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Clinical Cancer Research Vol. 9, 1698-1704, May 2003
© 2003 American Association for Cancer Research

Clinical Trials

Induction Docetaxel and Carboplatin Followed by Weekly Docetaxel and Carboplatin with Concurrent Radiotherapy, then Surgery in Stage III Non-Small Cell Lung Cancer

A Phase I Study1

Lori J. Wirth, Joan Lucca, Patricia Ostler, Panos Fidias, Cathy Lynch, Pasi A. Jänne, Roy S. Herbst, Bruce E. Johnson, David J. Sugarbaker, Douglas J. Mathisen, Jeanne M. Lukanich, Noah C. Choi, Stuart M. Berman and Arthur T. Skarin2

Departments of Adult Oncology, Surgery, and Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [L. J. W., J. L., C. L., P. A. J., B. E. J., A. T. S.]; Massachusetts General Hospital, Boston, Massachusetts [P. O., P. F., D. J. M., N. C. C.]; Brigham and Women’s Hospital, Boston, Massachusetts [D. J. S., J. M. L.]; M. D. Anderson Cancer Center, Houston, Texas; and Beth Israel Deaconess Medical Center, Boston, Massachusetts [S. M. B.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: To determine the maximum-tolerated dose of docetaxel (DOC) in combination with carboplatin (CAR) and thoracic radiotherapy (RT), in the setting of trimodality treatment of patients with stage III non-small cell lung cancer (NSCLC).

Experimental Design: Thirty-two patients with biopsy-proven stage IIIA (n = 20) or IIIB (n = 12) NSCLC were given two initial cycles of CAR (area under the curve = 6) and DOC (75 mg/m2), subsequent RT (54 Gy) with concurrent weekly CAR (area under the curve = 2), and DOC at six dose levels from 10 to 40 mg/m2, then surgery if the patient’s disease was resectable.

Results: Three patients did not complete induction computed tomography (CT). Twenty-nine patients received concurrent CT/RT. Fifteen patients were eligible for surgery. Dose-limiting toxicities occurred in 2 patients, at dose levels two (atrial fibrillation) and three (transaminitis). The maximum-tolerated dose, as defined by the protocol, was not reached, although grade 3 and 4 toxicities were encountered at all dose levels. The most common more than or equal to grades 3 toxicities were neutropenia, nausea, vomiting, and fatigue. Four patients (13.3%) responded to induction CT. Ten patients (38.5%) responded to CT/RT. Eight surgical patients (57.1%) were downstaged, including 3 pathologic complete responses. Median relapse free and overall survivals are 8.5 and 12 months. One-year and estimated 2-year survival rates are 56.3 and 34.3%.

Conclusion: This new regimen for stage III NSCLC of induction CAR/DOC, then weekly CAR/DOC with concurrent RT followed by surgery, can be safely administered and offers encouraging results. DOC at 30 mg/m2 in combination with CAR and RT is recommended for Phase II study.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lung cancer is a major health problem in the United States, causing more cancer deaths annually than any other malignancy. NSCLC3 will account for ~75% of the 169,400 lung cancer cases expected in 2002, and roughly one-quarter of these will present with locally advanced stage IIIA or IIIB disease (1) .4 Although 5–15% of patients with locally advanced NSCLC can achieve long-term survival with treatment, local relapse and distant metastasis remain problematic (2, 3, 4, 5) . Improving treatment strategies in this group of patients is essential.

Combined modality therapy has become the standard approach to stage III NSCLC. A series of RCTs has established a clear benefit for the addition of CT to RT in this patient population. The first was a Cancer and Leukemia Group B trial randomizing patients with stage III disease to thoracic RT alone versus cisplatin plus vinblastine, then RT. Combined modality therapy increased median survival by 4 months and 5-year survival from 6 to 17% (6 , 7) . Three subsequent RCTs confirmed the survival benefit of CT, given either concurrently or sequentially, with RT in the treatment of locally advanced NSCLC, and evidence from other Phase III studies supports the use concurrent CT/RT over a sequential approach (8, 9, 10, 11, 12) .

Added benefit from neoadjuvant therapy before surgical resection of NSCLC has also been demonstrated. Two small, but influential RCTs of CT before surgery versus surgery alone in stage IIIA NSCLC showed significant improvement in survival with neoadjuvant therapy (13, 14, 15) . Surgery in combination with CT/RT has also been studied. In early trials from our institutions, neoadjuvant CT before surgery, then RT, was feasible in stage IIIA NSCLC and resulted in survival rates <=30% at 5 years (16, 17, 18) . Additional promising results were shown in a later study of preoperative twice daily radiation and concurrent chemotherapy in stage IIIA NSCLC, with significant tumor downstaging by CT/RT and a 5-year survival of 37% (19) . Studies from other groups have shown similar results, e.g., a Southwest Oncology Group trial of neoadjuvant cisplatin and etoposide with concurrent RT, then surgery in 126 stage IIIA and IIIB NSCLC patients demonstrated a 26% 3-year survival rate and 10% treatment-related mortality (20) . More recently, Thomas et al. studied induction chemotherapy with ifosfamide, CAR, and etoposide, followed by concurrent hyperfractionated RT plus weekly CAR and vindesine, then surgery in stage III NSCLC. Median survival was 20 months, with a 3-year survival of 30%. Therapy-related mortality was 9%, and surgery-specific mortality was 7.5%, indicating that surgery after CT/RT is safe (21) . The added benefit of surgery after CT/RT is, however, unproven by randomized data. Results from a Phase III Intergroup trial comparing trimodality therapy to CT/RT alone in this patient population are awaited.

Despite recent advances, survival in locally advanced NSCLC remains poor, and most patients will die of their disease. Currently, combined modality treatment of locally advanced NSCLC often involves RT plus CAR and paclitaxel. Phase I and II studies of these agents in varying doses and schedules have demonstrated response rates from 52 to 79% and median survival times from 14 to 26 months (22, 23, 24, 25, 26, 27) . One strategy for improving outcomes is to investigate newer chemotherapeutics in multimodality regimens. DOC offers several potential advantages, as suggested by preclinical studies. First, this taxane inhibits microtubule depolymerization and causes cell cycle arrest in the radiosensitive G2-M phase. Compared with molar equivalents of paclitaxel, DOC is associated with a higher percentage and more prolonged duration of G2-M arrest in human cancer cell lines (28) . DOC acts as a potent radiosensitizer, enhancing tumor response >2-fold, with the best gains achieved with intermittent multiple doses of DOC during a course of fractionated RT (29 , 30) . Furthermore, DOC aborts mitosis and causes cell death during S phase, thereby exerting its cytotoxic effect at more than one point in the cell cycle (31) . Thus, one rationale for this study is to investigate this taxane given concurrently with RT.

Clinical trials of DOC in NSCLC have shown consistent single agent activity, with response rates ranging from 19 to 63% (32, 33, 34, 35, 36, 37) . DOC has become a standard second-line therapy in advanced NSCLC on the basis of two RCTs showing improved survival and quality of life compared with best supportive care and vinorelbine or ifosfamide (38 , 39) . Moreover, two recent Phase III studies have shown that DOC in combination with CAR or cisplatin is at least as effective as other first-line regimens for stage IIIB and IV NSCLC (40 , 41) . Phase I and II studies of DOC plus RT in NSCLC have shown good overall response rates, from 35 to 80%, with CR rates ranging from 22 to 34% (42, 43, 44, 45, 46) . Even higher response rates, from 58 to 100%, have been seen in trials of DOC in combination with CAR or cisplatin and concurrent RT (47, 48, 49, 50) . One such study of weekly DOC plus CAR (AUC = 2) for 6 weeks with concurrent RT to 64 Gy in inoperable stage III NSCLC reported that the MTD of DOC was 20 mg/m2, with a primary DLT of esophagitis. In 26 evaluable patients, there were two CRs, and 13 PRs, with an overall response of 58% (50) .

Given the evidence that aggressive multimodality treatment can improve survival in stage III NSCLC, we undertook this Phase I study of induction CT with two cycles of standard dose CAR/DOC followed by 6 weekly escalating doses of DOC plus fixed doses of CAR with concurrent RT in patients with stage IIIA or IIIB NSCLC. Patients without progressive or unresectable disease at the completion of CT/RT proceeded to surgical resection. The MTD of DOC in this concurrent regimen was determined, and the safety profile of the regimen was described.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection.
Patients with histologically documented stage IIIA or IIIB NSCLC after mediastinoscopy, without previous CT or RT, were eligible to participate in this study. Measurable disease, assessable by radiograph, computed tomography, or magnetic resonance imaging, was encouraged, although not required. Other eligibility criteria included: (a) age >= 18 years; (b) ECOG PS <= 2 in patients <= 65 years and <=1 in patients > 65 years; (c) negative head computed tomography and bone scan; (d) adequate end organ function as defined by total WBC >= 3,000/µl; (e) hemoglobin >= 10 grams/dl; (f) platelets >= 100,000/µl; (g) total bilirubin <= IULN; (h) calculated creatinine clearance >= 30 ml/min; (i) serum transaminases <= 2.5 times IULN if alkaline phosphatase <= IULN; (j) serum transaminases <= IULN if alkaline phosphatase > IULN and <=4 times IULN, or if both transaminases and alkaline phosphatase were elevated; (k) transaminases <= 1.5 times IULN; and (l) alkaline phosphatase <= 2.5 times IULN. Women were required to have childbearing potential terminated previously by surgery or menopause or attenuated by the use of an approved contraceptive method. Patients were excluded from the study if they had documented distant metastases; malignant pleural effusion; preexisting cardiac, pulmonary, neurological, or other diseases that the investigator judged to be clinically significant; active infectious processes; severe malnutrition or intractable emesis; previous or concurrent malignancy except inactive nonmelanoma skin cancer, in situ carcinoma of the cervix, or other cancer if the patient has been disease free for >5 years if not treated previously with radiation or chemotherapy; or known allergy to polysorbate 80. Pregnant and/or lactating women were also excluded from participation.

Study Design.
This was an open-label, single-center, nonrandomized Phase I dose escalation study of DOC given with CAR plus RT, after two cycles of induction CT with DOC (75 mg/m2) plus CAR (AUC of 6 per the Calvert formula; Ref. 51 ) on days 0 and 21. The study was designed by investigators alone and sponsored by Aventis Oncology (Bridgewater, NJ). Ciprofloxacin (500 mg twice daily, days 5–15 after induction CT) was given for prophylaxis of febrile neutropenia. Dexamethasone (8 mg q12 h days -1, 0, and 1 with induction CT and 8 mg q12 h for three doses starting the night before weekly CT) plus diphenhydramine (25–50 mg i.v. before each dose of DOC) were prescribed for allergic prophylaxis. Response to induction CT was assessed by computed tomography. Patients with PD were taken off study and referred for appropriate therapy. All others went on to concomitant CT/RT for 6 weeks. Thoracic RT was administered in 1.8 Gy fractions, 5 days/week for 22–25 fractions, to a total dose of 39.6–45 Gy to the clinical target volume, defined as the gross tumor volume plus tissue with a high likelihood of harboring microscopic disease. A 9–14.4 Gy radiation boost to the gross tumor volume was then delivered in 5–8 fractions for a total dose of 54 Gy. At the completion of CT/RT, patients were assessed for response by computed tomography. Those with the equivalent of stage IIIA NSCLC or less, as per the International Staging System for Lung Cancer, were referred for standard surgical resection with mediastinal lymph node dissection. Preoperative criteria and the time from completion of CT/RT to surgery were at the discretion of the surgeon. If the patient did not undergo resection, an additional external beam boost RT of 9–12.6 Gy off protocol was recommended. Intraoperative electron beam therapy or interstitial boost was allowed at the discretion of investigators if there were positive margins at the time of surgery. A competing trial of concurrent chemotherapy and hybrid schedule of once and twice daily RT was available to patients with stage IIIA NSCLC at one of two Dana-Farber/Partners CancerCare sites during the period of this study. Informed consent was signed by all patients in accordance with NIH guidelines, and the study was approved by the Office for the Protection of Human Research Subjects of Dana-Farber/Partners CancerCare.

Dose Escalation and Definition of Study End Points.
During RT, all patients received six concomitant weekly doses of CAR (AUC = 2) and escalating doses of DOC. Enrollment of >=3 new patients at each dose level of 10, 20, 25, 30, 35, and 40 mg/m2 was planned until the MTD was established. There was no dose escalation in individual patients. The MTD of DOC was defined as one dose level below that which induces DLT in >=2 of 6 patients. DLT was defined as the occurrence of any one of the following: (a) any grade 4 nonhematologic toxicity except esophagitis and neurotoxicity; (b) any grade 4 hematological toxicity, except neutropenia or thrombocytopenia; (c) absolute neutrophil count < 500/µl for >7 days, platelet count < 20,000 for >7 days, or febrile neutropenia (defined as grade 4 neutropenia, leukopenia associated with p.o. temperature > 38.5°C, or three readings of p.o. temperature > 38°C in a 24-h period); (d) more than or equal to grade 3 neurosensory or motor neurotoxicity; (e) grade 4 mucositis or esophagitis skin toxicity resulting in a treatment break from RT of 14 days in aggregate; or (f) any drug-related toxicity that leads to holding CT for >=2 weeks during RT. Toxicities were graded according to the National Cancer Institute’s Common Toxicity Criteria. Patients were considered evaluable for MTD if they received >=75% of the total concurrent CT dose, and >=75% of the RT dose is delivered. Patients not meeting these requirements were replaced.

Pretreatment and Follow-up Studies.
Before starting therapy, all patients had a history and physical examination, assessment of ECOG PS, chest radiograph, electrocardiogram, determination of tumor measurements, urinalysis, and routine laboratory studies that included a complete blood count with differential, electrolytes, urea, creatinine, lactate dehydrogenase, alkaline phosphatase, total and direct bilirubin, and alanine aminotransferase and aspartate aminotransferase levels. Staging studies included head computed tomography with contrast or brain magnetic resonance imaging with gadolinium, chest and upper abdomen computed tomography with contrast, and bone scan. History, physical examination, and laboratory tests were repeated on day 1 of each cycle of both induction and weekly CT. Tumor assessments were performed after the two cycles of induction CT and on completion of CT/RT. CR was defined as the disappearance of all clinically detectable malignant disease for >=4 weeks. PR was defined by >=50% decrease in bidimensional tumor area or >=30% decrease in unidimensional linear tumor measurement for >=4 weeks without increase in size of any area of known malignant disease of >25% or appearance of new areas of malignant disease. SD was defined by no significant change in measurable disease for >=8 weeks, with no increase in any known malignant disease, and no appearance of new sites of malignant disease, including decrease in malignant disease of <50% of bidimensional tumor area or <30% of unidimensional tumor, increase in malignant disease of <25% in any site, and no deterioration in ECOG PS related to malignant disease. Tumor stage at resection was also assessed for those patients who underwent surgery. RFS and OS were measured from the 1st day of treatment until documentation of disease progression for the former and date of death or loss to follow-up for the latter.

Statistical Considerations.
Descriptive statistics were used to characterize study subjects and response to treatment. The Kaplan-Meier method was used to estimate survival probabilities (52) .


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients.
Thirty-two patients entered the study and started treatment. Three patients were enrolled at dose level 1 (10 mg/m2 DOC), 7 at level 2 (20 mg/m2), 10 at level 3 (25 mg/m2), 7 at level 4 (30 mg/m2), 3 at level 5 (35 mg/m2), and 2 at level 6 (40 mg/m2). Two patients were taken off study on day 1 of induction CT for grade 4 allergic reaction to DOC. Two patients had PD by completion of induction chemotherapy. Twenty-eight patients completed induction therapy and began concurrent CT/RT. Of these, 1 patient refused cycle 6 of concurrent CT but did complete RT, 2 patients experienced a DLT requiring them to be taken off study, and 2 patients were taken off study for PD. All patients were evaluable for toxicity, whereas 24 patients were evaluable for MTD. Thirty patients were evaluable for response to induction CT (2 patients removed for DOC allergy were not evaluated for response). Twenty-six patients were evaluable for response to concurrent CT/RT (1 patient was removed for DOC allergy, 2 patients with PD to induction therapy were not evaluable, and 1 patient with a DLT occurring with cycle 1 of concurrent CT/RT was not included in response analysis). All patients were included in the survival analysis. The demographic characteristics of those enrolled are listed in Table 1Citation . Twenty patients had IIIA disease; 12 had IIIB. There were 19 women and 13 men, and all patients had an ECOG PS <= 1.


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  		Table 1 Patient characteristics

 
Toxicities.
The most common toxicities more than or equal to grade 3, listed in Table 2Citation , were neutropenia, thrombocytopenia, nausea, vomiting, dysphagia (which, by definition, includes esophagitis), allergic reaction, fatigue, and hyperglycemia. The hyperglycemic events were attributed to corticosteroids given as DOC premedication and did not lead to additional complications. All but one neutropenic event more than or equal to grade 3 occurred during induction CT, whereas all dysphagia events more than or equal to grade 3 occurred in the latter weeks of concurrent CT/RT. There was no mucositis or dysphagia requiring a RT treatment break. One patient was treated for grade 3 febrile neutropenia during induction CT. Other toxicities more than or equal to grade 3, occurring two or fewer times, were thrombosis, infection without neutropenia, ataxia, mood changes, pain, amenorrhea, diarrhea, dehydration, and chronic-obstructive pulmonary disease exacerbation. One patient at dose level 2 experienced atrial fibrillation as a DLT in the setting of grade 4 dehydration, mucositis, and dysphagia. At dose level 3, 1 patient had a DLT of grade 4 transaminitis. Two patients died of PD within 1 month of being taken off study, and 1 patient died of unknown cause within 1 month of completing study therapy and with PD on restaging studies. One patient, who had a CR at completion of CT/RT, was diagnosed with small cell lung carcinoma at 31 months from enrollment and died of this disease at 37 months. Review of both tumor specimens confirmed that the second tumor was histologically distinct from the first.


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  		Table 2 Toxicities

 
The MTD was not reached by 40 mg/m2 DOC. However, other Phase I studies of weekly DOC +/- CAR with RT (50–60 Gy) that were completed while this study was underway generally recommended DOC at 20–30 mg/m2 because of esophagitis and neutropenia DLTs (43 , 44 , 47 , 50) . Given the existing data, dose escalations beyond 40 mg/m2 were ceased. After approval from the Office for the Protection of Human Research Subjects, we enrolled 3 additional patients at 30 mg/m2 to complete a total of 10 patients evaluable for MTD at the recommended dose level or higher, to gain adequate experience with this regimen.

Response and Survival.
Although assessment of tumor response and survival was not a primary objective of this study, prespecified response and survival analyses were performed. Of 30 patients evaluable on completion of induction CT, there were 4 PR, and 24 SD, with an ORR to induction CT of 13.3%. There were 26 patients evaluated for response to concurrent CT/RT. Of these, there were 2 CR (8%), 8 PR (30.8%), and 8 SD (30.8%), with an ORR of 38.8%. Eighteen patients (69.3%) had SD or better. Fifteen patients were eligible for surgery, but 1 of these refused. Of the surgical candidates, 12 originally had stage IIIA NSCLC, and 3 were downstaged by the study treatment from stage IIIB to less than or equal to stage IIIA disease. The time between completion of CT/RT and surgery ranged from 16 to 61 days, with a median of 35 days. Of the 14 who went to surgery, 1 patient, originally with stage IIIA disease, was unresectable. After concurrent CT/RT, 1 patient had a question of PD on restaging studies but still underwent surgery. Three pneumonectomies, 9 lobectomies, and 1 double segmentectomy were performed, all with radical mediastinal lymph node dissections. One patient had brachytherapy at surgery for positive margins. Eight of the 14 surgical patients (57.1%) were downstaged on pathologic inspection of the specimen. Seven of these were node negative, 3 of which (2 originally with IIIA and 1 IIIB disease) had pathologic CRs (Table 3)Citation . These CRs occurred at dose levels 2, 3, and 5. There were no perioperative deaths.


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  		Table 3 Results of surgerya

 
The median RFS was 9 months, with a range of 1–56 months, and the median OS was 12 months, with a range of 2–56 months (Fig. 1)Citation . The 1-year survival rate was 56.3%, and estimated 2-year survival was 34.3%. The median length of follow-up was 12 months. In patients presenting with stage IIIA disease, the median RFS and OS were 10 and 15 months, respectively. The 1-year and estimated 2-year survival rates were 65% and 48.6%. The patients with stage IIIB disease had a median RFS and OS of 8 and 9 months. Their 1-year and estimated 2-year survival rates were 41.7 and 8.9%. The median RFS for the 14 surgical patients was 14.5 months, with a median OS of 20.5 months.



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  		Fig. 1. Kaplan-Meier curves for RFS and OS.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This regimen of induction CAR/DOC, followed by RT with weekly concurrent CAR/DOC, then resection in appropriate surgical candidates was well tolerated. In fact, the MTD of DOC given concurrently with CAR and RT was not reached, despite dose levels that exceeded recommended doses derived from other Phase I studies (44 , 45 , 50) . Although 7 patients experienced dysphagia more than or equal to grade 3, no patients required a treatment break, and the criteria for DLT were not met. Additionally of note, episodes of more than or equal to grade 3 dysphagia were more frequent at early dose levels, rather than later dose levels of DOC. Only one neutropenic event more than or equal to grade 3 occurred during concurrent therapy, and other common toxicities, such as nausea, pulmonary toxicity, and dermatitis, were neither problematic nor dose limiting. Two patients were taken off study for grade 4 allergic reactions to DOC during cycle 1 of induction CT, but these were not considered DLTs, as per protocol design. Serious toxicities encountered in Phase I and II studies of combined modality therapy for locally advanced NSCLC with CAR and paclitaxel plus standard RT have included neutropenia, esophagitis, and pulmonary toxicity. In these trials, the range of neutropenia more than or equal to grade 3 was 0–15%, more than or equal to grade 3 esophagitis was 8–46%, and more than or equal to grade 3 pulmonary toxicity was 0–22%. Overall, this regimen demonstrated an acceptable toxicity profile in this patient population, although the degree of acute toxicity may have been minimized by patient selection bias and an efficient learning curve in the effective management of toxicities inherent in a single institution study such as this (53) . In addition, the absence of perioperative deaths and encouraging survival rates in the surgical patients indicate that surgery is feasible in this setting.

Although the response to induction CT of 13.3% was low, only 2 of 30 patients had PD to induction CT. The administration of full-dose CT, whether given as induction therapy or after concurrent CT/RT, is thought to be integral to the multimodality treatment of locally advanced NSCLC, because it addresses the likelihood that many of these patients harbor micrometastatic disease and the fact that the majority of relapses occur outside the radiated field (2 , 4 , 5) . The ORR of 38.5% at completion of concurrent CT/RT demonstrated reasonable antitumor activity of this multimodality regimen. More than half the patients who proceeded to surgery were successfully downstaged by this neoadjuvant treatment, including 3 patients with pathologic CRs and 7 who became node negative. Downstaging to node-negative status is of particular interest, as previous data have shown that the absence of tumor in mediastinal lymph nodes after thoracotomy is a strong predictor of survival (20) .

The survival rates (1-year survival = 56.3% for the entire cohort, 65% for stage IIIA, and 41.7% for stage IIIB patients) in this Phase I study compare well to those of large series published previously (1-year survival for stage IIIA 50% and IIIB 34%; Ref. 3 ). The survival is also comparable with that of similar Phase I studies of concurrent RT plus DOC, as a single agent or in combination with cisplatin, in locally advanced NSCLC, in which 1-year survival ranged from 60 to 74% (38 , 48 , 49 , 54) . Still, as seen in these earlier trials, our patients with stage IIIB NSCLC had relatively poor outcomes. This trimodality regimen alone may not offer a clear benefit to these patients.

The acceptable toxicity profile of this regimen and encouraging response to treatment, particularly in stage IIIA patients, must be interpreted cautiously in this Phase I single institution study. Nonetheless, this regimen of induction CAR/DOC, concurrent CAR/DOC with RT, and surgical resection in appropriate candidates with locally advanced NSCLC warrants further investigation. Evaluation in a Phase II study is recommended, using a weekly dose of 30 mg/m2 DOC in combination with CAR at an AUC of 2 and concurrent thoracic RT for stage III NSCLC.


   ACKNOWLEDGMENTS
 
We thank Dr. Lorraine Walker of Aventis Oncology for her assistance in preparation and careful review of this manuscript. We also thank Dr. Kao-Tai Tsai of Aventis Oncology for his assistance with the statistical analysis.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by Aventis Oncology, Bridgewater, NJ. Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001. Back

2 To whom requests for reprints should be addressed, at Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. E-mail: askarin{at}partners.org Back

3 The abbreviations used are: NSCLC, non-small cell lung cancer; RCT, randomized controlled trial; RT, radiotherapy; PD, progressive disease; CT, chemotherapy; DOC, docetaxel; ECOG, Eastern Cooperative Oncology Group; AUC, area under the curve; MTD, maximum-tolerated dose; IULN, institutional upper limit of normal; PS, performance status; DLT, dose-limiting toxicity; CAR, carboplatin; CR, complete response; RFS, relapse-free survival; SD, stable disease; PR, partial response; OS, overall survival; ORR, overall response rate. Back

4 Internet address: http://seer.cancer.gov. Back

Received 7/ 1/02; revised 10/ 3/02; accepted 10/28/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Correspondence re L. J. Wirth et al., Induction Docetaxel and Carboplatin Followed by Weekly Docetaxel and Carboplatin with Concurrent Radiotherapy, Then Surgery in Stage III Non-Small Cell Lung Cancer: a Phase I Study. Clin Cancer Res 2003;9:1698-704.
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