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Concurrent Hyperfractionated Radiotherapy and Low-Dose Daily Carboplatin and Paclitaxel in Patients With Stage III Non–Small-Cell Lung Cancer: Long-Term Results of a Phase II Study

From the Departments of Oncology and Surgery, University Hospital, Kragujevac, Serbia

Address reprint requests to Branislav Jeremic, MD, PhD, Applied Radiation Biology and Radiotherapy section, Division of Human Health, International Atomic Energy Agency, Wagramer Strasse 5, A-1400 Vienna, Austria; e-mail: b.jeremic{at}iaea.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To investigate the feasibility and activity of hyperfractionated radiation therapy (Hfx RT) and concurrent chemotherapy (CT) consisting of low-dose, daily carboplatin and paclitaxel in patients with stage III non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Sixty-four patients started their treatment on day 1 with 30 mg/m² of paclitaxel administered by 1-hour infusion. Hfx RT began on day 2 using 1.3 Gy bid to a total dose of 67.6 Gy and concurrent low-dose daily CT consisting of 25 mg/m² of carboplatin and 10 mg/m² of paclitaxel, both given Mondays to Fridays during RT course.

RESULTS: Objective response rate was 83% and included complete response in 27 patients (42%) and partial response in 26 patients (41%). Ten patients (16%) had stable disease, whereas only one patient (2%) had progressive disease. The median survival time was 28 months, and 3- and 5-year survival rates were 37% and 26%, respectively. The median time to local progression was 26 months, and 3- and 5-year local progression-free survival rates were 37% and 33%, respectively. The median time to distant metastasis was 25 months, and 3- and 5- year distant metastasis-free survival rates were 37% and 31%, respectively. Acute high-grade ( grade 3) toxicity was hematologic (25%), esophageal (17%), bronchopulmonary (13%), and skin (9%). Late high-grade toxicity was infrequent.

CONCLUSION: This combined Hfx RT/TC regimen produced results that are among the best ever reported and warrants further study in a prospective randomized fashion.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Stage III non–small-cell lung cancer (NSCLC) is one of the major targets for clinical research in thoracic oncology. The standard treatment for this patient population widely accepted in the 1970s and the 1980s, standard fraction radiation therapy (RT), offered poor results, with median survival times (MST) of 9 to 13 months and 2- and 5-year survival rates of 15% to 20% and 5% to 9%, respectively.^1-3

To overcome these figures, efforts have been concentrated on the combination of RT and chemotherapy (CT). Three large studies showed an advantage for sequential CT and RT over RT alone.^4-17 On the other hand, most of the concurrent RT/CT studies showed promising results,^8-11 and important controlled studies showed clear advantage for this type of treatment over RT alone.^12-14 Most recently, two large studies^15-18 showed that concurrent RT/CT is superior to sequential CT followed by RT, the former now considered as the standard treatment approach in inoperable patients with stage III NSCLC. Although sequential CT and RT studies showed improvement in survival resulting from a reduction in distant metastasis rate, studies of concurrent RT/CT showed improvement in survival resulting from a reduction in the local recurrence rate.

In our previous controlled studies,^12,13 we clearly demonstrated feasibility of concurrent RT/CT and its superiority over the same hyperfractionated (Hfx) RT alone. We have also shown that low-dose daily CT given concurrently with Hfx RT during the latter study led to an improvement in the local recurrence-free survival over that obtained with the same Hfx RT alone,¹³ which led to improvement in overall survival. Attempts to improve distant metastasis control by adding so-called weekend CT^19,20 did not lead to benefit over that obtained with Hfx RT and concurrent low-dose daily CT consisting of carboplatin and etoposide.¹³

The 1990s were also the time of wide introduction of the third-generation drugs, paclitaxel being one of them. Paclitaxel was shown to be active against NSCLC.^21-24 Laboratory findings indicated its radioenhancing properties based on cell cycle effects as well as apoptosis and reoxygenation.^25-30 Finally, some studies also indicated an existing synergism between carboplatin and paclitaxel.³¹ Given these premises, we undertook a phase II study on the use of RT and concurrent low-dose, daily paclitaxel and carboplatin in patients with stage III NSCLC.

	PATIENTS AND METHODS

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To be eligible for this study, adult ( 18 years) patients had to have histologically or cytologically confirmed advanced NSCLC classified as stage IIIA or IIIB by the International System,³² a Karnofsky performance score (KPS) of 70%, weight loss of less than 5%, and no previous therapy. Exclusion criteria included postoperative thoracic recurrence, a history of any prior or concurrent cancer (except skin cancer) unless the patient had shown no evidence of disease for more than 5 years, and malignant pleural effusion.

The pretreatment evaluation included medical history, physical examination, CBC, biochemical screening tests, chest radiography, and computed tomography of the thorax and upper abdomen. Brain computed tomography scanning and pulmonary function tests were performed whenever possible.

Treatment consisted of the following: on day 1 (always on Monday), patients received 30 mg/m² of paclitaxel administered over a 1-hour infusion. Premedication was not administered but was prepared for the case of any adverse effect and included dexamethasone, ranitidine, and diphenhydramine. Concurrent RT/CT started from day 2. Hfx RT with 1.3 Gy was administered twice daily to a total dose of 67.6 Gy, with concurrent intravenous CT consisting of 25 mg/m² of carboplatin and 10 mg/m² of paclitaxel on each RT day. Daily paclitaxel dose was administered using a 1-hour infusion scheduled to start at least 2 hours before the first daily fraction, thus leaving a 1-hour gap between the end of paclitaxel infusion and the first daily RT fraction. Carboplatin was administered as short (30 minutes) infusion administered 3 to 4 hours after the first daily fraction (ie, 1.5 to 2 hours before the second one). This study was performed at the University Hospital, Kragujevac, Serbia, between January 1996 and October 1998 as a single-institution phase II study. It was performed after approval was obtained from the institutional ethics committee, and informed consent was obtained from all patients.

RT was administered with 6- to 10-MV photons using linear accelerators. The primary tumor was encompassed with a minimum 2-cm margin, as was the entire mediastinum from the suprasternal notch to a level 6 cm below the carina (upper and middle lobe lesions) or to the diaphragm (lower lobe lesions); the ipsilateral hilum was encompassed with a 2-cm margin and the contralateral hilum with a 1-cm margin. The ipsilateral supraclavicular fossa was included in the treatment field only when the primary tumor was located in the upper or middle lobe. The initial target volume was treated with a minimum dose of 49.4 Gy, after which the RT field was reduced but still included all detectable tumors (total dose, 67.6 Gy). Doses were specified at mid-depth at central axis for parallel-opposed fields or at the intersection of central axes for other techniques. The maximum dose of 20.8 Gy was planned for the contralateral lung, 44.2 Gy for the entire heart, 52 Gy for the spinal cord, and 57.2 Gy for the esophagus. Two daily fractions of 1.3 Gy were administered five times per week, with an interfraction interval of 4.5 to 6 hours. An interfraction interval (short [4.5 to 5.0 hours] or long [5.5 to 6.0 hours]) was nonrandomly assigned to each patient and under no circumstances was it allowed to change from the shorter (n = 33) interval to the longer (n = 31) interval or vice versa.

Patients were first examined at the end of Hfx RT, then every month for 6 months after completion of Hfx RT, then every 2 months for 2 years thereafter, and finally every 4 months thereafter. A medical history for the intervening period was obtained, and physical examination, CBC, biochemical tests, and chest radiography were performed at each visit. Symptomatic biopsies were not performed routinely but were recommended if signs of tumor persistence or recurrence were present. Restaging at the time of any progression was performed using computed tomography scans of the thorax, brain, and abdomen; bone scan; abdominal ultrasound images; and radiographs of the bones, whenever necessary, in addition to the previous procedures.

Response criteria included a complete response (CR), defined as the disappearance for at least 4 weeks of all measurable or assessable disease and the absence of new lesions. For measurable disease, partial response (PR) was defined as a 4-week reduction of greater than 50% of the sum of the products of the cross-sectional diameters of all measurable lesions, together with the absence of new lesions. For assessable lesions, PR was defined as a decreased tumor size observed for at least 8 weeks. Stable disease was defined as a reduction of less than 50% or an increase of less than 25% in the sum of the products of the cross-sectional diameters of all measurable lesions and no clear pattern of either regression or progression of disease for at least 8 weeks. Progression of disease was defined as an increase of greater than 25% in the sum of the products of the cross-sectional diameters of measured lesions, together with an increase in assessable disease or the appearance of new lesions.

The radiation-induced effects on normal tissue were assessed as either acute or late phenomena, according to criteria of the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer.³³ Survival and relapse-free survival rates were calculated from the first day of treatment by the Kaplan-Meier method, and the differences were evaluated by the log-rank method. All these statistical analyses were carried out using the computer program SPSS (SPSS Inc, Chicago, IL).

	RESULTS

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Between January 1996 and October 1998, 64 patients were treated with this approach. All patients completed treatment as planned. For all patients, follow-up ranged from 1 to 75 months (median, 25 months). For patients with no evidence of disease, it ranged from 59 to 75 months (median, 65.5 months), whereas two patients were lost to follow-up after 9 and 17 months, both being with no evidence of the disease when last seen. The data for these two patients were used as censored data. All deaths in this study were due to local recurrence or distant metastasis, and no patient died of other causes. Patient characteristics are given in Table 1.

View larger version (9K): [in this window] [in a new window]   Fig 1. Overall survival.

View larger version (11K): [in this window] [in a new window]   Fig 2. Local progression-free survival.

View larger version (10K): [in this window] [in a new window]   Fig 3. Distant metastasis-free survival.

On univariate analysis of potential prognostic factors (Table 2), female patients did significantly better than male patients, whereas age was not found to influence survival. Patients with higher KPS did better than those with lower KPS. Although patients with stage IIIA disease did better than those with stage IIIB disease, the difference was not significant. Finally, patients having squamous cell carcinoma histology did better than patients with any other histologic variant of NSCLC, but the difference was not significant.

View this table: [in this window] [in a new window]   Table 3. Acute High-Grade ( 3) Toxicity

View this table: [in this window] [in a new window]   Table 4. Late High-Grade ( 3) Toxicity

	DISCUSSION

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Several different attempts were made on further optimization of concurrent RT/CT. A recent Southwest Oncology Group (SWOG) phase II study by Albain et al³⁷ used two cycles of cisplatin/etoposide administered concurrently with conventionally fractionated 45 Gy of RT in patients with pathologic stage IIIB NSCLC. In the absence of progressive disease, an additional 16 Gy was administered with two additional cycles of cisplatin/etoposide. The MST was 15 months and 5-year survival was 15%. However, grade 4 neutropenia was observed in 32% of patients, grade 3 to 4 anemia was experienced in 28% of patients, and grade 3 to 4 esophagitis was experienced in 20% of patients. More recently, and quite encouragingly, the SWOG reported a trial in which concurrent RT/cisplatin/etoposide was followed by three cycles of adjuvant high-dose docetaxel.³⁸ Because the median survival in that phase II study was 26 months, this treatment approach has become the basis for ongoing SWOG phase III studies.

With concurrent RT and paclitaxel alone, numerous phase I/II studies identified RT doses of 60 to 65 Gy (standard fractionation) and maximum-tolerated doses (MTD) of paclitaxel of 55 to 70 mg/m² when weekly paclitaxel was given^39,40 or 135 mg/m² when paclitaxel was administered every 2 weeks.⁴¹ With continuous infusion of paclitaxel, the MTD was approximately 100 to 120 mg/m^{2 42,43} during a 7-week period, whereas those studies in which twice-weekly paclitaxel was used set the MTD at 15 to 25 mg/m².^44,45 Data from phase II studies showed that RT and weekly paclitaxel could obtain response rates ranging from 75% to 85%, with a 2-year survival rate of 33%.^46-48 When carboplatin was added to RT/paclitaxel, response rates were 71% to 79%, MST ranged from 14.3 to 20.5 months, and 2-year survival rates ranged from 35% to 40%.^{44,46,47,49-51} Most recently, testing paclitaxel/carboplatin combination and standard-fraction RT (63 Gy) in three schedules, Choy et al⁵² studied pre-RT paclitaxel/carboplatin followed by RT (arm 1), pre-RT paclitaxel/carboplatin and concurrent RT/paclitaxel/carboplatin (arm 2), and concurrent RT/paclitaxel/carboplatin and post-RT paclitaxel/carboplatin (arm 3). Although this phase II randomized study was not designed to statistically compare treatment arms, the best results were achieved in arm 3 (MST, 16.1 months; 2-year survival rate, 33%). Also, in arm 2, there was suboptimal compliance with concurrent RT/paclitaxel/carboplatin after induction paclitaxel/carboplatin. Finally, the first prospective study comparing RT/paclitaxel versus RT alone recently appeared and showed advantage for RT/paclitaxel (MST, 15.2 v 12 months; P = .027).⁵³ It is expected that a number of ongoing or recently completed studies bring new insight into the issue of optimization of RT and CT in this disease.

Results of the current study seem favorable when compared with those of the above-mentioned studies. We have observed a response rate of 83%, and the long-term results were also very encouraging, with the MST of 28 months and 5-year survival rate of 26%. These results were achieved at the expense of acceptable toxicity. In early phase I/II studies on the use of concurrent RT and paclitaxel, alone or with cisplatin or carboplatin, dose-limiting toxicities included esophagitis and neutropenia^{39,41,42,45,48,54} and only occasionally pneumonitis and infection.^40,48,55 More mature data coming from phase II studies on RT and paclitaxel/carboplatin showed almost the same. In these studies, the weekly dose of paclitaxel was 45 to 60 mg/m². Esophagitis was observed in 10% to 46% of patients,^{44,46,47,50,56} whereas hematologic toxicity was experienced in 38% of patients.^{44,46,47,50,51,56} Results of the current study with the weekly paclitaxel dose of 50 mg/m² are in agreement with these, although they seem somewhat lower. Grade 3 esophagitis was observed in 17% of patients, pneumonitis was experienced in 13% of patients, and hematologic toxicity was observed in 25% of patients. Only the study of Zajda et al⁵¹ showed absence of high-grade esophagitis and pneumonitis when 68 Gy were given concurrently with paclitaxel (6 mg daily) and carboplatin (area under the curve of 6, days 1 and 21), possibly because of the low daily dose of paclitaxel used in that study. The majority of these studies also used two to four cycles of adjuvant CT, which may have contributed to the occurrence of toxicity. Furthermore, we did not experience a single case of either hypersensitivity or infection, possibly because of the low daily dose of paclitaxel and lack of administration of corticosteroids (unless dictated by the pneumonitis), which was in sharp contrast with studies of Reckzeh et al⁵⁵ and Vogt et al,⁴⁰ which both experienced these events. It must be clearly stated that these events are almost unseen nowadays.^42-47,49-53 Late toxicity was also infrequent, with high-grade bronchopulmonary toxicity occurring in 5% of patients and esophageal toxicity occurring in 3% of patients. Exclusion of patients with weight loss of 5% from the current study may have been another possible explanation for the somewhat lower toxicity that we observed, achieved using conventional tools. With widespread use of more sophisticated tools, such as three-dimensional treatment planning and conformal therapy,^57,58 it is not unrealistic that better tumor control and/or decrease in toxicity would be achievable. This is the goal for the future studies in this disease, which may also benefit from somewhat higher RT doses, achievable also through the use of somewhat limited RT fields or, perhaps, a slight increase in the paclitaxel and/or carboplatin daily dose, which may not improve only local progression-free survival but also the distant metastasis-free survival as well. This largely favorable patient population, with no patients having weight loss of 5%, more stage IIIA patients, and more squamous cell histology, may be a suitable target for such intensified studies.

It must be clearly stated, however, that these results were achieved with a somewhat lower total dose of paclitaxel, which was 290 mg/m² in the current study. This seems to be at least 10% to 20% less total dose than in the vast majority of studies using paclitaxel concurrently with RT, which range from 330 to 420 mg/m².^{39,40,43,44,54} This lower total dose of paclitaxel, however, did not compromise the overall outcome. A possible explanation for this observation may lie in both the pharmacokinetic and pharmacodynamic properties of paclitaxel when administered in the manner in which we did in this study. As proved in a laboratory environment by Zanelli et al,⁵⁹ the period of at least 18 hours is necessary for measurable radioenhancing effects of paclitaxel. These data predicted that 15 mg/m² of paclitaxel given as a 1-hour infusion 5 days/wk for 3 weeks during RT should achieve both cytotoxicity and radioenhancement. These results implied that low-dose, daily infusions of paclitaxel administered for as long as possible during a course of RT are more likely to result in radioenhancement and prolonged cytotoxicity than high-dose infusions given once a week. That this is an effective yet low toxic approach had already been proven by Dowell et al,⁴³ who used a continuous infusion of paclitaxel and observed no DLT at the level of 17 mg/m² daily dose. In a way, our low-dose daily approach resembles this one, and our results enable clinical support of the pharmacokinetic calculations and implications of Zanelli et al.⁵⁹

In conclusion, the long-term results of the current study, with somewhat unusual design, add new substance to the growing evidence that concurrent RT and low-dose, daily paclitaxel/carboplatin represents an effective approach in patients with stage III NSCLC (MST, 28 months; 5-year survival, 26%) and warrant its verification in a prospective randomized fashion with other approaches currently tested.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Honoraria: Branislav Jeremic, Bristol-Myers Squibb.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted July 6, 2004; accepted November 30, 2004.

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