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Ann Thorac Surg 1999;68:1144-1149
© 1999 The Society of Thoracic Surgeons
a Department of Thoracic Surgery and Endoscopy, Ruhrlandklinik, West German Cancer Center, University of Essen Medical School, Essen, Germany
b Cancer Research, Department of Internal Medicine, West German Cancer Center, University of Essen Medical School, Essen, Germany
c Department of Radiation Therapy, West German Cancer Center, University of Essen Medical School, Essen, Germany
Address reprint requests to Dr Stamatis, Ruhrlandklinik, Tüschener Weg 40, 45239 Essen-Heidhausen, Germany
e-mail: arbeitsgem.-Thoraxchirurgie{at}t.online
Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.
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Abstract |
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Methods. From March 1991 to June 1996, 56 patients were entered. Three cycles of cisplatin (P) (60 mg/m2, days 1 + 7) and etoposide (E) (150 mg/m2, days 3 to 5 qd 22) were followed by one cycle of radiotherapy/chemotherapy (RTx/CTx) (45 Gy, 1.5 Gy bid/3 weeks with P 50 mg/m2 days 2 + 9/E 100 mg/m2 days 4 to 6) followed by repeat mediastinoscopy and surgery.
Results. There were 46 men and 10 women (age 34 to 69 years, median 55 years; World Health Organization status 0 to 2, median 1). Twenty-eight had T4, and 32 had proven N3, in detail: T4N0/1, 10; T4N2, 14; T3N3, 9; T4N3, 4; and T1/2N3, 19. Thirty-four (61%) were operated on; 27 (48%) were completely (R0) resected. Survival at 5 years is 26% for all, and 43% for R0 patients. Toxicity included two deaths (one septicemia, one anastomosis insufficiency).
Conclusions. This intensive program proved to be highly effective in unfavorable IIIB subgroups with promising long-term survival for T4 tumors as well as N3 disease.
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Introduction |
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Material and methods |
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Not eligible for the study were patients with: 1) involved supraclavicular nodes (N3 supraclavicular); 2) esophageal infiltration (T4 esophagus); 3) infiltration of aorta thoracica (T4 aorta); 4) ipsilateral satellite pulmonary nodules in the same lobe (T4 satellite nodule); 4) malignant pleural effusion (T4 pleural effusion); and 5) invasion of the myocardium on angiographic CT scan/MRI (T4 myocardium).
To rule out distant metastases, all patients underwent the following staging investigations: CT scans of the chest, abdomen, and brain, radionuclide bone scan, abdominal ultrasound, and physical examination. A complete blood cell count, serum chemistry, coagulation tests, and urinalysis were performed to give normal values. Patients underwent a preoperative cardiovascular risk assesment including cardiopulmonary function testing. Patients were ineligible due to a predicted postoperative forced expiratory volume at 1 s of less than 1 L (quantitative ventilation-perfusion lung scanning), cardiac infarction or unstable angina pectoris 6 months before study entry, or cardiac disability of class III or more (New York Heart Association [NYHA] criteria). Further excluded were patients with: 1) mixed histologies including small cell lung cancer; 2) any other concurrent or previous malignancy; 3) age above 70 years; 4) WHO status greater than 2; and 5) prior oncological treatment (chemotherapy, radiotherapy, surgery). All patients were fully informed about the nature and purpose of this study, and had to give informed consent before study entry. The trial had the local/institutional ethics committee approval. Eligible patients were planned to receive three cycles of induction chemotherapy with split-dose cisplatin and etoposide, followed by one cycle of concurrent hyperfractionated accelerated chemoradiotherapy (Table 1). From 1993 onwards, all patients were routinely offered prophylactic cranial irradiation of 30 Gy in 2-Gy fractions given over 3 weeks (PCI). Patients then were planned for restaging investigations including repeat mediastinoscopy (with biopsies) for those with initially proven positive mediastinal nodes. If reevaluation showed continuing medical/functional operability and repeat mediastinoscopy showed no more than one ipsilateral lymph node station involved (minimal mediastinal disease), patients were taken to thoracotomy 3 to 5 weeks after the end of radiation. Patients still contralaterally involved at repeat mediastinoscopy were generally excluded from surgery. Furthermore, if results of restaging investigations (angiographic CT scans, MRI) clearly indicated persistent T4 disease, thoracotomy was not performed. However, stable disease in N3 patients in spite of mediastinal clearance did not itself render patients ineligible for thoracotomy, nor did biopsy-proven involvement of one single ipsilateral mediastinal lymph node.
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After treatment completion, follow-up visits were arranged for all patients every 2 months in the first 2 years from the end of treatment and from then on every 3 months. Investigations included physical examination, complete blood cell count and serum chemistry, chest radiographs, and abdominal ultrasound. Bronchoscopy was performed once every year or if relapse was suspected. Follow-up CT scans were only performed if clinically indicated.
Overall survival was calculated from the first day of chemotherapy until death, loss of follow-up, or time of evaluation for this report. Event-free survival was calculated from the first day of chemotherapy until any event such as tumor progression, incidence of second cancer, death due to toxicity, or secondary conditions [12]. Survival curves were estimated by the method of Kaplan and Meier, and differences between the individual curves were evaluated using log-rank test [13, 14]. A forward stepwise Cox regression model was used to examine the prognostic significance of covariates on survival. Significance was accepted if any two-tailed p value was less than 0.05.
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Results |
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There were 46 men and 10 women, with a median age of 55 years (range 34 to 69 years). Median performance status at the time of enrollement into the study was World Health Organization grade 1, with a range between 0 and 2. Median lactate dehydrogenase value was 192 U/L (range 127 to 501). T4 disease criteria were met in 28 patients (50%), whereas N3 nodes were involved in 32 (57%) (four patients with T4N3). Detailed primary tumor, regional lymph nodes, distant metastasis (TNM) stages of the patients and subgroups of T4 disease included in this trial are:
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b.i.d. = twice daily; CIS = cisplatin; CTx = chemotherapy;ETO = etoposide; Hf-C/RTx = hyperfractionated accelerated chemoradiotherapy; PCI = prophylactic cranial irradiation; SCLC = small cell lung cancer; TI = thoracic irradiation.
None of the patients in the N3 subset had supraclavicular nodes involved, and N3 criteria were met by biopsy-proven positive contralateral mediastinal nodes. Included non-small cell histologies were 29 patients with squamous cell carcinoma (52%), 22 patients with adenocarcinoma (39%), and 5 patients with large cell carcinoma (9%).
During the phase of induction treatment, only 2 patients showed an early progression. In the beginning of the study, 5 patients refused to follow protocol treatment. From 1993 onwards, no patient has refused any treatment planned on protocol. Five patients could not be considered for surgical procedures after induction because of medical reasons (decline in cardiopulmonary functions or performance status), and 1 patient experienced an early death due to septicemia. Due to results of restaging investigations, 9 patients were assessed clinically unresectable, 4 with persistent T4 disease (angiographic CT scans, MRI) and 5 with N3 or more than one N2 level still biopsy-proven positive at repeat mediastinoscopy. Overall, 34 patients underwent a right- or left-sided thoracotomy (61%). The operative procedures in 34 patients taken to thoracotomy included:
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b.i.d. = twice daily; CIS = cisplatin; CTx = chemotherapy;ETO = etoposide; Hf-C/RTx = hyperfractionated accelerated chemoradiotherapy; PCI = prophylactic cranial irradiation; SCLC = small cell lung cancer; TI = thoracic irradiation.
All patients were approached by a standard lateral thoracotomy to remove the primary tumor and the ipsilateral mediastinal nodes. Contralateral nodes were generally not resected. From 1993 onwards, the bronchial stump was routinely sutured with 2-0 monofilament, nonabsorbal continuous horizontal mattress suture, that runs the length of the stump. A flap of intercostal muscle or mediastinal fat was used to cover the bronchial stump after right-sided pneumonectomies. The mean intraoperative blood loss was 360 mL (range 110 to 720 mL) and the mean duration of operation was 178 minutes (range 125 to 375 minutes). Twenty-seven patients (48%) had a complete resection performed as far as the pathology results of repeat mediastinoscopy biopsies as well as resected specimen gave information about. Downstaging data available from surgical exploration revealed that 11 of 16 (69%) initially involved N3 nodes, and 5 of 6 (83%) initially involved N2 nodes (T4N2 disease) had become microscopically tumor free after induction, whereas only 8 of 22 (36%) initially evaluated T4 tumors had a pathological complete response. One patient had proven T4 disease at the mediastinum surrounding the vena cava and distal trachea, so that surgery ended as an exploratory thoractomy. Six patients had incomplete resections (R1/R2 in peribronchial tissue in 2, in pericardial margin in 1, and in mediastinal fat in 3 patients) and 3 of them received boost irradiation to the areas of residual disease between 20 and 25 Gy on an individual basis. The other 3 patients refused any further treatment. Deaths during stay in hospital were not observed. One of the 34 patients (2.9%) who underwent thoracotomy died at home 43 days after right-sided lobectomy and carinal resection from massive hemoptysis. Postmortem examination revealed an insufficiency of the tracheobronchial anastomosis and perforation of the pulmonary artery. Seventeen patients did not have any postoperative complication. Complications in the remaining 16 patients included: rethoracotomy for bleeding (2), cardiac arrythmias (4), atelectasis (3), air leakage longer than 7 days (4), pneumonia (1), pleural empyema (1), and nonfatal lung embolism (1). Mean stay in hospital was 11.6 days (range 9 to 26 days).
The actuarial survival rate for all 56 patients entered into the study was 35% at 4 years and 26% at 5 years, with a median survival of 20 months. The corresponding rates were 60% and 43% for the 27 R0 patients, with an overall median survival of 58 months. Seventeen patients with a proven pathological complete response (pCR) had comparable 4- and 5-year survival rates of 75% and 50%, the median survival being 52 months. All 28 patients fulfilling the T4 criteria had 4- and 5-year survival rates of 34% and 17%, and a median survival of 20 months. All 32 patients with mediastinoscopically proven N3 nodes had 4- and 5-year survival rates of 34% and 28%, and a median survival of 20 months. Survival as well as surgical results for the different TN groups are summarized in detail in Table 2. Six patients survived more than 5 years, 4 of them with R0 resection and 2 with pCR. The only subgroup with a tendency, although not statistically significant, to shortened median survival, lower 4- and 5-year survival rates, as well as complete resection and PCR rates was that with combined higher T and N stages of T3N3 and T4N3.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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We have reported here mature follow-up data of 56 IIIb patients entered onto our trimodality protocol from March 1991 through June 1996 at the West German Cancer Center Essen. Sixty-one percent of the patients selected for participation could be operated on, and in 27 (48%), eventually complete resection was performed. Long-term survival at 4 and 5 years of 35% and 26% looks very promising for these advanced-stage subgroups. So far, prognosis of our patients with T4 disease and N3 disease are comparable. Long-term survival became possible in T4N0/1, T4N2, or T1/2N3. The only group with more unfavorable prognosis seems to be the one with higher combined T and N stages (T3N3 and T4N3). This was also the group with the lowest rate of complete resection possible after induction (35%).
The toxicity of this multimodality approach was acceptable (overall mortality 3.6%). We generally used repeat mediastinoscopy (N3) or repeat imaging studies (T4) to select our patients for thoracotomy. We did only operate on those N3 patients in whom initially involved nodes were without evidence for residual cancer postinduction or if not more than one intially involved ipsilateral node remained positive. Further, repeat imaging studies (angiographis CT scan/MRI) had to clearly visualize mediastinal structures without tumor invasion. The rates of intrapericardial pneumonectomies and complex resections (47%), mostly in T4 tumors, seems adequate for these locally far-advanced stages. In most cases with N3 disease, standard surgical procedures turned out to be sufficient and contralateral mediastinal nodes were not removed. It is still not clear, whether after such an intensive preoperative downstaging the extension of resection can be confined to the primary tumor and the ipsilateral mediastinal nodes or has to include the contralateral mediastinum for achieving an anatomically complete resection of initially involved tissue. Our relapse pattern in the patients with N3 nodes proves that local or locoregional relapse after negative rebiopsies of contralateral nodes is rarely observed. Induction treatment turned out to be much more effective in the mediastinum (69% initially involved N3 nodes free of cancer) than at the primary tumor site (36% pathological complete responses).
The Southwest Oncology Group (SWOG) had some differences in their patient selection as well as in the selection for thoracotomy for the stage IIIB subset. Most of their N3 patients (2/3) had involved supraclavicular nodes, whereas in our trial, this group was generally excluded. The SWOG did not include repeat mediastinoscopy in the postinduction selection for thoracotomy. However, the database of the SWOG did concisively show that N2 or N3 disease at thoracotomy was the most significant negative prognostic factor for postoperative survival duration and prognosis in their patients. Different from our results, the SWOG did find significantly better survival results for the stage subgroup T4N0/1 [4, 5]. Other investigators, Grunenwald and associates from Paris [18] and Choi and associates from Boston [19], have also included IIIb patients into trimodality protocols (T4 as well as N3), comparable with our trial and that of the SWOG [18, 19]. However, in the Boston study, the induction chemoradiotherapy was more intensive with a complex irradiation scheme of combining once- with twice-daily irradiation up to 60 Gy. The Paris trial had comparable radiation doses preoperatively (45 Gy) but included a more complex and extensive surgical approach (sternotomy). They reported a complete resection rate of 57% among 30 patients and a 3-year actuarial survival rate of 25% [18]. Choi and associates found among 26 IIIb patients (T4 or N3) a complete resection rate of 52% and an actuarial 3-year survival of 52% [19].
Some investigators reported a high incidence of bronchopleural fistulas or adult respiratory distress syndrome (ARDS) after induction chemoradiotherapy, especially for pneumonectomies [20]. In our experience, postoperative mortality was low (2.9%), whereas perioperative morbidity seemed to be more pronounced compared with standard operations without pretreatment. However, the rate of bronchopleural fistulas could be reduced, if monofilament, nonabsorbal sutures were used and the bronchial stump was routinely covered with autologous tissue such as intercostal muscle or mediastinal fat. To prevent increased alveolar capillary edema, we routinely administered prophylactic corticosteroids (eg, 1.0 to 1.5 mg/kg/body weight prednisolon) postoperatively for 3 days. Similar to our results, the SWOG, Boston, and Paris trials did not report such high incidences of stump fistulas and ARDS as those observed in Fowler’s group [18–20]. It may be that an inclusion of twice-daily radiotherapy is a possible means to shorten radiation duration time and thus leads to decreased evolvement of fibrosis at the time of thoracotomy.
Long-term survival rates now achievable with multimodality treatment with or without surgery for selected IIIb subgroups look very promising if compared with historical controls. This could be partly explained due to selection procedures necessary for these aggressive protocols and, therefore, results of the randomized intergroup trial are urgently awaited. However, if the long-term survival improvement after inclusion of surgery as a definitive local modality would be in the range between 5% and 10% at 5 years for selected subgroups of IIIb, this could easily be missed in one randomized trial alone. Another research priority should be to identify prognostic subgroups of IIIb that definitely profit from such trimodality approaches by including new molecular markers from translational research (eg, K-ras mutations, p53 mutations) into the prognostical analyses.
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