| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 1995;60:586-591
© 1995 The Society of Thoracic Surgeons
Departments of Thoracic and Cardiovascular Surgery, Hematology and Medical Oncology, and Radiation Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio
 |
Abstract |
|---|
 TopFootnotes Abstract IntroductionPatients and MethodsResultsCommentReferences |
|---|
Methods. Forty-two surgically staged patients with poor prognosis stage III non–small cell lung cancer received 11 days of induction treatment consisting of 96 hours of continuous chemotherapy infusions of cisplatin (20 mg • m-2 • day-2), 5 fluorouracil (1,000 mg • m-2 • day-2), and etoposide (75 mg • m-2 • day-2) concurrent with accelerated fractionation radiation therapy (1.5 Gy twice a day, to a dose of 27 Gy). Induction was followed in 4 weeks by resection. Postoperatively, a second course of continuous chemotherapy and concurrent accelerated fractionation radiation therapy (postoperative dose 13 to 36 Gy) was given.
Results. Despite some degree of induction toxicity in all patients there was only one induction death (2.4%). A clinical partial response was seen in 24 patients (57%). Thirty-six patients (86%) underwent thoracotomy, and resection was possible in 33 (79%). Pathologic downstaging was seen in 17 patients (40%), and 2 patients (5%) had no residual carcinoma at operation. There were 11 postoperative complications (31%) and 4 postoperative deaths (11%). Thirteen patients (31%) are alive and disease-free, 24 (57%) have persistent disease or have recurred (15 distant, 5 locoregional, 4 both), and 9 patients are alive with disease. The median survival is 21 months and the 2-year Kaplan-Meier survival is 43%, with no differences identified between stages IIIA and IIIB patients (p= 0.63).
Conclusions. We conclude that accelerated induction therapy and resection in poor prognosis stage III non–small cell lung cancer (1) is toxic, with a 12% treatment mortality; (2) is effective with a 79% resection rate and 40% pathologic downstaging rate; (3) provides excellent local control; (4) may prolong survival; and (5) is of value in stage IIIB as well as stage IIIA patients.
|
Introduction |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
|---|
Stage III non–small cell lung carcinoma is a heterogeneous group of locally advanced malignancies. Although T3 N0 M0 disease has a 30% to 50% 5-year survival after resection, survival for the other subgroups of stage III is dismal, with less than 10% of unselected patients surviving 5 years after single modality therapy. These data have prompted extensive phase II exploration of neoadjuvant treatment schedules using combinations of chemotherapy and resection; or chemotherapy, radiotherapy, and resection. Recently, two small phase III trials have demonstrated a significant survival advantage for stage IIIA patients (including T3 N0 M0) receiving induction chemotherapy followed by resection compared to patients undergoing resection alone [1, 2]. However, most neoadjuvant protocols require 2 to 3 months to complete induction. This treatment prolongation is costly and is of both physiologic and psychologic concern. Patient compliance is difficult to maintain and delay in definitive therapy has unknown effects on the biology of non–small cell lung carcinoma.
A neoadjuvant treatment schedule of radiosensitizing chemotherapy and concomitant radiation therapy, which is then followed by resection, is a theoretically attractive, but a clinically unproven approach. It allows the use of multiple treatment modalities in an attempt to maximize both locoregional and distant control. The specifics of concomitant chemotherapy and radiation therapy administration are of considerable importance and the optimum treatment schedule has not yet been established.
Accelerated fractionation, the administration of two (or more) radiation treatments (fractions) daily, with a combined daily dose greater than conventionally delivered with one daily treatment, has sound theoretical advantages. Presumably, the multiple daily radiation fractions reduce the opportunity for tumor cells to recover from sublethal radiation injury, while conferring a selective survival advantage on normal tissue [3, 4]. Accelerated fractionation allows a larger portion of the radiation therapy to be administered with radiosensitizing chemotherapy. In addition the total treatment time is shortened. When accelerated fractionation radiation therapy is used in conjunction with radiosensitizing chemotherapy and resection, the potential for significant improvement in local control exists.
The purpose of this study was to assess toxicity, response, and survival in patients with poor prognosis stage III non–small cell lung carcinoma who received aggressive, accelerated, concurrent induction chemotherapy and accelerated fractionation radiation therapy followed by resection.
|
Patients and Methods |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
|---|
Medical suitability for pulmonary resection and an initial Eastern Cooperative Oncology Group performance status 0 or 1 were required. Patients could not be entered on study if any previous treatment for this malignancy had been given or if there was any evidence of significant preexisting renal, hepatic, hematologic, or metabolic dysfunction. Existence of an uncontrolled second primary malignancy was cause for exclusion from this trial. This study was approved by the Institutional Review Board of the Cleveland Clinic Foundation (RPC 3383, initial approval 6/13/90) and was reviewed on an annual basis. Written informed consent was required and was obtained from all patients before the commencement of therapy.
Treatment, as detailed in Figure 1
, consisted of a single course of preoperative chemotherapy with continuous intravenous infusions of cisplatin (20 mg • m-2 • day-1), 5-fluorouracil (1,000 mg • m-2 • day-1), and etoposide (75 mg • m-2 • day-1), all given for 4 days coincident with the institution of radiation therapy. Chemotherapy required hospitalization and placement of two peripheral intravenous lines or a double-lumen central venous line. Cisplatin and etoposide were mixed and infused together, whereas 5-fluorouracil was infused by itself through the second intravenous access site. Careful attention was paid to intravenous site care to avoid 5-fluorouracil-induced phlebitis. At least 4 L of intravenous fluid were infused daily and intensive ondansetron-based antiemetic therapy was administered.
|
After induction therapy, patients were followed up closely for the detection and management of any toxicity. Clinical restaging was performed approximately 2 to 4 weeks after completion of induction therapy and consisted of a second computerized tomographic chest scan and a second set of pulmonary function studies. Conventional response definitions were used for this computed tomographic scan-based clinical response. A complete response was defined as the complete disappearance of all radiographic and clinical evidence of disease. A partial response was defined as any response less than complete, but with greater than 50% reduction in the sum of the products of the crossed diameters of all measurable lesions. Patients with less tumor shrinkage were considered nonresponders. Progressive disease was defined as greater than a 25% increase in the sum of the products of the crossed diameters of all measurable lesions or the appearance of new locoregional or metastatic disease. Progressive disease at any time mandated removal of the patient from the study, and the demonstration of metastatic disease at any time was scored as disease progression, irrespective of any locoregional improvement. All patients with a clinical response or stable disease proceeded to thoracotomy.
A second mediastinoscopy was not performed routinely and resection was attempted regardless of the presence or absence of mediastinal lymph node involvement at clinical restaging. A posterolateral muscle sparing thoracotomy was used for all except 1 patient, who underwent median sternotomy and anterior thoracotomy. Lobectomy was the preferred resection; however, if primary tumor invasion or regional lymph node metastases required, a bilobectomy or pneumonectomy was done. Resection and reconstruction of the chest wall, diaphragm, or superior vena cava were also performed if necessary. An extensive mediastinal lymphadenectomy was accomplished with all pulmonary resections.
Demonstration of a pathologic response after resection required pathologic downstaging. A reduction of either T or N stage from the pretreatment surgical stage was considered a partial response. Complete disappearance of all tumor at operation qualified as a complete response. Reduction in T or N with reciprocal progression in N or T at the same time did not constitute a response.
After recovery from resection, patients were referred for a second postoperative course of chemoradiation therapy. Chemotherapy was identical to the pretreatment regimen and was given concurrent with postoperative accelerated fractionation radiation. A radiation therapy dose of 27 to 33 Gy was planned but, in selected cases, was not completely administered either because of the size or because of the location of the treatment portals. A minimum postoperative dose of 15 Gy was given to all but one of the treated patients.
After the completion of all treatment, patients were followed closely, with clinical reevaluations at least every 3 months. Radiographic and endoscopic procedures were repeated as indicated. Recurrences were classified as locoregional (within the ipsilateral thorax), distant (outside the ipsilateral thorax), or both. Survival curves were constructed using the Kaplan-Meier method, and compared using the log rank test. Survival times were calculated from the date chemoradiotherapy was initiated and the results were analyzed as of November 30, 1994.
|
Results |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
|---|
All patients were previously untreated for their malignancy. Their clinical characteristics and staging are detailed in Table 1. Surgical staging was accomplished by cervical mediastinoscopy in 39 patients, supraclavicular node biopsy in 2 patients, and at exploratory thoracotomy in 1 patient. Three patients had Pancoast tumors staged as T4 N0 M0. All other patients had at least N2 nodal involvement. Two of the N3 patients had contralateral supraclavicular node disease. No patient with T3 N0 M0 disease or single station, intranodal, microscopic N2 disease were entered on this trial. No patient had metastatic disease.
|
After induction chemoradiotherapy and before resection, a clinical response determination was made based on the second computerized tomographic chest scan. At this time, 24 of the 42 patients (57%) were thought to have achieved a partial response. No complete responses were seen.
Nine of the 42 patients had tumors that proved unresectable; 6 because of extensive locoregional disease (3 after an exploratory thoracotomy, 1 after supraclavicular node biopsy, 1 after an anterior mediastinoscopy, and 1 by clinical criteria) and 1 patient because of a deteriorating medical condition resulting from multiple pulmonary emboli. These 7 patients all received a second course of chemoradiotherapy. One nonsurgical patient had development of bone metastases before operation and was taken off the study, receiving no further treatment, and 1 patient died during induction chemoradiotherapy.
Thirty-six (84%) patients underwent thoracotomy and surgical resection was possible in 33 (79%). Pneumonectomy was required in 16 patients, lobectomy in 12, bilobectomy in 4, and a wedge resection was performed in 1 patient (Table 2). Nine resections (27%) were complex and two required cardiopulmonary bypass (Table 3). Eleven patients (31%) experienced significant postoperative complications and are listed as follows: left vocal cord paralysis, 2 patients; atelectasis requiring bronchoscopy, 2; pulmonary embolus, 1; urinary retention, 1; pericarditis, 1; stroke, 1; common femoral artery thrombosis, 1; empyema, 1; and persistent air leak, 1 patient. Four patients died in the perioperative period from respiratory failure secondary to postoperative pneumonia or adult respiratory distress syndrome. Two of these deaths occurred among the 9 patients who underwent right pneumonectomy. At the time of operation a pathologic response was found in 17 of the 42 patients (40%). No pathologic evidence of residual disease was found in 2 (5%) of these patients.
|
|
Thirteen patients (31%) are currently alive and disease-free. There have been 29 treatment failures, including the 5 patients dying during treatment, and 24 patients with disease progression or recurrence. Fifteen of these 24 patients have subsequently died; 9 patients remain alive with disease. Disease recurrence patterns are detailed in Table 4. Locoregional control was possible in 28 of the 42 patients (67%). Among the 17 patients experiencing a pathologic partial response to chemoradiotherapy, there was no difference in the pattern of disease recurrence. Indeed, locoregional recurrence developed in one of the two pathologic complete responders.
|
), with a median overall survival of 21 months (Table 5). Median survival for the 23 stage IIIA patients was 27 months and was not statistically different than the 15-month median survival in the 19 stage IIIB patients (p = 0.63) (Fig 3). Marginally significant survival advantages were seen in those patients experiencing a pathologic response to induction treatment, and in patients found to have T0–3 N0 disease at operation (p = 0.08). Inoperable patients had a median survival of 14 months.
|
|
|
|
Comment |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
|---|
Recent efforts using multimodality therapy for patients with stage III non-small cell lung carcinoma have focused on the sequential or concurrent addition of chemotherapy to this definitive radiation therapy. A modest survival prolongation has been reported in several randomized trials, although many of these studies have included good prognosis (T3 N0 M0) patients [6–11]. Indeed, recent trials have excluded poor prognosis patients (based on weight loss and performance status) in an effort to identify these stage III individuals most likely to benefit from multimodality treatment approaches. Despite this patient selection, even the best of the randomized trials report median survivals in the multimodality treated patients of only 14 months, with a statistically significant, but perhaps clinically unimportant improvement in survival over the control population treated with radiation only. Furthermore, despite these more aggressive approaches, locoregional control was dismal with up to 90% of patients failing in the chest [7, 12].
This high incidence of locoregional failure despite aggressive nonsurgical therapy is frustrating, as many patients have no gross evidence of distant disease at diagnosis. The addition of operation would seem to be a logical next step in an effort to improve local control and perhaps survival. Two recent phase III trials of induction chemotherapy followed by resection in stage IIIA non-small cell lung carcinoma have reported an improved survival in the combined modality group, and a relatively low likelihood of locoregional recurrence, suggesting that surgical resection has a role in the management of stage III non–small cell lung carcinoma [1, 2].
Building on this approach, and in an attempt to further improve local control rates we chose to add concurrent radiation therapy to induction chemotherapy. Surgical resection was subsequently planned for all individuals. In our protocol, an accelerated fractionation scheme of 1.5 Gy twice daily to a preoperative dose of 27 Gy was used. Using the linear quadratic model, this gives a biologically equivalent dose for late responding tissues of 40.5 Gy and a tumor/acute tissue biologically equivalent dose of 31 Gy. The theoretical advantage of delivering more than one fraction of radiation daily is that a higher daily dose can be given than with conventional fractionation while still allowing for repair of sublethal damage of normal tissues. Furthermore, total treatment duration is shortened and the total radiation dose that can be given concurrent with chemotherapy is increased. Thus, it was hoped that we could shorten overall treatment duration, minimize any delay in definitive surgical treatment, avoid protracted and repeated toxicities, maximize the potential for locoregional control, increase overall patient compliance, and improve survival.
We chose to include only those patients with anatomically poor prognosis stage III carcinomas, given the acceptable surgical results seen after resection of the good prognosis T3 N0 M0 and microscopic single nodal station N2 neoplasms. The recent demonstration by the Southwest Oncology Group that concurrent induction chemoradiotherapy followed by operation is feasible and capable of producing acceptable survival in patients with stage IIIB carcinomas led us to include these patients in this study [13, 14]. Our patient cohort included 10 patients with T4 disease and 10 patients with N3 disease, including individuals with supraclavicular nodal involvement. This extensive locoregional disease was mirrored by the complexity of the surgical resection. Not unexpectedly significant but manageable postoperative complications resulted. The perioperative mortality also reflected the complexity of the operation undertaken. In part, because of the success of induction treatment, and in part because of a commitment to surgical therapy, 79% of the patient population ultimately proved resectable.
The overall treatment success is encouraging. Median survival for those with stage IIIA disease was 27 months with a 2-year projected survival of 54%. The group of patients with pathologic T0–3 N0 M0 or T0–3 N1 M0 disease had a projected 2-year survival of 80%. Clearly this represents a select patient population, but it suggests the possibility that the best prognosis patients can be identified preoperatively. Furthermore, those patients with a historically poorer survival benefited from this therapy, with a median 15-month survival in those with stage IIIB carcinomas and a 2-year projected survival of 22%. In addition, local control was excellent despite extensive locoregional disease at presentation, and 67% of patients achieved locoregional disease control.
Thus, it can be concluded that this accelerated induction approach followed by resection is highly feasible and associated with encouraging local control rates and a suggestion of improved survival. Toxicity is significant but manageable, and is acceptable if these results prove durable. Patients with advanced, poor prognosis stage III non-small cell lung carcinoma have a potential for disease control, and resection is an important component of multimodality treatment regimens. Distant metastases remain the most significant cause for failure and reflect the inadequacy of current chemotherapy. Better chemotherapeutic agents and an improved understanding of the optimal combination of chemotherapy with radiation are challenges for the future.
|
Footnotes |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
|---|
Address reprint requests to Dr Rice, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
|
References |
|---|
|
TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
|---|
Related Article
This article has been cited by other articles:
|
|
 |
|
  C. Pottgen, S. Levegrun, D. Theegarten, S. Marnitz, S. Grehl, R. Pink, W. Eberhardt, G. Stamatis, T. Gauler, G. Antoch, et al. Value of 18F-Fluoro-2-Deoxy-D-Glucose-Positron Emission Tomography/Computed Tomography in Non-Small-Cell Lung Cancer for Prediction of Pathologic Response and Times to Relapse after Neoadjuvant Chemoradiotherapy Clin. Cancer Res., January 1, 2006; 12(1): 97 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Doddoli, F. Barlesi, D. Trousse, S. Robitail, S. Yena, P. Astoul, R. Giudicelli, P. Fuentes, and P. Thomas One hundred consecutive pneumonectomies after induction therapy for non-small cell lung cancer: An uncertain balance between risks and benefits J. Thorac. Cardiovasc. Surg., August 1, 2005; 130(2): 416 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Ferguson Optimal management when unsuspected N2 nodal disease is identified during thoracotomy for lung cancer: cost-effectiveness analysis J. Thorac. Cardiovasc. Surg., December 1, 2003; 126(6): 1935 - 1942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. DeCamp, T. W. Rice, D. J. Adelstein, M. A. Chidel, L. A. Rybicki, S. C. Murthy, and E. H. Blackstone Value of accelerated multimodality therapy in stage IIIA and IIIB non-small cell lung cancer J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 17 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Stamatis, D. Djuric, W. Eberhardt, C. Pottken, G. Zaboura, S. Fechner, and T. Fujimoto Postoperative morbidity and mortality after induction chemoradiotherapy for locally advanced lung cancer: an analysis of 350 operated patients Eur. J. Cardiothorac. Surg., August 1, 2002; 22(2): 292 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.F. Vansteenkiste Imaging in lung cancer: positron emission tomography scan Eur. Respir. J., February 1, 2002; 19(35_suppl): 49S - 60s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Novoa, G. Varela, and M.F. Jimenez Morbidity after surgery for non-small cell lung carcinoma is not related to neoadjuvant chemotherapy Eur. J. Cardiothorac. Surg., October 1, 2001; 20(4): 700 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Doddoli, P. Thomas, X. Thirion, Y. Seree, R. Giudicelli, and P. Fuentes Postoperative complications in relation with induction therapy for lung cancer Eur. J. Cardiothorac. Surg., August 1, 2001; 20(2): 385 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.F. Vansteenkiste and S.G. Stroobants The role of positron emission tomography with 18F-fluoro-2-deoxy-D-glucose in respiratory oncology Eur. Respir. J., April 1, 2001; 17(4): 802 - 820. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. W. Rice, D. J. Adelstein, J. P. Ciezki, M. E. Becker, L. A. Rybicki, C. F. Farver, M. A. Larto, and E. H. Blackstone Short-course induction chemoradiotherapy with paclitaxel for stage III non-small-cell lung cancer Ann. Thorac. Surg., December 1, 1998; 66(6): 1909 - 1914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Vansteenkiste, P. De Leyn, G. Deneffe, J. Menten, T. Lerut, and M. Demedts Present status of induction treatment in stage IIIA-N2 non-small cell lung cancer: a review Eur. J. Cardiothorac. Surg., January 1, 1998; 13(1): 1 - 12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Lee and R. J. Ginsberg Lung Cancer Staging: The Value of Ipsilateral Scalene Lymph Node Biopsy Performed at Mediastinoscopy Ann. Thorac. Surg., August 1, 1996; 62(2): 338 - 341. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
