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Ann Thorac Surg 2003;76:1810-1814
© 2003 The Society of Thoracic Surgeons
a Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan
Accepted for publication June 5, 2003.
* Address reprint requests to Dr Ichinose, Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka 811-1395, Japan
e-mail: yichinos{at}nk-cc.go.jp
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Abstract |
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METHODS: Patients with marginally resectable stage IIIB NSCLC, an age younger than 70 years, a performance status of 0 or 1, and good organ function were eligible. The UFT (400 mg/m2) was administered orally on days 1 through 14 and 22 through 35 and cisplatin (80 mg/m2) was injected intravenously on days 8 and 29. Radiotherapy with a total dose of 40 Gy was delivered in 20 fractions from day 1. A surgical resection was performed from 3 to 6 weeks after completing the induction treatment.
RESULTS: Twenty-seven patients, 18 male and 9 female with a median age of 56 years and ranging from 36 to 69 years, were entered into the phase II trial. Clinical T4 and N3 cancers were observed in 22 and 7 patients, respectively. Twenty-five (93%) achieved a partial response. The most frequently observed adverse event was grade 3 leukopenia in 26%. Of 25 patients who underwent a thoracotomy, 22 had a tumor resection. In all 22 patients a complex resection including a resection of the superior vena cava, carina, and vertebrae was required. Operative morbidity and mortality rates were 36% and 4% respectively. The calculated 1-year and 3-year survival rates of all 27 patients were 73% and 56% respectively.
CONCLUSIONS: Chemotherapy using UFT plus cisplatin and concurrent radiotherapy as induction treatment and a surgical resection for patients with marginally resectable stage IIIB NSCLC is feasible and promising. However it is difficult to conduct multi-institutional trials even for selected stage IIIB disease as a complex resection in almost all patients is necessary.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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Although clinical stage IIIB disease is generally considered to be either unresectable or inoperable from an oncologic point of view, several phase II trials of preoperative concurrent chemoradiotherapy for that stage indicate that this treatment modality is feasible and a long-term survival rate at 5 or 6 years has been reported to be 19% to 26% [6–8]. The operative mortality rate of the patients with preoperative chemoradiotherapy is reported to be 3% to 7% [7–9]. However, preoperative chemoradiotherapy induced a significantly higher incidence of major postoperative complications than preoperative chemotherapy alone [10]. In the present phase II trial of trimodality treatment for clinical stage IIIB disease we used UP-RT as preoperative chemoradiotherapy and thereafter analyzed the efficacy as well as the safety of this trimodality treatment.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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Stage IIIB disease was assigned as either N3 disease (involvement of contralateral mediastinal or supraclavicular lymph nodes) or T4 disease (tumor invasion of mediastinal structures, heart, great vessels, trachea, carina, esophagus, or vertebral body).
Tumor involvement of the trachea or carina observed by bronchoscopy or direct invasion of the heart, esophagus, great vessels including superior vena cava (SVC), esophagus, or vertebral body observed by enhanced CT scan, magnetic resonance imaging scan, or transesophageal ultrasonography determined T4 disease. A biopsy of the supraclavicular lymph nodes determined N3 disease. A contralateral mediastinal lymph node was defined as metastasis when both the ipsilateral and contralateral mediastinal lymph nodes were swollen in a shortest diameter of more than 1.0 cm by CT scans.
The disease was defined to be marginally resectable if a tumor appeared to be removable by the replacement of SVC or great vessels, a carinal resection, a partial resection of esophagus or vertebrae, a resection of involved bilateral mediastinal or supraclavicular lymph nodes, or combinations of these modalities.
Treatment regimen
Treatment with UFT (400 mg/m2 daily) in the form of a 100 mg capsule (100 mg tegafur and 224 mg uracil) was given orally in two separate doses from days 1 to 14 and from days 22 to 36. If the number of capsules could not be divided equally, then the higher dose was administered in the morning and the lower dose in the evening. As a dose higher than 600 mg per day is not allowed in Japan, most patients received 600 mg of UFT per day. Cisplatin (80 mg/m2) was administered by 90-minute infusion on days 8 and 29 when patients were hydrated with an at least 2,500 mL saline infusion.
Radiotherapy was administered in five fractions per week from a megavolt linear accelerator at a daily dose of 2 Gy from day 1 up to a total dose of 40 Gy (20 fractions). The target volume included the primary disease site with a 2-cm margin around the mass and the ipsilateral hilum. The entire width of the mediastinum was included with a 2-cm margin around the radiographically visible area of involvement (as determined by a pretreatment CT scan). The inferior margin extended 4 cm below the carina or 2 cm below the radiographically visible tumor mass. When no tumor in the supraclavicular fossa was detected by either a physical or radiographic examination, the area was not irradiated.
Complete blood cell counts and biochemistry were performed weekly. If leukocytes decreased to less than 2,000/µL, platelets decreased to less than 50,000/µL, or abnormal results of hepatic or renal function tests (levels higher than eligibility criteria) were observed, the administration of cisplatin was suspended. Cisplatin and UFT administration were discontinued if grade 3 or greater hematologic or nonhematologic toxicity occurred. Radiotherapy was discontinued if grade 4 hematologic or grade 3 nonhematologic toxicity occurred.
Evaluations
The response was evaluated according to the World Health Organization criteria [11] and toxicity was evaluated according to the Japan Clinical Oncology Group criteria [12]. Before an operation, which was planned from 3 to 6 weeks after completion of an induction treatment, restaging was performed based on the same means used for entry into this trial.
Statistical analysis
The primary endpoint of this study was to determine the 3-year survival rate of patients who underwent this trimodality treatment. Based on the assumption that a 3-year survival rate of higher than 35% would warrant further investigation of this treatment whereas a rate below 15% would make such an investigation unnecessary, a sample size of 24 patients was required with an alpha error of 0.05 and a beta error of 0.2. The overall survival was estimated by the Kaplan-Meier technique.
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Results |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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Surgery
One patient refused to undergo an operation and 1 patient left the study before operation owing to adverse events. Of the 25 patients who underwent a thoracotomy the tumor in 3 patients was found to be unresectable (Table 3).
The remaining 22 patients underwent a surgical resection and among them 1 patient had an incomplete resection due to carcinomatous effusion and pleural dissemination. There was no standard resection for the 22 resected patients. All 11 patients with a pneumonectomy required an intrapericardial pneumonectomy or combined resection or both. All 11 patients who underwent a lobectomy also needed a combined resection. The most frequently combined resected site in the 22 patients was the SVC: partial resection of the SVC was performed in 4 patients and total resection of the SVC using a tube graft of ringed polytetrafluoroethylene was performed in 4 patients. Four patients underwent a right-sided sleeve pneumonectomy; a partial resection of the SVC (1 patient) and a total resection of the SVC with graft replacement (2 patients) was also simultaneously performed. A total vertebrectomy was performed in 1 patient and a partial vertebrectomy in 5 patients.
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Surgical morbidity and mortality
Nine (36%) of 25 patients undergoing surgery had either minor (n = 7) or major (n = 2) complications. Minor complications included atrial fibrillation (n = 1), atelectasis (n = 1), chylothorax (n = 1), interstitial pneumonia (n = 2), and restorage of pleural effusion (n = 2) for which redrainage was required. Major complications were the following: a 55-year-old patient had bilateral vocal cord paralysis due to an injury of the recurrent nerve after a bilateral mediastinal and supraclavicular lymph nodal dissection with a right upper lobectomy plus a partial resection of the SVC was performed; pneumonia and empyema developed and the patient died 7.4 months after the operation. The other case was a 44-year-old patient who had been given steroid therapy for rheumatoid arthritis for several years and a bronchial fistula developed at 21 days after a right-sided intrapericardial pneumonectomy with a total resection of SVC and replacement by a graft; he underwent an emergent operation on the same day and was eventually cured by omentopexy. Therefore the mortality rate was 4% (1 of 25).
Survival and recurrence
The median observation time was 33 months. The calculated 1- and 3-year survival rates in all 27 patients were 73% (95% confidence interval: 56% to 90%) and 56% (37% to 76%) respectively (Fig 1). The 1- and 3-year survival rates in the 22 resected patients were 82% (66% to 98%) and 67% (47% to 87%). Of the 22 resected patients, recurrence developed in 8 patients. The recurrent site of 7 patients was distant and 1 patient had recurrence in the contralateral supraclavicular lymph nodes that had not been irradiated.
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Comment |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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In the diagnosis of mediastinal lymph nodal metastasis a CT scan with a sensitivity and specificity of 40% to 60% is markedly inferior to mediastinoscopy with a sensitivity of 80% to 90% and a specificity of 100% [12–14]. In the present study, contralateral mediastinal lymph nodal swelling of 3 patients was defined as N3 disease if ipsilateral mediastinal lymph nodes were also swollen. Although our criteria for N3 disease of contralateral mediastinal lymph nodal metastasis still need to be validated, only 3 patients with N3 disease were classified by these criteria, and whose T status was T1, T2, and T4 respectively. Furthermore the exact staging of T4 tumors is far more difficult to perform. Computed tomography scans are reported to provide only a sensitivity ranging from 25% to 40% in assessing the irresectability of T4 tumors [15]. Whether magnetic resonance imaging in addition to CT scan can provide definitive information in the diagnosis of T4 tumor remains to be clarified. Therefore surgical intervention should be employed to accurately diagnose T4 disease. However it is impossible to perform surgical intervention in all patients to confirm the staging even in a prospective trial.
If the lesion is truly T4 disease and even if such T4 disease responds to the induction treatment, a complex resection is considered to be necessary in order to perform a complete resection as a safe resection margin is unclear owing to fibrosis or a residual tumor. In the present study there was no standard resection and all resected patients were required to undergo a complex resection. However in a SWOG trial a standard resection was performed in 3 (17%) of 18 patients with resected T4 disease [9]. In the trial of the West German Cancer Center a standard resection in 45% (15 of 33) was reported [7]. However there was no information on why such patients could receive a standard resection.
The resection rates in previous trials of induction chemoradiotherapy for stage IIIB disease are reported to range from 24% to 68% [7–9, 11]. In the present trial it was 81% (22 of 27). The main reason for the different resection rates is thought to be the different entry criteria and surgical approachs among those trials. We selected patients with marginally resectable stage IIIB disease if a tumor appeared to be potentially removable with a resection of the SVC, great vessels, carina, esophagus, vertebrae, bilateral mediastinal lymph node, supraclaviclar lymph node, or combinations of these modalities. A resection of both the SVC and carina was simultaneously performed in the present trial whereas a lesion that required that kind of resection appeared to be judged unresectable in the other trial [9]. A trial with an aggressive surgical approach similar to ours also showed a complete resection rate of 91% [10].
Although a long-term follow-up is necessary, the survival rate of 73% at 1 year and 56% at 3 years in the present study indicates that this trimodality treatment may be promising. The long-term survival rates in a couple of trials have also demonstrated encouraging information: (1) the 5-year survival rate was 26% for all 56 patients and 43% for 27 completely resected patients in a trial of the West German Cancer Center [7]; (2) the 6-year survival rate in a SWOG trial was 22% for 51 patients [6]. Especially the 6-year survival rate of patients with T4N0 to 1 disease in the SWOG trial was reported to be as high as 49%. Although a poor prognosis of stage IIIB patients with N3 disease is expected from the SWOG data, the 5-year survival rate of those patients in the German trial was 31% in T1 to 2N3 (n = 19) and 23% in T3 to 4N3 (n = 13). In another SWOG trial using concurrent chemoradiotherapy for unresectable stage IIIB patients, which was performed after the trial mentioned above, the 5-year survival rate in 18 patients with T4N0 to 1 disease was 17% and it was 15% in 20 patients with N3 disease [16]. Therefore at present there is no sufficient information on what substage of stage IIIB should be excluded from a future combined modality trial.
In conclusion the trimodality treatment using UP with concurrent radiotherapy followed by surgery for clinical stage IIIB NSCLC was found to be a feasible and promising treatment for our institute. However there are two main obstacles that must be resolved before a multi-institutional trial can be started: one, a clearer definition of marginally resectable T4 disease must be established in order to reduce variations between investigators; and two, both the operative techniques for complete resections and postoperative management skills of participating investigators or teams must be assessed. [1]
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Acknowledgments |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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References |
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