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Carboplatin/Paclitaxel or Carboplatin/Vinorelbine Followed by Accelerated Hyperfractionated Conformal Radiation Therapy: A Preliminary Report of a Phase I Dose Escalation Trial from the Carolina Conformal Therapy Consortium

Departments of Radiation Oncology, Medical Oncology, and Biometry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Duke University Medical Center, Durham, North Carolina, USA; Wake Forest University, Winston Salem, North Carolina, USA; and Medical University of South Carolina, Columbia, South Carolina, USA

Correspondence: M. A. Socinski, M.D., Multidisciplinary Thoracic Oncology Program, University of North Carolina, Chapel Hill, Division of Hematology/Oncology, CB 7305, Chapel Hill, North Carolina 27514, USA. Telephone: 919-966-4431; Fax: 919-966-6735; e-mail: socinski{at}med.unc.edu

	ABSTRACT

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The maximum tolerated dose of conformal radiation therapy delivered at 1.6 Gy bid is being assessed in patients with unresectable stage IIB-IIIB non-small cell lung cancer who have been treated with induction regimens consisting of carboplatin plus paclitaxel or carboplatin plus vinorelbine. Data from the early stages of this parallel phase I study show that the two induction regimens are similar in toxicity and that both induce partial responses in 45% of patients. Both regimens can be followed by conformal radiotherapy using an accelerated hyperfractionated schedule to a dose of at least 80 Gy without experiencing unacceptable toxicity. Key morbidity observed thus far has involved the esophagus. Further cohorts of patients will receive higher doses of conformal radiotherapy (in 6.4 Gy increments) until the maximum tolerated dose is reached.

Key Words. Carboplatin • Paclitaxel • Vinorelbine • AHCRT • TRT

	INTRODUCTION

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Conventional doses of thoracic radiation therapy (TRT) (i.e., 60-66 Gy) have been ineffective at sterilizing local tumor in patients with unresectable stage III non-small cell lung cancer (NSCLC) [1-4]. Attempts at dose escalation of TRT have been limited because of toxicity issues when higher doses are used. Using conformal planning techniques, it is possible to increase the radiation dose administered, perhaps by improving tumor targeting and limiting excessive dose to normal tissue [5]. Other strategies with fractionated accelerated schedules may also lead to improved local efficacy of TRT. In a trial in which 49 patients received TRT therapy alone, a novel concurrent boost technique (in which treatment was administered at 1.6 Gy bid) enabled a total radiation dose of 73.6 Gy to be delivered without incurring unacceptable toxicity [6]. In this study, the median survival was 15.3 months. The two-year survival rate of 46% was also promising, and 64% of these patients were free from local progression at two years.

Occult systemic involvement is often present at the time of diagnosis in the form of micrometastases in patients with unresectable stage III NSCLC [7-10]. The rationale for the use of induction chemotherapy in stage IIIA/IIIB NSCLC includes eradication of systemic micrometastases, which has been suggested by Arriagada and colleagues [11]. Several trials comparing platinum-based induction regimens followed by TRT, compared to TRT alone in unresectable stage IIIA/B disease, have reported longer median and long-term survival among patients receiving the induction chemotherapy [3, 12-14]. Unfortunately both local and distant control remains suboptimal, and novel approaches addressing strategies designed to improve both local and distant control are needed [3, 5, 12-14].

The trial (C-3DRC 9701) presented in this paper was undertaken to address these issues. The primary purpose of the study was to incorporate conformal planning techniques in a dose-escalation trial of accelerated hyperfractionated conformal radiation therapy (AHCRT) in patients who had received one of two "modern" induction chemotherapy regimens. In essence, the design of the trial was that of two phase I studies run in parallel. The induction chemotherapy regimens consisted of paclitaxel plus carboplatin (CP) and vinorelbine plus carboplatin (CV). The reasons for the inclusion of carboplatin were based on the improved survival observed with the platinum-based induction regimens in previous randomized trials and the potential for a lower incidence of adverse events. Vinorelbine or paclitaxel combined with platinum have demonstrated appreciable activity as induction therapies, with manageable safety profiles [15-21].

	OBJECTIVES

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The primary objective of the trial was to determine the maximum tolerated dose (MTD) of three-dimensional AHCRT in patients with inoperable stage IIB or IIIA/B NSCLC following induction chemotherapy.

The study has several secondary objectives. First, it was intended to compare the pattern of toxicities of the two induction regimens in the context of subsequent escalating doses of AHCRT. Second, it was designed to examine the influence of AHCRT and chemotherapy regimen on survival, failure-free survival and sites of relapse. Third (although no data on this aspect of the trial are available to date), the study contains a correlative science component: toxicity (particularly lung toxicity) is to be examined in relation to serial levels of transforming growth factor-ß/macrophage inflammatory protein-1 , aspects of radiation dose and volume, and patients' initial pulmonary function tests.

	DESIGN AND METHODS

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Eligible patients had a histologic or cytologic diagnosis of NSCLC and inoperable stage IIB or stage IIIA/B disease. Patients with supraclavicular or contralateral hilar lymphadenopathy were excluded, as were those with malignant pleural effusion. Patients were required to have a performance status (PS) of 0-2, a forced expiratory ventilation in one second (FEV₁) greater than 1L, or a predicted post-radiation FEV₁ of 0.8L or greater, and adequate end-organ function.

All patients received two cycles of induction chemotherapy, followed by escalating doses of AHCRT starting on day 43 of treatment. The MTD of radiation therapy is to be determined separately for patients receiving CP and those receiving CV. At each dose level of radiation, it was intended that seven patients be accrued to each chemotherapy regimen, and dose level of AHCRT with a minimum of five patients evaluable for toxicity. Toxicity was assessed using the SOMA-LENT criteria [22].

The MTD was determined according to two criteria. The first related to the numbers of patients experiencing toxicities of a defined grade within a minimum of six weeks following the completion of radiotherapy. Thus does escalation was stopped (and hence the MTD reached) if there were three or more cases of grade 3 toxicity, two or more cases of grade 4-5 toxicity, or two cases of grade 3 toxicity plus one case of grade 4-5 toxicity. The second stopping rule required an end to does escalation if toxicity necessitated a does delay in AHCRT of more than two weeks in 50% or more patients.

Chemotherapy
The treatment schema is shown in Figure 1. Two induction regimens were studied: CP and CV. Patients were enrolled in groups of 14 per radiation dose level, the first seven receiving CP and the second seven CV. At the start of the study, the doses used were: carboplatin area under the concentration time curve (AUC) = 7; paclitaxel 225 mg/m² infused over 3 h and vinorelbine 30 mg/m². Patients treated with CV were supported by 100 mg G-CSF q.d. The doses of carboplatin and vinorelbine were later reduced (see below).

View larger version (24K): [in this window] [in a new window]   Figure 1. Study 9701 treatment schema.

The initial 57.6 Gy (in 36 fractions) were given using the concurrent boost technique (1.25 Gy bid to the clinical target volume and 1.6 Gy total to all areas of prechemotherapy gross disease). The remaining dose was delivered to the post-chemotherapy gross target volume. The normal tissue tolerances were taken as spinal cord <50 Gy, heart <40 Gy, esophagus <73.6 Gy to >6 cm, and chest wall <70 Gy.

	RESULTS

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Patients
The data presented here relate to the first 29 patients studied, representing the first two cohorts in the trial, i.e., those treated at AHCRT doses of 73.6 Gy and 80 Gy. Their median age was 61; 19 were male. One patient had stage IIB disease, 21 were stage IIIA and seven stage IIIB. The median tumor size was 4.5 cm and median tumor volume 71 cc. The patients' PS was 0 in 17 cases, 1 in 11, and 2 in 1. Six patients (21%) had experienced weight loss of greater than 5%. The most common histology was squamous carcinoma (11 patients), with the remainder divided among adenocarcinoma, large cell carcinoma, and carcinoma not otherwise specified.

Treatment
In both combination chemotherapy regimens, dose adjustments were made after the first cohort of patients had been treated. Thus patients who received 80 Gy of AHCRT received a reduced dose of carboplatin, targeted to achieve an AUC of 6. Patients assigned to CV chemotherapy received a lower dose of 20 mg/m² vinorelbine without G-CSF from the second cohort onwards.

A total of 14 patients received CP induction chemotherapy and 15 received CV. Of the former, half were enrolled in the first cohort and half in the second; all seven patients in the first group and six patients in the second group were evaluable for radiation therapy MTD. Of the 15 CV patients, eight were enrolled to receive 73.6 Gy radiation and seven to receive 80 Gy. In both groups, six patients were evaluable for radiation toxicity. The four non-evaluable exhibited progressive disease and therefore did not complete AHCRT. Of the five non-evaluable patients, three progressed, one expired before radiotherapy, and one removed herself from the study.

Induction Chemotherapy: Adverse Events and Response
The toxicities associated with the two induction chemotherapy regimens were broadly similar, and primarily hematological. It should be noted that half the patients whose data contributed to Table 1 were treated with doses of carboplatin and vinorelbine which were subsequently reduced following experience with the first cohort.

Adverse Events Following Radiotherapy
The toxicities experienced following AHCRT in the first two cohorts of patients studied (73.6 and 80.0 Gy) have not yet met the criteria for MTD. There were no instances of grade 3 or 4 lung toxicity. The most frequent toxicity encountered was esophagitis: there was one case of grade 3 toxicity in a patient receiving CP chemotherapy plus 80 Gy radiation, one case of grade 3 toxicity among a patient receiving CV chemotherapy plus 80 Gy radiation, and one case of grade 4 toxicity in a patient receiving CV + 73.6 Gy radiation.

On the basis of these data, radiotherapy dose escalation continues in both arms of the study. Currently, patients are being treated to an AHCRT dose of 86.4 Gy.

Overall Response and Survival
Following induction chemotherapy and AHCRT, four patients (14%) have experienced a complete response and eight (28%) a partial response. In two patients, lesions show fibrosis and five (17%) have stable disease. Median and one-year survival for the entire group of 29 patients is 16.2 months and 65%, respectively.

	DISCUSSION

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This study, which is still in progress, provides data suggesting that either paclitaxel or vinorelbine can be used in combination with carboplatin in induction chemotherapy for patients who will subsequently be treated with AHCRT. The 29 patients for whom data are available at this stage are representative of the wider population of patients with unresectable stage IIB/IIIB NSCLC.

The exciting aspect of this trial involved the novel radiotherapy strategy which utilizes conformal planning techniques to escalate the total dose of radiation delivered in this disease setting. Our preliminary data suggest that dose escalation of AHCRT on this schedule is possible at least to 80 Gy with acceptable levels of toxicity. Accrual continues in a phase I fashion to determine the MTD of AHCRT following induction CP and CV.

	ACKNOWLEDGEMENT

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Supported in part by a grant from Glaxo Wellcome. Thanks to Robert Clough and Andrea Tisch for data management support.

	REFERENCES

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1. Perez CA, Stanley K, Rubin P et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Cancer 1980;45:2744-2753.[CrossRef][Medline]
2. Perez CA, Pajak TF, Rubin P et al. Long-term observations of the pattern of failure in patients with unresectable non-oat-cell carcinoma of the lung treated with definite radiotherapy. Cancer 1987;59:1874-1881.[CrossRef][Medline]
3. Le Chevalier T, Arriagada R, Quoix E et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small cell lung cancer: first analysis of a randomized trial in 535 patients. J Natl Cancer Inst 1991;83:417-423.[Abstract/Free Full Text]
4. Nestle U, Nieder C, Walter K et al. A palliative accelerated irradiation regimen for advanced non-small-cell lung cancer vs. conventionally fractionated 60 GY: results of a randomized equivalence study. Int J Radiat Oncol Biol Phys 2000;48:95-103.[CrossRef][Medline]
5. Hazuka MB, Turrisi AT III, Lutz ST et al. Results of high-dose thoracic irradiation incorporating beam's eye view display in non-small cell lung cancer: a retrospective multivariate analysis. Int J Radiat Oncol Biol Phys 1993;27:273-284.[Medline]
6. King SC, Acker JC, Kussin PS et al. High-dose, hyperfractionated, accelerated radiotherapy using a concurrent boost for the treatment of nonsmall cell lung cancer: unusual toxicity and promising early results. Int J Radiat Oncol Biol Phys 1996;36:593-599.[CrossRef][Medline]
7. Klastersky J, Burkers R, Choi N et al. Induction therapy for NSCLC: a consensus report. Lung Cancer 1991;7:15-17.
8. Pastorino U. Benefits of neoadjuvant chemotherapy in NSCLC. Chest 1996;109:96S-101S.[Abstract/Free Full Text]
9. Rosell R, Font A, Pifarré A et al. The role of induction (neoadjuvant) chemotherapy in Stage IIIA NSCLC. Chest 1996;109:102S-106S.[Abstract/Free Full Text]
10. Pantel K, Izbicki J, Passlick B et al. Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non-small cell lung cancer without overt metastases. Lancet 1996;347:649-653.[CrossRef][Medline]
11. Arriagada R, Le Chevalier T, Quoix E et al. ASTRO (American Society for Therapeutic Radiology and Oncology) plenary: Effect of chemotherapy on locally advanced non-small cell lung carcinoma: a randomized study of 353 patients. GETCB (Groupe d'Etude et Traitement des Cancers Bronchiques), FNCLCC (Federation Nationale des Centres de Lutte contre le Cancer) and the CEBI trialists. Int J Radiat Oncol Biol Phys 1991;20:1183-1190.[Medline]
12. Dillman RO, Seargren SL, Propert K. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small cell lung cancer. N Engl J Med 1990;323:940-945.[Abstract]
13. 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 non-small cell lung cancer. J Natl Cancer Inst 1995;87:198-205.[Abstract/Free Full Text]
14. Non-Small Cell Lung Cancer Co-operative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899-909.[Abstract/Free Full Text]
15. Felip E, Del Campo JM, Bodi R et al. Cisplatin and vinorelbine followed by radiotherapy in the treatment of stage III-B non-small cell lung cancer patients. Am J Clin Oncol 1997;20:404-406.[CrossRef][Medline]
16. Bardete E, Douillard JY, Riviere A et al. Induction chemotherapy (ICT cisplatin and vinorelbine) followed by a combination of daily irradiation and carboplatin (CBCDA) stage IIIB non-small cell lung cancer (NSCLC): final analysis of a phase II trial. Lung Cancer 1997;18(suppl 1):352a.
17. Iaffaiolo RV, Caponigro F, Tortoriello A et al. Accelerated split-course (type B) thoracic radiation therapy plus vinorelbine/ carboplatin combination chemotherapy in stage III inoperable non-small cell lung cancer. Eur J Cancer 1996;32:1901-1904.[CrossRef]
18. Choy H, Yee L, Cole BF. Combined-modality therapy for advanced non-small cell lung cancer: paclitaxel and thoracic irradiation. Semin Oncol 1995;22(suppl 15):38-44.
19. Langer CJ, Movsas B, Hudes R et al. Induction paclitaxel and carboplatin followed by concurrent chemoradiotherapy in patients with unresectable, locally advanced non-small cell lung carcinoma: report of Fox Chase Cancer Center study 94-001. Semin Oncol 1997;24(suppl 12):S12-89-S12-95.
20. Isokangas OP, Joensuu H, Halme M et al. Paclitaxel (Taxol) and carboplatin followed by concomitant paclitaxel, cisplatin and radiotherapy for inoperable stage III NSCLC. Lung Cancer 1998;20:127-133.[CrossRef][Medline]
21. Socinski MA, Rosenman JG, Schell MJ et al. Induction carboplatin/paclitaxel followed by concurrent carboplatin/ paclitaxel and dose-escalating conformal thoracic radiation therapy in unresectable stage IIIA/B nonsmall cell lung carcinoma: a modified Phase I trial. Cancer 2000;89:534-542.[CrossRef][Medline]
22. LENT SOMA scales for all anatomic sites. Int J Radiat Oncol Biol Phys 1995;31:1049-1091[CrossRef][Medline]

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