of consolidation chemotherapy. Other studies also have reported the brain as one of the most frequent sites of initial failure. Overall CNS failure rates range from 21 to 54%, and rates of CNS as first site of relapse range from 15 to 30% [15—17]. The high incidence of brain metastasis raises the question of whether prophylactic cranial irradiation (PCI) should be used in patients with locally advanced inoperable stage III NSCLC, similar to com-
H. Sakai et al. mon practice in limited-disease (LD) small cell lung cancer (SCLC). Stuschke et al. [17] reported results of a phase II study in which PCI reduced the rate of brain metastases as the first site of relapse from 30 to 8% at 4 years (P = 0.005) and the rate of overall brain relapse from 54 to 13% (P < 0.0001), comparable to that achieved in LD-SCLC. Three small randomized trials in patients with LA-NSCLC showed that PCI decreases or delays the occurrence of brain metastases [18—20]. An ongoing, large-scale, randomized phase III study (RTOG 0214) of PCI after effective locoregional/systemic therapy for LA-NSCLC patients is expected to resolve whether PCI improves survival. In conclusion, bi-weekly docetaxel and carboplatin with concurrent radiation therapy followed by consolidation chemotherapy with the same regimen was highly active with manageable toxicity in patients with stage III unresectable NSCLC. Regardless of the administration sequence of therapies for patients with NSCLC, the majority eventually develop local recurrence and distant metastasis. Therapeutic results using current multimodality treatments have reached a plateau, underscoring the need to investigate new therapeutic strategies.
References [1] 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. [2] Curran WJ, Scott C, Langer C, et al. Phase III comparison of sequential vs. concurrent chemoradiation for patients (pts) with unresected stage III non-small cell lung cancer (NSCLC): initial report of Radiation Therapy Oncology Group (RTOG) 9410. Proc Am Soc Clin Oncol 2000;19:484a [Abstract 1891]. [3] Choy H, Rodriguez F, Koester S, et al. Synergistic effects of Taxol/Taxotere on radiation sensitivity of human cell lines. Int J Radiat Oncol Biol Phys 1993;24(Suppl 1):1059. [4] Manson KA, Hunter NR, Milas M, et al. Docetaxel enhances tumor radioresponse in vivo. Clin Cancer Res 1997;3:2431— 8. [5] Douple EB, Richmond RC, O’Hara JA, et al. Carboplatin as a potentiator of radiation therapy. Cancer Treat Rep 1985;12:111—24. [6] Koukourakis MI, Kourousis C, Kamilaki M, et al. Weekly docetaxel and concomitant boost radiotherapy for non-small cell lung cancer. A phase I/II dose escalation trial. Eur J Cancer 1998;34:833—44. [7] Mauer AN, Masters GA, Haraf DJ, et al. Phase I study of docetaxel with concomitant thoracic radiation therapy. J Clin Oncol 1998;16:159—64. [8] Segawa Y, Ueoka H, Kiura K, et al. A phase I/II study of docetaxel (TXT) and cisplatin (CDDP) with concurrent thoracic radiotherapy (TRT) for locally advanced non-small cell lung cancer (LA-NSCLC). Proc Am Soc Clin Oncol 2000;19:508a [Abstract 1988].
Phase II study of bi-weekly docetaxel and carboplatin with concurrent thoracic radiation therapy [9] Choy H, DeVore RF, Hande KR, et al. Phase I trial of outpatient weekly docetaxel carboplatin and concurrent thoracic radiation therapy for stage III unresectable non-small cell lung cancer: a Vanderbilt Cancer Center Affiliate Network (VCCAN) trial. Lung Cancer 2001;34:441—9. [10] Choy H, Akerley W, Safran H, et al. Multiinstitutional phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small cell lung cancer. J Clin Oncol 1998;16:3316—22. [11] Sakai H, Yoneda S, Kobayashi K, et al. A phase I/II study of bi-weekly docetaxel (DOC) and carboplatin (CBDCA) with concurrent thoracic radiation therapy (TRT) followed by consolidation chemotherapy with DOC/CBDCA for stage III unresectable non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001;20:238b [Abstract 2704]. [12] Choy H, Curran WJ, Scott CB, et al. Preliminary report of locally advanced multimodality protocol (LAMP): ACR427: 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). Proc Am Soc Clin Oncol 2002;21:291a [Abstract 1160]. [13] Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small cell lung cancer: Phase II Southwest Oncology Group Study S9504. J Clin Oncol 2003;21:2004—10. [14] Rodriguez J, Pawel A, Pluzanska V, et al. A multicenter randomized phase III study of docetaxel + cisplatin (DC) and docetaxel + carboplatin (Dcb) vs. vinorelbine + cisplatin
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(VC) in chemotherapy-na¨ıve patients with advanced and metastatic non-small cell lung cancer. Proc Am Soc Clin Oncol 2001;20:314a [Abstract 1251]. Law A, Daly B, Madsen M, et al. High incidence of isolated brain metastases (CNS Mets) following complete response (CR) in advanced non-small cell lung cancer (NSCLC): a new challenge. Proc Am Soc Clin Oncol 1997;16:447a [Abstract 1604]. Andre F, Grunenwald D, Pujol JL, et al. Patterns of relapse of N2 nonsmall cell lung carcinoma in patients treated with preoperative chemotherapy: Should prophylactic cranial irradiation be considered? Cancer 2001;91:2394—400. Stuschke M, Eberhardt W, Pöttgen C, et al. Prophylactic cranial irradiation in locally advanced non-small cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects. J Clin Oncol 1999;17:2700—9. Cox JD, Stanley K, Petrovich Z, Paig C, Yesner R. Cranial irradiation in cancer of the lung of all cell types. JAMA 1981;245(5):469—72. Russell AH, Pajak TE, Selim HM, et al. Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Rad Onc Biol Phys 1991;21(3):637—43. Umsawasdi T, Valdivieso M, Chen TT, et al. Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer. J Neuro-Oncol 1984;2(3):253—9.
Phase II study of bi-weekly docetaxel and carboplatin with concurrent thoracic radiation therapy followed by consolidation chemotherapy with docetaxel plus carboplatin for stage III unresectable non-small cell lung cancer Hiroshi Sakai a,*, Shuichi Yoneda a , Kunihiko Kobayashi a , Hiroshi Komagata a , Seiji Kosaihira a , Tomoko Kazumoto b , Yoshihiro Saito b a
Division of Respiratory Disease, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan b Division of Radiation Oncology, Saitama Cancer Center, Saitama, Japan Received 24 April 2003 ; received in revised form 11 August 2003; accepted 22 August 2003
KEYWORDS Concurrent chemoradiotherapy; Docetaxel; Carboplatin; Non-small cell lung cancer
Summary Objective: Docetaxel and carboplatin (DC) have demonstrated activity as radiation sensitizers in pre-clinical studies. The aim of this phase II study was to evaluate the efficacy and toxicity of DC with concurrent thoracic radiation therapy (TRT) followed by consolidation chemotherapy with DC for stage III unresectable non-small cell lung cancer (NSCLC). Patients and methods: Thirty-three previously untreated patients with inoperable, locally advanced (LA) NSCLC received docetaxel 30 mg/m2 over 1 h and carboplatin at an AUC of 3 every 2 weeks for six courses–—four courses during concurrent chemoradiotherapy and two courses following completion of radiotherapy. Concurrent TRT was performed in 2-Gy daily fractions to a total dose of 60 Gy. Results: Among 32 evaluable patients, the overall response rate was 91%, with two complete responses (CR) and 27 partial responses (PR). Median survival time by intention-to-treat analysis was 27 months, with survival rates of 76% at 1 year and 61% at 2 years. Serious side effects were generally limited to grade 3 neutropenia in 6%, grades 3 and 4 pulmonary toxicity in 6 and 3%, respectively, and grade 3 esophagitis in 3% of patients. Conclusions: DC with concurrent TRT followed by consolidation chemotherapy was highly active with manageable toxicity in patients with stage III unresectable NSCLC. © 2003 Elsevier Ireland Ltd. All rights reserved.
1. Introduction * Corresponding
author. Tel.: +81-48-722-1111; fax: +81-48-723-5197. E-mail address: hiroshi [email protected] (H. Sakai).
Approximately 20—25% of non-small cell lung cancer (NSCLC) patients are initially diagnosed with stage III disease. This group of patients is of particular
0169-5002/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2003.08.021
196 interest, because results of several recent randomized studies indicate that such patients benefit from multimodality treatment with chemotherapy and radiotherapy. However, survival rates remain relatively low because local and distant treatment failures are common. Treatment goals in stage III NSCLC are to improve both locoregional and systemic control of disease. To further improve therapeutic efficacy and reduce toxicity, numerous issues remain to be investigated. For example, whether radiotherapy should be administered sequentially to, or concurrently with, chemotherapy is still unresolved, and the respective efficacies of induction chemotherapy given prior to chemoradiotherapy, and consolidation chemotherapy given after chemoradiotherapy, have not been determined. In this regard, results of trials conducted by the West Japan Lung Cancer Group, the Radiation Therapy Oncology Group (RTOG9410), and other phase III trials performed in the 1990s indicated that concurrent chemoradiotherapy was superior to sequential treatment [1,2]. This approach has become the accepted standard for unresectable stage III NSCLC. On the other hand, it is thought that adjuvant chemotherapy may increase or maintain the effects of primary chemoradiotherapy treatment; several clinical trials are evaluating this concept. Docetaxel has demonstrated activity as a radiation sensitizer in pre-clinical studies [3,4]. The mechanism of the radiation-enhancing effect is not well defined, although potential mechanisms include cell cycle synchronization, apoptosis and reoxygenation. Several in vitro studies using docetaxel with concurrent radiation have shown sensitizing enhancement ratios ranging from 1.45 to 2.33 in some cell lines [4]. Several pre-clinical studies have suggested that carboplatin also effectively modulates radiation cell damage [5]. The combination of docetaxel and radiotherapy has been studied in phases I and II clinical trials [6,7]. Optimal dosages were identified as 20—30 mg/m2 per week of docetaxel and 60 Gy of radiation. Response rates obtained in several phase II trials ranged from 34 to 80%, with 1 year survival rates of 48—59% [7]. In addition, concurrent combination therapy consisting of docetaxel + cisplatin (or carboplatin) + radiotherapy resulted in good response rates of 70—90%, 1 year survival rates of 55—74%, and 2 year survival rates of 41—43% [8,9]. A weekly administration schedule for chemotherapy in concurrent chemoradiotherapy regimens has been commonly reported. Choy et al. [10] used a weekly schedule in a study aimed at achieving a radiosensitizing effect in patients with locally advanced (LA) NSCLC. This chemoradiotherapy regimen resulted in a comparatively high incidence
H. Sakai et al. of esophagitis, which was dose-limiting. In this regard, we devised a novel bi-weekly administration schedule, and decided to use consolidation chemotherapy after chemoradiotherapy in attempts to improve both locoregional and systemic disease control. We previously reported results of a phase I study demonstrating the feasibility of bi-weekly docetaxel and carboplatin when administered with concurrent radiotherapy [11]. Doses recommended for use in the phase II setting were docetaxel 30 mg/m2 and carboplatin at an AUC of 3. Dose-limiting toxicity was neutropenia [11]. This paper reports results of a phase II study of the efficacy and toxicity of bi-weekly docetaxel and carboplatin with concurrent radiation therapy in patients with stages IIIA and IIIB NSCLC. Doses used were those recommended in our previous phase I trial.
2. Patients and methods 2.1. Patient selection Patients with histologically proven stage III NSCLC whose disease was not suitable for surgical treatment were enrolled in the study. Other eligibility criteria were: (i) no previous chemotherapy or radiotherapy; (ii) no malignant pleural effusion; (iii) presence of bidimensionally measurable lesion; (iv) age ≥18 and ≤75 years; (v) Eastern Cooperative Oncology Group (ECOG) performance status ≤1; (vi) adequate hematopoietic reserve: absolute neutrophil count ≥2000 mm−3 , platelet count ≥100,000 mm−3 ; (vii) adequate hepatic and renal functions: serum creatinine <1.5 times the upper normal limit (UNL), serum bilirubin, AST and ALT <1.5 times UNL; and (viii) arterial blood gases at PaO2 >70 mmHg. Other patient assessments performed before study entry were computed tomography (CT) scan and radiography of the chest, magnetic resonance imaging (MRI) of the brain, bone scan, and bronchoscopy. The institutional ethics committee approved the study protocol. Informed consent was obtained from all patients.
2.2. Treatment Patients received a 1 h infusion of docetaxel 30 mg/m2 followed by 1 h infusion of carboplatin at AUC = 3.0 every 2 weeks for six courses. All patients received prophylactic pre-medication with dexamethasone 4 mg intravenously (i.v.) on the day of chemotherapy. Antiemetics were administered as needed. Radiation therapy was administered
Phase II study of bi-weekly docetaxel and carboplatin with concurrent thoracic radiation therapy with 2.0 Gy daily fractions by a linear accelerator generating 10 MV photon. The initial radiotherapy target volume was primary tumor, ipsilateral hilar and mediastinal lymph nodes by antero-posterior parallel opposed fields with a 1—1.5 cm margin around the primary tumor and involved nodes. Ipsilateral supraclavicular fossa was included, when tumor existed in the upper lobe or the enlarged lymph nodes were seen. Paraesophageal nodes were included if the lesion was in the lower lobe. The contralateral hilum was excluded. A shrinking field technique was used. Mediastinal lymph nodes were irradiated up to 40 Gy for prophylaxis. Primary tumor, involved ipsilateral hilar and mediastinal lymph nodes were irradiated up to 60 Gy in 6 weeks without interruption. These doses were calculated at the central axis without the use of lung correction. Spinal cord was spared after 40—50 Gy. The first four chemotherapy courses were administered concurrently with radiotherapy, and the fifth and sixth courses were given after completion of radiotherapy. The use of granulocyte-colony stimulating factors (G-CSF) was not allowed during concurrent and consolidation phases, except for patients with febrile neutropenia, or WHO grade 4 leukopenia or neutropenia, according to investigator decision.
2.3. Dose adjustments Patients experiencing any toxicity ≥ grade 2 skipped chemotherapy. For patients with hematological toxicity ≥ grade 4 or non-hematological toxicity ≥ grade 2, radiotherapy was stopped until hematological effects recovered to ≤ grade 3 or non-hematological effects to ≤ grade 2, at which time radiotherapy was resumed. For patients with febrile neutropenia, or WHO grade 4 leukopenia or neutropenia, radiotherapy was stopped until hematological effects recovered to ≤ grade 3 with G-CSF.
2.4. Treatment evaluation A complete blood cell count and blood chemistry tests were performed weekly. Patients were assessed weekly for toxicity according to the National Cancer Institute-Common Toxicity Criteria. In addition, delayed radiation toxicities occurring more than 90 days after the start of radiotherapy were assessed according to the Late Radiation Morbidity Scoring Scheme of the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer (RTOG/EORTC). Response evaluation was based on World Health Organization (WHO) criteria. Tumor response was assessed by CT scan every 4 weeks. Responding patients
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had a confirmatory CT scan at least 4 weeks after the initial determination of response. CT scan of the chest and upper abdomen and chest radiograph were repeated 1 month post-chemotherapy. Progression-free survival and overall survival were measured from the date of first treatment administration to the date of disease progression or death for the former and the date of death for the latter. The Kaplan—Meier method was employed to determine medians and 95% confidence intervals (CI) of the time-related parameters.
3. Results 3.1. Patient characteristics From May 2000 to July 2001, a total of 33 patients were enrolled in the study. Patient characteristics are shown in Table 1. Thirty-two men and one woman, with a median age of 64 years (range, 33—74), were treated. ECOG performance status was 0 for four patients (12%) and one for 29 patients (88%). Fifteen patients (45%) had adenocarcinoma, 16 (48%) had squamous cell carcinoma, and two had large cell carcinoma. Thirteen patients (39%) had stage IIIA disease and 20 (61%) had stage IIIB disease (T4N0/1: 5, T4N2: 5, any TN3: 10). Of 33 patients enrolled, 1 withdrew from the study Table 1 Patient characteristics Characteristic
Number of patients (%)
Treated/eligible
33/33
Age (years) Median Range
64 33—75
Gender Male Female
32 (97) 1 (3)
ECOG performance status 0 1
4 (12) 29 (88)
Histology Adenocarcinoma Squamous Large cell
15 (45) 16 (48) 2 (6)
Stage IIIA IIIB T4N0/1 T4N2 anyTN3
13 (39) 20 (61) 5 5 10
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during the first week of treatment because of allergic reactions, leaving 32 patients evaluable for toxicity and response.
3.2. Dose administration The 32 evaluable patients received 99 cycles of bi-weekly docetaxel and carboplatin, or 77% of the planned chemotherapy doses during the concurrent phase. Twenty-eight of 32 patients received the planned 60 Gy of radiation. The mean duration of the radiation period was 41 days (range, 35—50 days). Fifty-one cycles of consolidation chemotherapy were administered, or 82% of the planned chemotherapy doses during the consolidation phase.
3.3. Response and survival Among 32 evaluable patients, two achieved a complete response (CR) and 27 a partial response (PR), for an overall response rate of 91% (95% confidence interval: 75—98). There were no differences in response rates between patients with squamous cell and non-squamous cell histologies (88% versus 94%). One patient had progressive disease and two had stable disease (Table 2). The median follow-up time was 19.3 months. Fig. 1 shows overall and progression-free survival curves for all 33 enrolled patients. Based on Kaplan—Meier analysis, 1 and 2 years overall estimated survival rates were 76 and 61%, respectively. Median overall survival time was 27 months. The 1 and 2 year progression-free survival rates were 52 and 39%, respectively, and median progression-free survival time was 12.1 months. Assessment of pattern of first failure in 19 patients showed that the first documented site of failure was within the irradiated field in 10 patients (31% of the total or 53% of the first failure) and outside of the irradiated field in nine (28% of the total or 47% of the first failure). The brain was the most common site of distant metastasis (9% of the total or 33% of the distant sites of first failure).
At the time of this report, 16 patients had died of cancer-related causes.
3.4. Toxicity Hematological and non-hematological toxicities are summarized in Table 3. The majority of toxicities were grade 1 or 2. Neutropenia was the most significant toxicity noted in the study, however, grade 3 or greater neutropenia occurred in only 6% of patients. Esophagitis rated as grade 3 was seen in one patient, grade 2 in one patient, and grade 1 in 29 patients. Fewer cases of serious esophagitis were noted in this trial than in other studies of concurrent chemoradiotherapy. Three patients (9%) had pulmonary toxicity of grade 3 or greater, of whom two had acute and one had late pulmonary toxicity. Most cases of pneumonitis improved rapidly in response to corticosteroid treatment.
3.5. Post-treatment No criteria were set with regard to treatment after completion of the study regimen. However, surgery was judged feasible based on down staging of disease in three patients (two stage IIIA patients, and one stage IIIB patient). The two stage IIIA patients gave informed consent and underwent surgery, and both achieved pathological CR. The stage IIIB patient refused surgery.
4. Discussion Chemoradiotherapy is currently being investigated as induction therapy and as consolidation therapy. At the 2002 meeting of the American Society of Clinical Oncology (ASCO), Choy et al. [12] reported interim results from the Locally Advanced Multimodality Protocol (LAMP) study, which compared three chemoradiotherapy schedules in patients with stages IIIA/IIIB NSCLC. Patients in a sequential administration group received chemotherapy (paclitaxel + carboplatin [PC]) followed by
Table 2 Efficacy Response Overall response Complete response Partial response Stable disease Progressive disease
No. of patients (%) Total
Squamous
Non-squamous
29 2 27 2 1
14 2 12 2 0
15 0 15 0 1
(91) (6) (84) (6) (3)
(88) (6) (75) (6) (0)
(94) (0) (94) (0) (3)
Phase II study of bi-weekly docetaxel and carboplatin with concurrent thoracic radiation therapy
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100 90
Survival (%)
80 70 60 50 40 30 20 10 0 0
0.5
1
1.5
2
2.5
Time (year) Fig. 1 Kaplan—Meier curves showing overall (solid line) and progression-free (dotted line) survival in 33 enrolled patients in phase II study of bi-weekly docetaxel and carboplatin with concurrent radiation therapy followed by consolidation therapy with docetaxel and carboplatin for stage III unresectable non-small cell lung cancer. Intention-to-treat analysis.
radiotherapy; a second patient group received induction chemotherapy (PC) and then chemoradiotherapy (PC); and the third patient group received chemoradiotherapy (PC) followed by consolidation chemotherapy (PC). Median survival times in the three groups were 12.5, 11, and 16.1 months, respectively. Thus, concurrent chemoradiotherapy followed by consolidation chemotherapy, the administration schedule used in the present study, produced the best results. The addition of consolidation chemotherapy may therefore have improved
the control of distant metastasis, which was reflected by the prolongation of survival time. Two approaches for consolidation chemotherapy include using a different chemotherapy regimen from that used during chemoradiotherapy (i.e. SWOG 9504) [13], and using the same regimen, as in our present study. In SWOG 9504, patients with pathologically confirmed stage IIIB NSCLC received consolidation chemotherapy with docetaxel after having received chemoradiotherapy using cisplatin and etopside. Median survival time was 26 months,
Table 3 Hematological and non-hematological toxicity per patient (worst of any course, n = 32) Grade, n (%)
Percentage ≥ grade 3
1
2
3
4
Neutropenia Anemia Thrombocytopenia
3 (9) 23 (72) 13 (41)
16 (50) 5 (16) 1 (3)
2 (6) 0 0
0 0 0
6 0 0
Nausea/vomiting Esophagitis Pneumonitis Allergy Asthenia
0 29 (91) 13 (41) 0 4 (12)
0 1 (3) 2 (6) 0 0
0 0 1 (3) 0 0
0 0 9 0 0
1 1 2 1 0
(3) (3) (6) (3)
200 and 1, 2, and 3 year survival rates were 76, 54, and 37%, respectively [13]. Various reasons for these excellent results were discussed, including the avoidance of development of resistance to the induction chemotherapy and potential molecular mechanisms of p53-independent apoptosis. On the other hand, in the current trial in which the same chemotherapy regimen was used for both concurrent and consolidation therapy, median survival time was 27 months–—even when considering only the stage IIIB patients. These findings were thus similar to those obtained in the SWOG 9504 study. The efficacy of the carboplatin and docetaxel regimen in controlling systemic NSCLC diseases is known from one phase III randomized trial (TAX 326), which was reported at ASCO in 2001 [14]. Both drugs were administered on day 1 every 3 weeks, with docetaxel at a high dose of 75 mg/m2 . However, no randomized studies on the efficacy of the bi-weekly regimen have been published. The regimen used in TAX 326 is a candidate as a consolidation chemotherapy regimen, but concurrent chemoradiotherapy is often followed immediately by worsening of the performance status and treatment-induced myelosuppression. Accordingly, it is possible that consolidation chemotherapy cannot be completed at the full drug doses. In fact, in SWOG 9504, only 78% of patients were able to advance to the consolidation phase, and a mere 41% completed the treatment according to the protocol. It is difficult to assess the contribution of the bi-weekly consolidation regimen to the encouraging results of our present study, however, further study is needed to develop an optimal regimen for consolidation chemotherapy. In the present trial, the severity of esophagitis tended to be milder than with other chemoradiotherapy regimens. This effect was of short duration, with no late-phase adverse reactions requiring surgery to dilate the esophagus. Hematological toxicities were comparatively mild, and it was concluded that this regimen was feasible. Similar patterns of disease recurrence were observed in the SWOG 9504 study and the present study. The brain was the most common site of distant metastasis, indicating that brain metastasis is extremely difficult to control even with the addition of consolidation chemotherapy. Other studies also have reported the brain as one of the most frequent sites of initial failure. Overall CNS failure rates range from 21 to 54%, and rates of CNS as first site of relapse range from 15 to 30% [15—17]. The high incidence of brain metastasis raises the question of whether prophylactic cranial irradiation (PCI) should be used in patients with locally advanced inoperable stage III NSCLC, similar to com-
H. Sakai et al. mon practice in limited-disease (LD) small cell lung cancer (SCLC). Stuschke et al. [17] reported results of a phase II study in which PCI reduced the rate of brain metastases as the first site of relapse from 30 to 8% at 4 years (P = 0.005) and the rate of overall brain relapse from 54 to 13% (P < 0.0001), comparable to that achieved in LD-SCLC. Three small randomized trials in patients with LA-NSCLC showed that PCI decreases or delays the occurrence of brain metastases [18—20]. An ongoing, large-scale, randomized phase III study (RTOG 0214) of PCI after effective locoregional/systemic therapy for LA-NSCLC patients is expected to resolve whether PCI improves survival. In conclusion, bi-weekly docetaxel and carboplatin with concurrent radiation therapy followed by consolidation chemotherapy with the same regimen was highly active with manageable toxicity in patients with stage III unresectable NSCLC. Regardless of the administration sequence of therapies for patients with NSCLC, the majority eventually develop local recurrence and distant metastasis. Therapeutic results using current multimodality treatments have reached a plateau, underscoring the need to investigate new therapeutic strategies.
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