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Neoadjuvant chemoradiotherapy of stage III non-small-cell lung cancer
Lung Cancer 30 (2000) 175 – 185 www.elsevier.nl/locate/lungcan
Neoadjuvant chemoradiotherapy of stage III non-small-cell lung cancer Godehard Friedel a,*, Dagmar Hruska b, Wilfried Budach c, Martin Wolf d, Thomas Kyriss a, Martin Hu¨rtgen a, Hans-Paul Eulenbruch b, Rainer Dierkesmann b, Heikki Toomes a a
Department of Thoracic Surgery, Klinik Schillerho¨he, Solitudestraße 18, 70839 Gerlingen, Germany b Department of Oncological Pneumology, Klinik Schillerho¨he, Gerlingen, Germany c Department of Radiotherapy, Uni6ersity of Tu¨bingen, Tu¨bingen, Germany d Department of Hematology and Oncology, Uni6ersity of Marburg, Marburg, Germany Received 16 November 1999; received in revised form 30 March 2000; accepted 3 April 2000
Abstract Twenty to 30% of patients with non-small-cell lung cancer (NSCLC) in stage III are not resectable primarily with 5-year survival less than 10%. Since the majority of patients die from metastases, efforts have been made in the past to improve prognosis by application of neoadjuvant chemoradiotherapy regimens followed by subsequent resection. In a phase II study performed between 1993 and 1998, 93 patients in stage III (IIIA, 16%; IIIB, 84%) received an induction chemotherapy consisting of two cycles cisplatin (100 mg/m2) and vindesine (3 mg/m2) with subsequent sequential radiotherapy of 36 Gy. Sixty-five patients demonstrated partial or complete remission. Sixty underwent surgery; in 49 of them complete resection was possible. Five-year survival in the whole group was 24%, and that in the surgical cohort 39%. Six patients had no residual tumor. Postoperative N0 status was associated with a 5-year survival of 75%, and stage N1–3 with 13%. Thirty-day mortality was 7% postoperatively. Neoadjuvant chemoradiotherapy can significantly improve long-term survival in stage III NSCLC with an acceptable therapy-induced mortality. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Neoadjuvant chemoradiotherapy; Stage III; Non-small-cell lung cancer; Surgery
1. Introduction Therapy of stage III non-small-cell lung cancer (NSCLC) is still associated with poor long-term * Corresponding author. Tel.: +49-7156-2032-241; fax: + 49-7156-2032-003. E-mail address: [email protected] (G. Friedel).
survival. In stage IIIA, postoperative 5-year survival (5-YS) rates of up to 30% can be achieved [1]. More radical surgical therapies with complete lymphadenectomy led to a minor improvement in past decades. However, with surgery alone, no further increase of survival will be possible. Stage IIIB is still declared as an inoperable disease. The 5-YS rates following radiotherapy and/or
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chemotherapy do not exceed 5% [2]. With extended surgical procedures including lymphadenectomy of the contralateral N3 lymph node stations, 5-YS rates of 10 – 15% can be achieved [3]. However, further improvement did not occur in the past few years. In order to provide more than palliative forms of therapy to stage III patients, intensive research was started in the late 1980s on the application of neoadjuvant therapeutical regimens. It seems that neoadjuvant chemotherapy and/or radiotherapy could improve resectability. Best results were obtained by combined chemoradiotherapy regarding resectability and long-term survival. It is still unclear which regimen of chemotherapy, and which dosage and fractionation of radiotherapy, lead to optimal long-term survival with low morbidity and mortality. In the following, we present the results of a study on neoadjuvant therapy with cisplatin/vindesine followed by sequential radiotherapy started in 1993. 2. Patients and methods
2.1. Eligibility criteria and staging procedures This prospective study was open to selected patients with cytologically or histologically proven stage IIIA (N2) and stage IIIB (T4 and/or N3) NSCLC who had not previously received treatment. In stage IIIA, only patients with bulky mediastinal lymph node swelling were included. The definition of bulky N2 disease was a malignant appearing lymph node grater than 2 cm in its shortest diameter. In stage IIIB, patients with supracalvicular lymph nodes involved were not included. Eligibility requirements included age less than 70 years, no concurrent malignancies, no other serious disease, and a good performance status (Eastern Cooperative Oncology Group, scale 0–2). Patients were required to have adequate pulmonary (FEV1 \65%, PaO2 \70 Torr and increasing in exercise test), cardiac (no active arrhythmia, congestive heart failure or myocardial infarction), renal (serum creatinine51.50 mg/dl) and hematological (hemoglobin]10 g/dl; white blood cell count (WBC)]4000/mm3; platelet count ]100 000/mm3) functions.
The pretreatment evaluation consisted of a complete history and physical examination, electrocardiogram and pulmonary function tests including stress exercises, and a complete laboratory work-up. Staging procedures included chest Xray, bone scan, computed tomography (CT) scan of brain and chest, and abdominal ultrasonography or CT scan of the abdomen. Magnetic resonance imaging, pulmonary angiography and transesophageal endosonography (TEES) were performed to evaluate local tumor invasion into surrounding organs if necessary. All patients underwent bronchoscopy before study entry.
2.2. Study design Neoadjuvant therapy consisted of an induction chemotherapy with two cycles of cisplatin and vindesine. On day 1 and 29, the patients received 100 mg/m2 cisplatin by intravenous infusion. Then 3 mg/m2 vindesine were administered on days 1, 8, 29, and 36 intravenously as bolus injection. The treatment was delayed up to 2 weeks if WBCB 3500 mm3 and platelet countB 100 000 mm3 were found. In cases of continuous leukopenia and thrombopenia, the dose was adjusted with 60 mg2 cisplatin and 3 mg vindesine, absolutely abandoning the second dose. On day 31, radiotherapy was initiated. Portals were designed to cover the macroscopic tumor volume with a 2 cm safety margin, including the mediastinum from the jugulum to 5 cm below the carina and contralateral hilus. Supraclavicular lymph nodes were not included. The caudal field borders were individually adapted for lower lobe tumors. Planned preoperative radiotherapy consisted of 5× 2 Gy per week to 36 Gy using ventrodorsal opposite fields (\ 4 MV photons). All dose calculations refer to 80% of the maximum dose. If a response was revealed at restaging, resection was performed within 4 weeks. All resected patients were approached by a standard lateral thoracotomy to remove the primary tumor and the complete ipsilateral mediastinal lymph nodes. In primary N3 stages, a sampling of the contralateral paratracheal lymph nodes was carried out. In case of no change or even progression, radiother-
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apy using oblique opposed fields excluding the myelon was supplemented up to 60 Gy before another restaging. If operability was achieved at this time, the patient underwent surgery disregarding the original protocol. Patients with postsurgical microscopic (R1) or macroscopic (R2) residual disease, as well as N2 or N3 tumor involvement, who had not received full dose of radiotherapy were administered to receive radiotherapy using oblique opposed fields excluding the myelon up to 60 Gy within 4 weeks following surgery (Fig. 1).
2.3. Response criteria and restaging Response evaluation was based on World Health Organization (WHO) criteria. Complete response was defined as complete disappearance of all disease on radiographic and bronchoscopic examination, and partial response was defined as a greater than 50% reduction of the volume of all measurable lesions; stable disease showed no detectable change in tumor volume of all lesions and progressive disease was defined as an increase in tumor volume or the appearance of new lesions. Toxicities were assessed using the WHO common toxicity criteria. Restaging procedures included chest X-ray, bone scan, CT scan of brain and chest, abdominal ultrasonography or CT scan of the abdomen and bronchoscopy, as well as an electrocardiogram and pulmonary function test including stress exercises, and a complete laboratory work-up.
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2.4. Follow-up and statistics Patients were evaluated every 3 months for 3 years, then every 6 months for 2 years, and every year thereafter. Visits included a history, physical examination, chest X-ray, abdominal ultrasonography and laboratory work-up (blood count, electrolytes, chemistry profiles). CT scans of the chest were carried out every year. The survival duration was the period elapsed between the first day of protocol treatment and the date of death. Patients alive at the time of analysis had their survival duration censored at their last follow-up. Survival was estimated by the Kaplan– Meier method. Survival differences between subgroups were compared by log-rank test.
3. Results
3.1. Patients characteristics Between 1993 and 1998, 93 patients (77 men, 16 women) with stage III NSCLC underwent neoadjuvant chemoradiotherapy. Median age was 55 years (35–69 years). According to primary staging, 15 patients (16%) were in stage IIIA (N2), and 78 patients (84%) in stage IIIB. The male–female ratio was 83%/17%. Adenocarcinomas were found in 29%, squamous cell carcinomas in 62%, and others in 9%. In stage IIIB, 92% had N2 or N3 disease, and in 81% a T4 tumor was diagnosed. In 69%, the pretherapeutic stage was confirmed by mediastinoscopy, video-assisted thoracoscopy or exploratory thoracotomy. In the remaining cases, invasion of the central pulmonary artery or the left atrium was confirmed by CT scan or TEES (Table 1). All patients were assessed by an interdisciplinary conference as inoperable for oncological reasons.
3.2. Chemoradiotherapy
Fig. 1. Study design.
Of 93 patients, 84 (90%) received the complete dosage of chemotherapy. All patients received radiotherapy of at least 36 Gy. In 70% of all patients, restaging showed a response (3% complete, 67% partial), 14% had no change and, in
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178 Table 1 Patient characteristics before treatment Characteristic
IIIA
IIIB
Tumor stage Male Female Mean age (years)
15 (16%) 12 (80%) 3 (20%) 55
78 (84%) 65 (83%) 13 (17%) 55
93 77 (83%) 16 (17%) 55
21 49 8
27 (29%) 58 (62%) 8 (9%)
3 3 39 33 9 6 63 52 (67%)
3 3 54 33 14 16 63 64
Histology Adenocarcinoma Squamous cell Other N0 N1 N2 N3 T2 T3 T4 Surgically staged
6 9 0 0 0 15 0 5 10 0 12 (80%)
Total
(3%) (3%) (58%) (36%) (15%) (17%) (68%) (69%)
16%, a progression was observed. In this respect, there were no significant differences between stage IIIA and IIIB (Fig. 2). On the basis of this staging, 66 patients (71%) were judged suitable for surgical treatment. Three patients (3%) rejected surgery: one with a radiologically and bronchoscopically confirmed complete response, and two with partial response. Another three patients (3%) could not be operated upon for functional reasons. Preoperatively, nine patients had already received a radiation dosage of more than 50 Gy. Postoperatively, 19 patients received a completion of radiotherapy up to 56–60 Gy. In three patients, local brachytherapy was also applied. Thus, 47% of the resected patients had received full dose radiotherapy. Among those patients who did not undergo surgery, 21 patients (64%) received complete radiation dose.
Fig. 2. Remission rates.
Fig. 3. Radicality of surgical procedure.
G. Friedel et al. / Lung Cancer 30 (2000) 175–185 Table 2 Operative procedures Procedure
IIIA
IIIB
Total
Lobectomy +Bronchoplastic sleeve resection +Chest wall resection +Cava resection
4 1
13 6
17 (29%) 7
Bilobectomy +Bronchoplastic sleeve resection Pneumonectomy +Sleeve pneumonectomy +Bronchoplastic procedure +Chest wall resection +Atrial resection +Diaphragma resection
them (82%), i.e. 53% of the whole cohort (Fig. 3). The surgical procedures applied are detailed in Table 2. In 34% of the cases, lobectomies or bilobectomies were carried out, and in 58% pneumonectomies were performed. Forty-seven percent of the patients underwent extended procedures including chest wall, diaphragmatic and atrial resection. Postoperative change in tumor stage was found in 53% of IIIA patients. In 30%, there was a downstaging to I and II, and in 23% an upstaging to IIIB. In stage IIIB, there was a downstaging in 64%, with six patients (13%) having a complete response (Fig. 4).
1 1
1 1
2 2
1 2
3 (5%)
6
29 3 2 3 3 1
35 (58%) 3 4 3 4 1
2 2
2 (3%) 2
3.4. Toxicity
2
3 (5%)
Chemoradiotherapy was very well tolerated with only minor toxicity. In nine cases, the chemotherapeutic dosage was reduced or only one cycle was given because of side effects. The main reason for dose reduction was heavy vomiting grade 2 and 3. Two patients had a therapy-relevant increase in creatinine level grade 2.
2 1
Segmentectomy +Chest wall resection Exploratory thoracotomy
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1
3.3. Surgery Thus, 60 patients (65%) underwent surgery. A complete resection could be performed in 49 of
Fig. 4. Stage migration in resected patients.
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Table 3 Complications of operated patients Complication
n
%
Chylothorax Ileus (carcinoma of the colon) Postoperative bleeding Edema of the lung Respiratory insufficiency Bronchopleural fistula Sepsis Recurrent nerve palsy Total
1 1 1 2 2 1 1 6
2 2 2 3 3 2 2 10 26
30-Day mortality Hospital mortality
4 6
7 10
During and after radiation, side effects requiring therapy did not occur apart from mild esophagitis grade 1 and 2. Complications occurred in 26% of the resected patients. Thirty-day mortality was 7%, and inhospital mortality 10%. Regarding all 93 patients, the mortality of the treatment was 6% (Table 3). The cause of death was Acute Respiratory Distress Syndrome (ARDS) in two patients, who developed a fulminant lung edema in the first postoperative day and died in cardiorespiratory failure on the third day. One patient developed an insufficiency of the bronchial anastomosis with hemoptysis. After urgent secondary pneumonec-
tomy, he died on fulminant pulmonary embolism. Three other patients died on respiratory failure due to pneumonia and sepsis. None of the patients who received more than 50 Gy preoperatively developed major complications.
3.5. Sur6i6al In the total group of 93 patients, cumulative 5-YS was 24% with a median survival of 15 months. At present, 36 patients are alive, two of them for more than 5 years. Mean follow-up of the surviving patients is 24 months, and that in the whole group is 18 months. There is no difference in 5-YS between the primary stages IIIA and IIIB, at 22 and 24%, respectively. There is, however, a significant difference between resected and unresected cases. So far, no patient without surgery have survived longer than 3 years; the longest present survival time is 34 months. Four of 33 nonresected patients are still alive. Median survival is 8 months. In the cohort of resected patients, cumulative 5-YS is 39% with a median survival of 25 months. The difference is significant with PB0.0001. Of 60 resected patients, 32 are still alive. The longest survival time is 73 months (Fig. 5). When differentiating the surgical group with regard to postoperative N-stage, there is a significant advantage in long-term survival for the N0
Fig. 5. Cumulative survival according to treatment.
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Fig. 6. Cumulative survival for resected patients according to postoperative N-stage.
Fig. 7. Cumulative survival for resected patients according to postoperative stage.
subgroup. Cumulative 5-YS is 75%; so far only three out of 19 patients have died. The N1 group cannot be assessed because of the low number of patients. In the N2 group, 5-YS is only 20%, 11 of 28 patients are alive. In the N3 group, 5-YS is 19% with two of seven patients being survivors (Fig. 6). When evaluating N1 – 3 patients in the log-rank test with regard to N0, the result turns out to be highly significant (PB 0.0001). In terms of postoperative stages, as expected, the best results are found among those patients with a complete pathohistological response. In
our study, this was true for six patients, all of them still being alive with a longest survival of 74 months. Eleven patients were in postoperative stage I. The 5-YS is 90%, and only one patient has died. Six patients were in stage II, and three of them died; 5-YS has not been reached so far. Seventeen and 19 patients were in stage IIIA and IIIB, respectively, with a 5-YS of 18 and 10%. Eight and five patients are alive. The log-rank test was significant with P B 0.0001 (Fig. 7). One patient who had rejected surgery because of radiologically confirmed complete response died 1 year
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later from hemoptysis because of local recurrence. Relapse in the resected patients occurred in 25 (42%) cases. Seven patients are alive with disease. Relapse was locoregional in 11 and distant in 14 cases. The mean time to progress was 12 months (1 – 48 m).
4. Discussion In stages IIIA, individual positive N2 lymph nodes, which had not been detected by preoperative imaging techniques or mediastinoscopy, are associated with a 5-YS of 20 – 33% [4,5]. In more advanced stages with N2 disease confirmed by mediastinoscopy, 5-year survival rates of 9 – 18% are described [6,7]. There is only a consensus on the resection of minimal N2 disease with one involved N2 lymph node station according to the IASLC [8]. At present, radiotherapy is commonly accepted as adjuvant therapy in stage IIIA, although various studies have revealed that only the rate of local recurrences can be reduced from 20 – 40 to 5 – 15%. The development of metastases is not affected, and a significant prolongation of survival cannot be proved by the available phase III studies [9]. The situation in stage IIIB is somewhat clearer. Patients with contralateral or supraclavicular N3 lymph node invasion are generally considered as inoperable from the oncological point of view. A study performed by Naruke et al. showed that patients with N3 disease undergoing surgery did not reach 5-year survival [10]. Among T4 tumors, there are only single cases, which are resectable in technical and oncological terms [11]. Van Remdonck et al. report on a 5-year survival of 20 – 40% in T4 N0 cases [12]. In terms of scientific comparability and evaluation of stage III studies, the kind and amount of investigations applied for staging purposes constitute a major problem. In the diagnosis of Nstages, CT scan with a sensitivity and specificity of 40–60% is markedly inferior to mediastinoscopy with a sensitivity of 80 – 90% and a specificity of 100% [13 – 15]. The first experiences obtained with positron emission tomography have
shown a sensitivity and specificity of 80–90%, equaling mediastinoscopy [16,17]. The situation is far more difficult with regard to the exact staging of T4 tumors. CT scan only provides a sensitivity of 25–40% in the assessment of irresectability of T4 tumors [18]. Whether nuclear magnetic resonance in these tumors might achieve better results is still unclear. In order to determine tumor infiltration of the left atrium, transesophageal ultrasound is the method of choice. When evaluating a possible invasion of central vessels and mediastinal structures, video-assisted thoracoscopy and intraoperative videothoracoscopic sonography have provided satisfying first results [19,20]. In our own study, surgical interventions were employed for staging in 69%. In the other 31%, CT scan and TEES were used for staging in T4 tumors. Between 1950 and 1970, radiotherapy was employed in studies as neoadjuvant therapy with good response rates [21,22]. These results, however, could not be confirmed in randomized studies [23,24]. Thereafter, chemotherapy was preferred as neoadjuvant therapy with response rates ranging between 46 and 78%. Resection rates, however, only amounted to 51–68% in stage IIIA. Long-term survival rates were at most 22% [24–27]. Two randomized trials have compared chemotherapy+ surgery and surgery alone for stage IIIA NSCLC. Both groups found significant advantages in long-term survival for the chemotherapy groups, with 5-YS of 36% versus 17% in the M.D. Anderson trial and with only 17% versus 0% 5-YS in the Spanish trial [28,29]. Pass et al. found no significant differences between the groups, but a trend toward increased disease-free interval in the chemotherapy+ surgery group with 27 stage IIIA patients [30]. In the past few years, chemoradiotherapy has been increasingly applied for induction. In several phase II studies, encouraging survival rates could be achieved, but very few data are available for stage IIIB. In 1993, Rusch et al. reported for the Southwest Oncology Group (SWOG) on 28 patients in stage IIIB. After two cycles of cisplatin/ VP 16 and simultaneous radiotherapy of 45 Gy, a complete resection was possible in 72%. Two-year survival was 40% and postoperative mortality 6%,
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without differences in survival between IIIA and IIIB [31]. After a cycle of cisplatin and taxol combined with 30 Gy radiotherapy and another postoperative chemoradiotherapy cycle in ten resected patients, Rice et al. reported on a 2-year survival of 17% in stage IIIB, as opposed to 61% in 35 stage IIIA patients. Postoperative mortality was 5% [32]. In our own study, the neoadjuvant chemoradiotherapy with cisplatin and vindesine proved to be tolerated well. In 90%, the scheduled chemotherapy dosage and, in 100%, the dosage of radiotherapy could be administered. There were no deaths during induction therapy. In 70%, a response according to radiological criteria could be achieved. This corresponds to the experiences in the literature [32,33]. The rate of pathologically complete responses is 13% in the resected group with the patients who received 60 Gy radiotherapy preoperatively. In the reports by Elias et al. [27], Weiden and Piantadosi [34] and Rice et al. [32], similar rates of pathologically complete responses of 10–15% are described; only Stamatis and coworkers [33,37] reported on the markedly higher rate of 25%. In our study with 93 patients (84% in stage IIIB), 65% underwent surgery. In 82% of the operated patients, a complete resection could be performed, which corresponds to 53% of the whole group. These data are comparable with those of SWOG (75 and 63%, respectively) and Katakami et al. (41%) [32,35,36]. Although in 47%, extended resection procedures had to be performed, the 30-day mortality was only 7%. This is comparable with the surgical mortality of patient groups without neoadjuvant therapy and other study groups [1,37]. Up to now, we have seen no major long-term morbidity even in six patients who received 60 Gy radiotherapy preoperatively. Cumulative 5-YS including all patients is 24%. We found no differences in survival between the primary stages IIIA and IIIB. The cumulative 5-YS of patients with surgery is 39%; in the group of patients without surgery, all patients had died within 3 years. One patient with radiologically complete response died without operation after 1 year from a recurrence. When differentiating the patients as to their postoperative stage, all six patients with a pathologically
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complete response are alive: in stage I, 5-YS is 90%; in stage II, it has not so far been achieved. In the stages IIIA and IIIB, 5-YS dramatically declines to 18 and 10%, respectively, The results are similar when comparing postoperative N0 patients with N1–3 stages. In the N0 stage, 5-YS is 75% and is comparable with primary stage I. In stage N1–3, the survival rate with 13% is significantly worse and is only slightly more favorable than in those patients without operation. This tendency is confirmed by the study of the Southwest Oncology Group, who report a 3-year survival of 44% in postoperative N0 stage [35]. The long-term survival in this study was identical in an update presented at ASCO 1999. 5. Conclusion All data published so far on neoadjuvant chemoradiotherapy in advanced non-small-cell lung cancer have shown improved survival rates. The numbers of stage IIIB patients, however, were very small. In this investigation comprising 78 patients in stage IIIB, the possibility of longterm survival and possibly even cure at this stage could be shown. Whether these results with regard to the postoperative N-stages will influence the future strategy in multimodal therapeutical concepts has to be evaluated by further studies. We started a new trial in 1999 using weekly paclitaxel/ carboplatin as induction chemotherapy, followed by concurrent chemoradiotherapy with paclitaxel/ carboplatin in reduced dosage together with hyperfractioned radiotherapy twice daily up to 45 Gy. References [1] Friedel G, Linder A, Weigang S, Froeschle P, Toomes H. The surgical treatment of Stage III (N2). In: Carpagnano F, De Lena M, editors. Recent Advances in Lung Cancer. Milan: Masson, 1995:119 – 27. [2] Perez CA, Stanley K, Grundy G, Hanson W, Rubin P, Kramer S, Brady LW, Marks JE, Perez-Tamayo R, Brown GS, Concannon JP, Rotman M. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung. Cancer 1982;50:1091 – 9.
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III non-small-cell lung cancer: a phase II study of the lung cancer study group. J Natl Cancer Inst 1991;83:266 – 73. [35] Albain KS, Rusch VW, Crowley JJ, Rice TW, Turrisi AT, Weick JK. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stage IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880 – 92. [36] Katakami N, Okazaki M, Nishiuchi S, Fukuda H, Horikawa T, Nishiyama H, Inui H, Bando K. Induction chemoradiotherapy for advanced stage III non-small-cell lung cancer: long term follow-up in 42 patients. Lung Cancer 1998;22:127 – 37. [37] Eberhard W, Wilke H, Stamatis G, Stuschke M, Harstrick A, Menker H, Krause B, Mueller MR, Stahl M, Flasshove M, Budach V, Greschuchna D, Konietzko N, Sack H, Seeber S. Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small-cell lung cancer: mature results of a phase II trial. J Clin Oncol 1998;16:622 – 34.
Neoadjuvant chemoradiotherapy of stage III non-small-cell lung cancer Godehard Friedel a,*, Dagmar Hruska b, Wilfried Budach c, Martin Wolf d, Thomas Kyriss a, Martin Hu¨rtgen a, Hans-Paul Eulenbruch b, Rainer Dierkesmann b, Heikki Toomes a a
Department of Thoracic Surgery, Klinik Schillerho¨he, Solitudestraße 18, 70839 Gerlingen, Germany b Department of Oncological Pneumology, Klinik Schillerho¨he, Gerlingen, Germany c Department of Radiotherapy, Uni6ersity of Tu¨bingen, Tu¨bingen, Germany d Department of Hematology and Oncology, Uni6ersity of Marburg, Marburg, Germany Received 16 November 1999; received in revised form 30 March 2000; accepted 3 April 2000
Abstract Twenty to 30% of patients with non-small-cell lung cancer (NSCLC) in stage III are not resectable primarily with 5-year survival less than 10%. Since the majority of patients die from metastases, efforts have been made in the past to improve prognosis by application of neoadjuvant chemoradiotherapy regimens followed by subsequent resection. In a phase II study performed between 1993 and 1998, 93 patients in stage III (IIIA, 16%; IIIB, 84%) received an induction chemotherapy consisting of two cycles cisplatin (100 mg/m2) and vindesine (3 mg/m2) with subsequent sequential radiotherapy of 36 Gy. Sixty-five patients demonstrated partial or complete remission. Sixty underwent surgery; in 49 of them complete resection was possible. Five-year survival in the whole group was 24%, and that in the surgical cohort 39%. Six patients had no residual tumor. Postoperative N0 status was associated with a 5-year survival of 75%, and stage N1–3 with 13%. Thirty-day mortality was 7% postoperatively. Neoadjuvant chemoradiotherapy can significantly improve long-term survival in stage III NSCLC with an acceptable therapy-induced mortality. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Neoadjuvant chemoradiotherapy; Stage III; Non-small-cell lung cancer; Surgery
1. Introduction Therapy of stage III non-small-cell lung cancer (NSCLC) is still associated with poor long-term * Corresponding author. Tel.: +49-7156-2032-241; fax: + 49-7156-2032-003. E-mail address: [email protected] (G. Friedel).
survival. In stage IIIA, postoperative 5-year survival (5-YS) rates of up to 30% can be achieved [1]. More radical surgical therapies with complete lymphadenectomy led to a minor improvement in past decades. However, with surgery alone, no further increase of survival will be possible. Stage IIIB is still declared as an inoperable disease. The 5-YS rates following radiotherapy and/or
0169-5002/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 0 ) 0 0 1 5 1 - 3
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chemotherapy do not exceed 5% [2]. With extended surgical procedures including lymphadenectomy of the contralateral N3 lymph node stations, 5-YS rates of 10 – 15% can be achieved [3]. However, further improvement did not occur in the past few years. In order to provide more than palliative forms of therapy to stage III patients, intensive research was started in the late 1980s on the application of neoadjuvant therapeutical regimens. It seems that neoadjuvant chemotherapy and/or radiotherapy could improve resectability. Best results were obtained by combined chemoradiotherapy regarding resectability and long-term survival. It is still unclear which regimen of chemotherapy, and which dosage and fractionation of radiotherapy, lead to optimal long-term survival with low morbidity and mortality. In the following, we present the results of a study on neoadjuvant therapy with cisplatin/vindesine followed by sequential radiotherapy started in 1993. 2. Patients and methods
2.1. Eligibility criteria and staging procedures This prospective study was open to selected patients with cytologically or histologically proven stage IIIA (N2) and stage IIIB (T4 and/or N3) NSCLC who had not previously received treatment. In stage IIIA, only patients with bulky mediastinal lymph node swelling were included. The definition of bulky N2 disease was a malignant appearing lymph node grater than 2 cm in its shortest diameter. In stage IIIB, patients with supracalvicular lymph nodes involved were not included. Eligibility requirements included age less than 70 years, no concurrent malignancies, no other serious disease, and a good performance status (Eastern Cooperative Oncology Group, scale 0–2). Patients were required to have adequate pulmonary (FEV1 \65%, PaO2 \70 Torr and increasing in exercise test), cardiac (no active arrhythmia, congestive heart failure or myocardial infarction), renal (serum creatinine51.50 mg/dl) and hematological (hemoglobin]10 g/dl; white blood cell count (WBC)]4000/mm3; platelet count ]100 000/mm3) functions.
The pretreatment evaluation consisted of a complete history and physical examination, electrocardiogram and pulmonary function tests including stress exercises, and a complete laboratory work-up. Staging procedures included chest Xray, bone scan, computed tomography (CT) scan of brain and chest, and abdominal ultrasonography or CT scan of the abdomen. Magnetic resonance imaging, pulmonary angiography and transesophageal endosonography (TEES) were performed to evaluate local tumor invasion into surrounding organs if necessary. All patients underwent bronchoscopy before study entry.
2.2. Study design Neoadjuvant therapy consisted of an induction chemotherapy with two cycles of cisplatin and vindesine. On day 1 and 29, the patients received 100 mg/m2 cisplatin by intravenous infusion. Then 3 mg/m2 vindesine were administered on days 1, 8, 29, and 36 intravenously as bolus injection. The treatment was delayed up to 2 weeks if WBCB 3500 mm3 and platelet countB 100 000 mm3 were found. In cases of continuous leukopenia and thrombopenia, the dose was adjusted with 60 mg2 cisplatin and 3 mg vindesine, absolutely abandoning the second dose. On day 31, radiotherapy was initiated. Portals were designed to cover the macroscopic tumor volume with a 2 cm safety margin, including the mediastinum from the jugulum to 5 cm below the carina and contralateral hilus. Supraclavicular lymph nodes were not included. The caudal field borders were individually adapted for lower lobe tumors. Planned preoperative radiotherapy consisted of 5× 2 Gy per week to 36 Gy using ventrodorsal opposite fields (\ 4 MV photons). All dose calculations refer to 80% of the maximum dose. If a response was revealed at restaging, resection was performed within 4 weeks. All resected patients were approached by a standard lateral thoracotomy to remove the primary tumor and the complete ipsilateral mediastinal lymph nodes. In primary N3 stages, a sampling of the contralateral paratracheal lymph nodes was carried out. In case of no change or even progression, radiother-
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apy using oblique opposed fields excluding the myelon was supplemented up to 60 Gy before another restaging. If operability was achieved at this time, the patient underwent surgery disregarding the original protocol. Patients with postsurgical microscopic (R1) or macroscopic (R2) residual disease, as well as N2 or N3 tumor involvement, who had not received full dose of radiotherapy were administered to receive radiotherapy using oblique opposed fields excluding the myelon up to 60 Gy within 4 weeks following surgery (Fig. 1).
2.3. Response criteria and restaging Response evaluation was based on World Health Organization (WHO) criteria. Complete response was defined as complete disappearance of all disease on radiographic and bronchoscopic examination, and partial response was defined as a greater than 50% reduction of the volume of all measurable lesions; stable disease showed no detectable change in tumor volume of all lesions and progressive disease was defined as an increase in tumor volume or the appearance of new lesions. Toxicities were assessed using the WHO common toxicity criteria. Restaging procedures included chest X-ray, bone scan, CT scan of brain and chest, abdominal ultrasonography or CT scan of the abdomen and bronchoscopy, as well as an electrocardiogram and pulmonary function test including stress exercises, and a complete laboratory work-up.
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2.4. Follow-up and statistics Patients were evaluated every 3 months for 3 years, then every 6 months for 2 years, and every year thereafter. Visits included a history, physical examination, chest X-ray, abdominal ultrasonography and laboratory work-up (blood count, electrolytes, chemistry profiles). CT scans of the chest were carried out every year. The survival duration was the period elapsed between the first day of protocol treatment and the date of death. Patients alive at the time of analysis had their survival duration censored at their last follow-up. Survival was estimated by the Kaplan– Meier method. Survival differences between subgroups were compared by log-rank test.
3. Results
3.1. Patients characteristics Between 1993 and 1998, 93 patients (77 men, 16 women) with stage III NSCLC underwent neoadjuvant chemoradiotherapy. Median age was 55 years (35–69 years). According to primary staging, 15 patients (16%) were in stage IIIA (N2), and 78 patients (84%) in stage IIIB. The male–female ratio was 83%/17%. Adenocarcinomas were found in 29%, squamous cell carcinomas in 62%, and others in 9%. In stage IIIB, 92% had N2 or N3 disease, and in 81% a T4 tumor was diagnosed. In 69%, the pretherapeutic stage was confirmed by mediastinoscopy, video-assisted thoracoscopy or exploratory thoracotomy. In the remaining cases, invasion of the central pulmonary artery or the left atrium was confirmed by CT scan or TEES (Table 1). All patients were assessed by an interdisciplinary conference as inoperable for oncological reasons.
3.2. Chemoradiotherapy
Fig. 1. Study design.
Of 93 patients, 84 (90%) received the complete dosage of chemotherapy. All patients received radiotherapy of at least 36 Gy. In 70% of all patients, restaging showed a response (3% complete, 67% partial), 14% had no change and, in
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178 Table 1 Patient characteristics before treatment Characteristic
IIIA
IIIB
Tumor stage Male Female Mean age (years)
15 (16%) 12 (80%) 3 (20%) 55
78 (84%) 65 (83%) 13 (17%) 55
93 77 (83%) 16 (17%) 55
21 49 8
27 (29%) 58 (62%) 8 (9%)
3 3 39 33 9 6 63 52 (67%)
3 3 54 33 14 16 63 64
Histology Adenocarcinoma Squamous cell Other N0 N1 N2 N3 T2 T3 T4 Surgically staged
6 9 0 0 0 15 0 5 10 0 12 (80%)
Total
(3%) (3%) (58%) (36%) (15%) (17%) (68%) (69%)
16%, a progression was observed. In this respect, there were no significant differences between stage IIIA and IIIB (Fig. 2). On the basis of this staging, 66 patients (71%) were judged suitable for surgical treatment. Three patients (3%) rejected surgery: one with a radiologically and bronchoscopically confirmed complete response, and two with partial response. Another three patients (3%) could not be operated upon for functional reasons. Preoperatively, nine patients had already received a radiation dosage of more than 50 Gy. Postoperatively, 19 patients received a completion of radiotherapy up to 56–60 Gy. In three patients, local brachytherapy was also applied. Thus, 47% of the resected patients had received full dose radiotherapy. Among those patients who did not undergo surgery, 21 patients (64%) received complete radiation dose.
Fig. 2. Remission rates.
Fig. 3. Radicality of surgical procedure.
G. Friedel et al. / Lung Cancer 30 (2000) 175–185 Table 2 Operative procedures Procedure
IIIA
IIIB
Total
Lobectomy +Bronchoplastic sleeve resection +Chest wall resection +Cava resection
4 1
13 6
17 (29%) 7
Bilobectomy +Bronchoplastic sleeve resection Pneumonectomy +Sleeve pneumonectomy +Bronchoplastic procedure +Chest wall resection +Atrial resection +Diaphragma resection
them (82%), i.e. 53% of the whole cohort (Fig. 3). The surgical procedures applied are detailed in Table 2. In 34% of the cases, lobectomies or bilobectomies were carried out, and in 58% pneumonectomies were performed. Forty-seven percent of the patients underwent extended procedures including chest wall, diaphragmatic and atrial resection. Postoperative change in tumor stage was found in 53% of IIIA patients. In 30%, there was a downstaging to I and II, and in 23% an upstaging to IIIB. In stage IIIB, there was a downstaging in 64%, with six patients (13%) having a complete response (Fig. 4).
1 1
1 1
2 2
1 2
3 (5%)
6
29 3 2 3 3 1
35 (58%) 3 4 3 4 1
2 2
2 (3%) 2
3.4. Toxicity
2
3 (5%)
Chemoradiotherapy was very well tolerated with only minor toxicity. In nine cases, the chemotherapeutic dosage was reduced or only one cycle was given because of side effects. The main reason for dose reduction was heavy vomiting grade 2 and 3. Two patients had a therapy-relevant increase in creatinine level grade 2.
2 1
Segmentectomy +Chest wall resection Exploratory thoracotomy
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1
3.3. Surgery Thus, 60 patients (65%) underwent surgery. A complete resection could be performed in 49 of
Fig. 4. Stage migration in resected patients.
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Table 3 Complications of operated patients Complication
n
%
Chylothorax Ileus (carcinoma of the colon) Postoperative bleeding Edema of the lung Respiratory insufficiency Bronchopleural fistula Sepsis Recurrent nerve palsy Total
1 1 1 2 2 1 1 6
2 2 2 3 3 2 2 10 26
30-Day mortality Hospital mortality
4 6
7 10
During and after radiation, side effects requiring therapy did not occur apart from mild esophagitis grade 1 and 2. Complications occurred in 26% of the resected patients. Thirty-day mortality was 7%, and inhospital mortality 10%. Regarding all 93 patients, the mortality of the treatment was 6% (Table 3). The cause of death was Acute Respiratory Distress Syndrome (ARDS) in two patients, who developed a fulminant lung edema in the first postoperative day and died in cardiorespiratory failure on the third day. One patient developed an insufficiency of the bronchial anastomosis with hemoptysis. After urgent secondary pneumonec-
tomy, he died on fulminant pulmonary embolism. Three other patients died on respiratory failure due to pneumonia and sepsis. None of the patients who received more than 50 Gy preoperatively developed major complications.
3.5. Sur6i6al In the total group of 93 patients, cumulative 5-YS was 24% with a median survival of 15 months. At present, 36 patients are alive, two of them for more than 5 years. Mean follow-up of the surviving patients is 24 months, and that in the whole group is 18 months. There is no difference in 5-YS between the primary stages IIIA and IIIB, at 22 and 24%, respectively. There is, however, a significant difference between resected and unresected cases. So far, no patient without surgery have survived longer than 3 years; the longest present survival time is 34 months. Four of 33 nonresected patients are still alive. Median survival is 8 months. In the cohort of resected patients, cumulative 5-YS is 39% with a median survival of 25 months. The difference is significant with PB0.0001. Of 60 resected patients, 32 are still alive. The longest survival time is 73 months (Fig. 5). When differentiating the surgical group with regard to postoperative N-stage, there is a significant advantage in long-term survival for the N0
Fig. 5. Cumulative survival according to treatment.
G. Friedel et al. / Lung Cancer 30 (2000) 175–185
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Fig. 6. Cumulative survival for resected patients according to postoperative N-stage.
Fig. 7. Cumulative survival for resected patients according to postoperative stage.
subgroup. Cumulative 5-YS is 75%; so far only three out of 19 patients have died. The N1 group cannot be assessed because of the low number of patients. In the N2 group, 5-YS is only 20%, 11 of 28 patients are alive. In the N3 group, 5-YS is 19% with two of seven patients being survivors (Fig. 6). When evaluating N1 – 3 patients in the log-rank test with regard to N0, the result turns out to be highly significant (PB 0.0001). In terms of postoperative stages, as expected, the best results are found among those patients with a complete pathohistological response. In
our study, this was true for six patients, all of them still being alive with a longest survival of 74 months. Eleven patients were in postoperative stage I. The 5-YS is 90%, and only one patient has died. Six patients were in stage II, and three of them died; 5-YS has not been reached so far. Seventeen and 19 patients were in stage IIIA and IIIB, respectively, with a 5-YS of 18 and 10%. Eight and five patients are alive. The log-rank test was significant with P B 0.0001 (Fig. 7). One patient who had rejected surgery because of radiologically confirmed complete response died 1 year
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later from hemoptysis because of local recurrence. Relapse in the resected patients occurred in 25 (42%) cases. Seven patients are alive with disease. Relapse was locoregional in 11 and distant in 14 cases. The mean time to progress was 12 months (1 – 48 m).
4. Discussion In stages IIIA, individual positive N2 lymph nodes, which had not been detected by preoperative imaging techniques or mediastinoscopy, are associated with a 5-YS of 20 – 33% [4,5]. In more advanced stages with N2 disease confirmed by mediastinoscopy, 5-year survival rates of 9 – 18% are described [6,7]. There is only a consensus on the resection of minimal N2 disease with one involved N2 lymph node station according to the IASLC [8]. At present, radiotherapy is commonly accepted as adjuvant therapy in stage IIIA, although various studies have revealed that only the rate of local recurrences can be reduced from 20 – 40 to 5 – 15%. The development of metastases is not affected, and a significant prolongation of survival cannot be proved by the available phase III studies [9]. The situation in stage IIIB is somewhat clearer. Patients with contralateral or supraclavicular N3 lymph node invasion are generally considered as inoperable from the oncological point of view. A study performed by Naruke et al. showed that patients with N3 disease undergoing surgery did not reach 5-year survival [10]. Among T4 tumors, there are only single cases, which are resectable in technical and oncological terms [11]. Van Remdonck et al. report on a 5-year survival of 20 – 40% in T4 N0 cases [12]. In terms of scientific comparability and evaluation of stage III studies, the kind and amount of investigations applied for staging purposes constitute a major problem. In the diagnosis of Nstages, CT scan with a sensitivity and specificity of 40–60% is markedly inferior to mediastinoscopy with a sensitivity of 80 – 90% and a specificity of 100% [13 – 15]. The first experiences obtained with positron emission tomography have
shown a sensitivity and specificity of 80–90%, equaling mediastinoscopy [16,17]. The situation is far more difficult with regard to the exact staging of T4 tumors. CT scan only provides a sensitivity of 25–40% in the assessment of irresectability of T4 tumors [18]. Whether nuclear magnetic resonance in these tumors might achieve better results is still unclear. In order to determine tumor infiltration of the left atrium, transesophageal ultrasound is the method of choice. When evaluating a possible invasion of central vessels and mediastinal structures, video-assisted thoracoscopy and intraoperative videothoracoscopic sonography have provided satisfying first results [19,20]. In our own study, surgical interventions were employed for staging in 69%. In the other 31%, CT scan and TEES were used for staging in T4 tumors. Between 1950 and 1970, radiotherapy was employed in studies as neoadjuvant therapy with good response rates [21,22]. These results, however, could not be confirmed in randomized studies [23,24]. Thereafter, chemotherapy was preferred as neoadjuvant therapy with response rates ranging between 46 and 78%. Resection rates, however, only amounted to 51–68% in stage IIIA. Long-term survival rates were at most 22% [24–27]. Two randomized trials have compared chemotherapy+ surgery and surgery alone for stage IIIA NSCLC. Both groups found significant advantages in long-term survival for the chemotherapy groups, with 5-YS of 36% versus 17% in the M.D. Anderson trial and with only 17% versus 0% 5-YS in the Spanish trial [28,29]. Pass et al. found no significant differences between the groups, but a trend toward increased disease-free interval in the chemotherapy+ surgery group with 27 stage IIIA patients [30]. In the past few years, chemoradiotherapy has been increasingly applied for induction. In several phase II studies, encouraging survival rates could be achieved, but very few data are available for stage IIIB. In 1993, Rusch et al. reported for the Southwest Oncology Group (SWOG) on 28 patients in stage IIIB. After two cycles of cisplatin/ VP 16 and simultaneous radiotherapy of 45 Gy, a complete resection was possible in 72%. Two-year survival was 40% and postoperative mortality 6%,
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without differences in survival between IIIA and IIIB [31]. After a cycle of cisplatin and taxol combined with 30 Gy radiotherapy and another postoperative chemoradiotherapy cycle in ten resected patients, Rice et al. reported on a 2-year survival of 17% in stage IIIB, as opposed to 61% in 35 stage IIIA patients. Postoperative mortality was 5% [32]. In our own study, the neoadjuvant chemoradiotherapy with cisplatin and vindesine proved to be tolerated well. In 90%, the scheduled chemotherapy dosage and, in 100%, the dosage of radiotherapy could be administered. There were no deaths during induction therapy. In 70%, a response according to radiological criteria could be achieved. This corresponds to the experiences in the literature [32,33]. The rate of pathologically complete responses is 13% in the resected group with the patients who received 60 Gy radiotherapy preoperatively. In the reports by Elias et al. [27], Weiden and Piantadosi [34] and Rice et al. [32], similar rates of pathologically complete responses of 10–15% are described; only Stamatis and coworkers [33,37] reported on the markedly higher rate of 25%. In our study with 93 patients (84% in stage IIIB), 65% underwent surgery. In 82% of the operated patients, a complete resection could be performed, which corresponds to 53% of the whole group. These data are comparable with those of SWOG (75 and 63%, respectively) and Katakami et al. (41%) [32,35,36]. Although in 47%, extended resection procedures had to be performed, the 30-day mortality was only 7%. This is comparable with the surgical mortality of patient groups without neoadjuvant therapy and other study groups [1,37]. Up to now, we have seen no major long-term morbidity even in six patients who received 60 Gy radiotherapy preoperatively. Cumulative 5-YS including all patients is 24%. We found no differences in survival between the primary stages IIIA and IIIB. The cumulative 5-YS of patients with surgery is 39%; in the group of patients without surgery, all patients had died within 3 years. One patient with radiologically complete response died without operation after 1 year from a recurrence. When differentiating the patients as to their postoperative stage, all six patients with a pathologically
183
complete response are alive: in stage I, 5-YS is 90%; in stage II, it has not so far been achieved. In the stages IIIA and IIIB, 5-YS dramatically declines to 18 and 10%, respectively, The results are similar when comparing postoperative N0 patients with N1–3 stages. In the N0 stage, 5-YS is 75% and is comparable with primary stage I. In stage N1–3, the survival rate with 13% is significantly worse and is only slightly more favorable than in those patients without operation. This tendency is confirmed by the study of the Southwest Oncology Group, who report a 3-year survival of 44% in postoperative N0 stage [35]. The long-term survival in this study was identical in an update presented at ASCO 1999. 5. Conclusion All data published so far on neoadjuvant chemoradiotherapy in advanced non-small-cell lung cancer have shown improved survival rates. The numbers of stage IIIB patients, however, were very small. In this investigation comprising 78 patients in stage IIIB, the possibility of longterm survival and possibly even cure at this stage could be shown. Whether these results with regard to the postoperative N-stages will influence the future strategy in multimodal therapeutical concepts has to be evaluated by further studies. We started a new trial in 1999 using weekly paclitaxel/ carboplatin as induction chemotherapy, followed by concurrent chemoradiotherapy with paclitaxel/ carboplatin in reduced dosage together with hyperfractioned radiotherapy twice daily up to 45 Gy. References [1] Friedel G, Linder A, Weigang S, Froeschle P, Toomes H. The surgical treatment of Stage III (N2). In: Carpagnano F, De Lena M, editors. Recent Advances in Lung Cancer. Milan: Masson, 1995:119 – 27. [2] Perez CA, Stanley K, Grundy G, Hanson W, Rubin P, Kramer S, Brady LW, Marks JE, Perez-Tamayo R, Brown GS, Concannon JP, Rotman M. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung. Cancer 1982;50:1091 – 9.
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[30]
[31]
[32]
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