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Ann Thorac Surg 2003;76:1802-1809
© 2003 The Society of Thoracic Surgeons
a Department of Surgical Sciences, Catholic University, Rome, Italy
b Department of Radiology, Catholic University, Rome, Italy
c Department of Radiotherapy, Catholic University, Rome, Italy
d Department of Rehabilitation, Campus Biomedico University, Rome, Italy
* Address reprint requests to Dr Galetta, Division of General Thoracic Surgery, Catholic University, Largo A. Gemelli, 8, 00168 Rome, Italy.
e-mail: mimgaletta{at}yahoo.com
Presented at the Thirty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31–Feb 2, 2003.
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Abstract |
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METHODS: From November 1992 to June 2000, 39 patients (37 men and 2 women, mean age 65 years) with clinical stage IIIb (34 T4N0 to 2, 4 T2 to 3N3, 1 T4N3, excluding T4 for malignant pleural effusion) entered the study. They received intravenous infusions of cisplatin 20 mg/m2 and 5-fluorouracil 1,000 mg/m2 (days 1 to 4 and 25 to 28) combined with a total dose of 50.4 Gy radiotherapy delivered over 4 weeks (1.8 Gy daily). Upon clinical restaging responders underwent surgery.
RESULTS: All patients were available for clinical restaging. No complete response was observed. Twenty-one patients had partial response (53.8%), 16 had stable disease (41%), and 2 had progressive disease (5.2%). Hematologic toxicity was moderate. Twenty-two patients (56.4%), 21 with partial response and 1 with stable disease, underwent surgery with no perioperative death. A radical resection was possible in 21 cases. Nine lobectomies, 3 bilobectomies, and 9 pneumonectomies were performed. Complications occurred in 5 patients (23.6%). Fourteen of the patients who underwent surgery (66.6%) showed a pathologic downstaging. A complete pathologic response was obtained in 9 cases (49%). Overall 5-year survival (Kaplan-Meier) was 23%. Resected versus non-resected patients showed a significant difference: 38% versus 5.6% (p = 0.028, log rank).
CONCLUSIONS: This trimodal approach for stage IIIb NSCLC appears safe and effective. It provides good therapeutic results with acceptable morbidity in surgical cases.
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Introduction |
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Although radiotherapy or chemotherapy is generally accepted as the most appropriate primary therapy [3] the treatment outcome for such patients has remained poor due to both locoregional and systemic failures. To improve this disappointing situation many approaches have been attempted including a fractionation method for radiation [6], combined chemoradiotherapy [7, 8], and preoperative chemoradiotherapy [9–12].
After the promising results of the first induction treatments in the late 1980s [5, 9, 13, 14] a Southwest Oncology Group (SWOG) phase II trial [11, 15] tested the feasibility of a multimodality treatment (induction therapy and surgery) in patients with IIIa and IIIb NSCLC reporting a 3-year survival of 24% for the IIIb group.
The encouraging results of these studies induced our team to start an induction therapy trial in 1992 in patients with clinical IIIb NSCLC. In this study, we employed a combination of cisplatin and 5-fluorouracil (5-FU) demonstrated to have a synergistic antitumor activity in both preclinical [16, 17] and clinical studies [18, 19]. For lung cancer, this combination yielded a response rate ranging from 25% to 74% [20–22] although 5-FU alone is thought to be inactive against NSCLC [23]. The mechanism of synergism between these two drugs remains unclear. There are various hypotheses concerning the modulatory effect of cisplatin on 5-FU and vice versa: concerning the former it has been suggested that cisplatin-induced increase of reduced intracellular folate level potentiates the effect of 5-fluorodeoxyuridine by forming a covalent ternary complex with thymidylate synthase, leading to enhanced 5-FU cytotoxicity [16]; regarding the latter it has been suggested that modulation of cisplatin-induced DNA-adduct repair by 5-FU results in enhanced cisplatin cytotoxicity [17]. Considering the radiosensitizing effects of cisplatin and 5-FU [24] it appears possible that concurrent combination of radiation therapy with these drugs will increase their antitumor effects by increasing the frequency of interaction between chemotherapy and radiotherapy.
Based on this background we conducted a prospective phase II study to evaluate as primary endpoints the feasibility and the efficacy of this combined trimodality regimen in patients with locally advanced NSCLC. Secondary endpoints included treatment-related toxicity, clinical and pathologic response, resectability rate, surgical morbidity and mortality, local disease control, and survival. We report herein the consolidated results of this single-institution trial.
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Material and methods |
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2000/mL, platelets 100,000/mL, and hemoglobin 11 g/dL), and pulmonary functional tests were required to document a predicted postoperative forced expiratory volume in 1 second (FEV1) of greater than 800 mL.
Diagnostic procedures
The pretreatment evaluation included complete history and physical examination, complete blood cell count, standard chemistry profile, urinalysis, creatinine clearance, electrocardiogram, fiberoptic bronchoscopy, arterial blood gas analysis, pulmonary function test, and ventilation-perfusion nuclide scintigraphy. Chest roentgenogram, computed tomography (CT) scan of the chest, brain and upper abdomen, and radionuclide bone scan were performed to ensure the absence of metastatic dissemination. Diagnosis of NSCLC was obtained by endobronchial biopsy or by fine needle aspiration biopsy. Surgical staging of enlarged mediastinal lymph nodes on CT scan was made by cervical mediastinoscopy. Pulmonary angiogram and venocavogram or more recently angiographic CT scan of the thorax were performed in cases of suspected great vessels invasion. Esophageal endoscopy, magnetic resonance imaging, or ultrasound endoscopy were also performed when indicated.
Before the initiation of the treatment protocol, evaluations of all patients were performed by thoracic surgeons, radiation oncologists, medical oncologists, and pneumologists. This trial was approved by the local ethics committee. Written informed consent was obtained from all patients before treatment.
Treatment plan
The treatment plan is summarized in Figure 1.
After registration in the study each patient was started on induction treatment of chemoradiotherapy. Chemotherapy consisted of cisplatin (20 mg/m2) delivered intravenously on days 1 to 4 and on days 24 to 28 over a period of 30 to 60 minutes with at least 2,000 mL fluids. It was followed in the same days by intravenous administration of 5-FU at a dose of 1,000 mg/m2. Patients were hospitalized throughout the duration of chemotherapy for supportive therapy. Hematopoietic growth factors were permitted in presence of prolonged neutropenia.
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During induction regimen patients were evaluated on a weekly basis. Patient evaluation included interim history and physical examination, performance status, and laboratory testing. Three to 4 weeks after induction chemoradiotherapy was completed patients were restaged to assess clinical response. Restaging procedures included fiberoptic bronchoscopy, CT scan of the chest and upper abdomen, pulmonary function tests, and re-do mediastinoscopy only in patients clinically staged as N3.
Criteria for response and toxicity evaluation
Tumor response was evaluated according to the World Health Organization (WHO) response criteria [25] by the multidisciplinary team (radiologists, thoracic surgeons, radiotherapists, and pneumologists). Complete response was defined as the complete disappearance of all measurable intrathoracic disease. Partial response required a decrease of at least 50% of the sum of the cross-sectional areas of all measured lesions. Stable disease was defined as an evaluation that failed to qualify for any of the response notes. Progression of disease was defined as an increase of at least 25% in the size of one or more measurable lesions or the appearance of any new lesions.
Patients with progression of disease who were medically unfit or who refused any further treatment were not eligible for surgery. These patients received multidrug chemotherapy and in selected cases boost irradiation up to 60 Gy. Patients with major clinical response (complete or partial) or with stable disease underwent thoracotomy 1 to 2 weeks after restaging. Operations were performed through a lateral "muscle-sparing" thoracotomy. The goal was to remove the entire tumor area. Resection was considered complete if proximal resection margins were free of tumor. Operative procedures included major parenchyma resections as indicated (lobectomies, bilobectomies, or pneumonectomies) and a complete ipsilateral lymph node dissection.
Toxicities were assessed using WHO criteria and Radiation Therapy Oncology Group (RTOG) acute radiation toxicity criteria.
Follow-up
Patients were evaluated monthly for the first 3 months, every 3 months for the next 2 years, every 6 months for the next 3 years, and then annually. Investigations included interim history and physical examination, laboratory tests, and chest roentgenogram. Fiberoptic bronchoscopy and CT of the chest, abdomen, and brain were done every 3 months for the first year, every 6 months for the next 3 years, and yearly thereafter or when clinical signs of recurrence developed. Recurrences were classified as locoregional (inside the ipsilateral thorax), distant (outside the ipsilateral thorax), or both.
Statistical analysis
Survival times were calculated from the first day of neoadjuvant therapy until death, loss to follow-up, or time of evaluation for this report. Disease-free survival was calculated from the first day of surgery until any event such as tumor recurrence, incidence of second cancer, or secondary condition [26]. Survival curves were constructed using the Kaplan-Meier method [27] and differences between the individual curves were evaluated using log-rank test [28]. Significance was accepted if any two-tailed p value was less than 0.05.
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No significant correlations were found among response to treatment and clinical characteristics (age, sex, performance status, TNM stage, and histologic type).
Surgery
All the 21 patients with a partial response were operated on; only 1 of 16 patients with stable disease underwent thoracotomy. Of the remaining 15 patients, 2 refused surgery, 5 had the operation precluded because of poor general condition, and 8 were judged unresectable. Thus a total of 22 patients (56.4%) underwent surgery. One patient (4.5%) had an exploratory thoracotomy. Nine patients (40.9%) were treated with a lobectomy, 3 (13.7%) with a bilobectomy, and 9 (40.9%) with pneumonectomy. Overall resectability rate (resected patients of the entire population) was 53.8% (21 of 39). Complex resections included 5 intrapericardial pneumonectomies (23.8%) and 2 sleeve lobectomies (2.5%). In the majority of patients some technical difficulties due to chemoradiotherapy-induced fibrosis were encountered; nevertheless a standard major procedure was performed. Thus the surgical resectability rate (resected patients of all patients judged to be resectable) was 95.4% (21 of 22). Complete resection was obtained in all resected cases and verified by frozen sections. In all resected patients the bronchial stump was wrapped in an intercostal pedicled muscle flap.
Thirty-day mortality was nil. Postoperative morbidity is summarized in Table 3. The overall median postoperative hospital stay was 16 days (range, 6 to 78).
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Comment |
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For T4 disease two large retrospective studies [2, 4] reported a 5-year survival rate of 7% and 8.4%, respectively. Induction regimen (chemotherapy or chemoradiotherapy) may downstage patients with IIIb disease allowing in selected cases tumor resection with acceptable morbidity, mortality, and improved outcome. A number of phase II studies including surgery have focused on patients with stage IIIb disease and the reported results correspond with ours.
Rusch [30] reported a clinical response of 78% with a resectability rate of 63%. Morbidity was 23%, mortality 5.2%, and 2-year overall survival was 39%. In the experience of the Marie Lannelongue Hospital [31], despite the small number of patients (N = 23) the clinical response was 100% with the highest resectability rate ever published (91%). Twenty-six percent of these patients experienced a major postoperative complication and 8.6% died. The 3-year survival was 54%. Katakami and colleagues [32] used induction chemotherapy and resection to treat 32 IIIb patients. A clinical response was obtained in 78%, overall resectability rate was 41%, complications and mortality rates were 19% and 4.4%, respectively. Five-year overall survival was 8%. Rendina and colleagues [33] used induction chemotherapy and resection to treat 57 IIIb patients with centrally located T4 tumor. Clinical response was 73%, resectability rate 63%, complications 16%, and mortality 2.3%. Survival at 4-year was 26% for all patients and 30.5% for those who were completely resected. Stamatis and colleagues [34] treated 56 patients with T4/N3 lung cancer achieving a 59% resectability rate, a 48% complications rate, and no mortality. Five-year survival for the R0 subgroup was 43%.
In a prospective multicenter trial of neoadjuvant chemotherapy followed by surgery or radiotherapy or both, conducted by Pitz and associates [35] on 41 patients with stage IIIb disease, the overall response rate was 66%. Resection could be achieved in only 10 patients (37%, 10 of 27), with a mortality rate of 2.4% and a morbidity rate of 30%. In that series the 3-year survival rate for all the patients was 15%. In Grunenwald's experience [36], 40 T4 or N3 NSCLC patients underwent induction chemoradiotherapy and radical resection. Twenty-nine patients (73%) had a clinical response and were operated on through a median sternotomy to allow the tumor resection and bilateral extended lymphadenectomy. The resectability rate was 60%, associated with 2.4% mortality. The 5-year survival rate was 19% for all patients and 28% for those who completed resection. Comparable results were achieved by our study. It showed a clinical response rate of 56% after induction therapy. No complete response was recorded. One patient was unresectable at thoracotomy, thus the resectability rate was 54% (21 of 39). Five-year overall survival was 23%, and it was 38% in the complete resection group. The complication rate in our study was 3.8% and mortality was nil. This complication rate is expected among patients who have undergone chemoradiotherapy. Among different series of induction therapy followed by surgery, only that of Stamatis and coworkers [34] reports a very high complication rate (48%).
As noted by Albain [11] in patients with locally advanced NSCLC the brain remains a major site of distant relapse. In our study 5 responders experienced brain metastasis (23.8%): 3 patients had a single brain metastasis that was surgically removed; the other 2 patients had multiple brain metastases treated by means of whole cranial radiotherapy. Despite the fact that prophylactic cranial irradiation has been indicated as a valuable tool to produce a reasonable reduction in the brain metastasis rate [37] we have no certain data in regard to this. Randomized studies are needed to evaluate the efficacy of prophylactic cranial irradiation.
We can conclude that the trimodality therapy trial we have described for the treatment of stage IIIB NSCLC has proved to be safe and effective and produced a mild toxicity rate. Clinical response to this treatment was satisfactory and complete surgery could be performed in a high number of patients (54%) who otherwise would have been denied surgery. Moreover patients who could be completely resected showed encouraging long-term survival rates that were unforeseen for their initial clinical status. Morbidity and mortality rates have proved to be acceptable. Surgical exploration should be recommended for responders as well as for selected patients with stable disease.
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Discussion |
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It is possible that up to 30 of these 39 patients had lower stage disease and may have been candidates for standard surgical resection. This is not a criticism of the authors but merely emphasizes the difficulty in clinical staging and assigning treatment to these patients. This problem is only exacerbated by the diversity of substages within stage IIIB lung cancer. We now have substantial experience with subsets of T4 cancers that are amenable to surgical resection.
Survival of these patients is primarily limited by systemic disease for which mediastinal nodal metastases is a strong surrogate. Therefore although T4 and N3 disease share the same tumor stage, mixing these two very different subsets of stage IIIB cancer prevents us from being able to make clear decisions how to handle either one. The T4 patients are more likely to benefit from locally aggressive therapy like extended surgery, whereas N3 disease nearly always denotes systemic disease that requires systemic therapy, probably without surgical benefit.
Finally, this experience reconfirms our knowledge that radiologic staging after chemoradiotherapy is neither sensitive or specific. In the absence of disease progression all patients subjected to induction therapy deserve an attempt at surgical resection.
Doctor Margaritora, how do we define T4 tumors on our preoperative imaging and how much variability is there in that interpretation? Is pulmonary artery involvement T3 or T4 disease? Do you have information on the type of nodal involvement in these cases, that is, how often was nodal involvement due to direct invasion of tumor as opposed to distinct distant nodal disease? How do you plan to treat these patients in the future and can we better stratify which ones will benefit from induction therapy?
Congratulations and good work to you and your colleagues. Keep up your efforts to help us care for these difficult patients.
DR PAUL VAN SCHIL (Edegem, Belgium): Congratulations on this very excellent study. As you pointed out, restaging these patients is a difficult issue. Computed tomography scan and probably also positron emission tomography (PET) scan are not very reliable in restaging. I noticed that in some cases you performed a remediastinoscopy. Could you please comment on the accuracy and some technical details of performing the repeat mediastinoscopy? Do you have any experience with PET scan in restaging these patients?
DR MARGARITORA: Thank you very much for the comments, which I find appropriate. I completely agree with Dr Wood: the real problem in this kind of patients is staging. I mean that it is absolutely not easy even with a modern high resolution spiral CT scanner to precisely define the involvement by the tumor of the thoracic great vessels. In fact quite often it is not easy to discriminate a real direct infiltration from a simple adhesion. Moreover it is not easy to address this problem with other procedures as well. In this setting we know there are some groups around the world that try to define the T3 or T4 status with VATS. But since the process of finding, for example the dissection plane dividing the tumor from the wall of a vessel is very difficult, I do not think this is a useful option. I think we have to date to accept the fact that a real definition of the T3 or T4 status can be impossible in the preoperative setting of a locally advanced NSCLC. In our group there were 12 patients staged T4 owing to a suspect invasion of the pulmonary artery. I definitely agree with Dr Wood that some of these patients were probably T3 instead of T4 but we had to decide and take an initial step with a clear definition of this patients with surgery or induction therapy as options. We adopted a simple criterion to indicate a T4 status for vessel involvement: we considered as T4 all those cases where a direct sign of infiltration was clearly evident (an irregular "minus" sign inside the vessel with irregular margins of the vessel wall) or when the tumor surrounded completely the vessel with an evident significant stricture of the vessel lumen itself. Regarding the N3 status we may front a similar problem in the definitions too. The N3 means several and different conditions: from the hylar to the mediastinal controlateral and from a single, CT criteria based only, lymph-node involvement to a bulky multilevel one. It is a big family and quite often it may be not really easy to clearly define the level and the entity of involvement. In our series we considered for this three-stage therapeutic approach only five N3 cases and all in a very initial condition: none had more than two stations involved and the maximum diameter of any involved lymph node was smaller than 2 cm. Regarding the very interesting question raised by Dr van Schil, whom I thank for giving me the opportunity to clarify this point, I would like to underline that remediastinoscopy that is currently undertaken by very few groups in Europe, for example in Spain, Belgium, and the Netherlands, is a new and widely discussed issue. We performed only five procedures. In four, neoplastic remnants were detected and the operation was stopped. I have to say that I don't like remediastinoscopy because it is a tremendous procedure and can be very tough especially in those cases where a previous radiotherapy has been administered on the mediastinum. The timing from the radiotherapy to the procedure may have its importance. Traditional imaging techniques such as CT and NMR still fail to give us the opportunity of a good mediastinal assessment, especially after an induction therapy has been administered due to the impossible discrimination of the neoplastic from the scar and fibrous tissue. Positron emission tomography seems to fit better our needing in this setting and a PET scan before and after the induction therapy is already scheduled in our new protocols but we have to remember that the false positive rate may be disturbingly high. Moreover PET is not yet widely available.
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