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© 2003 European Association of Cardio-Thoracic Surgery
Combined surgery of intrapleural perfusion hyperthermic chemotherapy and panpleuropneumonectomy for lung cancer with advanced pleural spread: a pilot study
a Division of the General Thoracic Surgery, Takarazuka Municipal Hospital, Hyogo, Japan
* Corresponding author. Department of Surgery, Osaka University Graduate School of Medicine, E1, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: +81-6-6879-3152; fax: +81-6-6879-3163 Received March 31, 2003; received in revised form July 4, 2003; accepted August 26, 2003
For the treatment of lung cancer with advanced pleural spread, aggressive local treatment could offer a chance of cure. This study evaluates the early and midterm results of our Phase I trial for the new modality of two-stage approach combining thoracoscopic intrapleural perfusion hyperthermic chemotherapy (TIPHC) and panpleuropneumonectomy for the disease. Five patients were enrolled in this study. All had proven lung cancer with major malignant pleural effusion or numerous pleural dissemination. The combined regimen was planned first with TIPHC using high doses of cisplatin, followed by a second stage with panpleuropneumonectomy with full-thoracotomy approach as radical surgery. All patients successfully completed this treatment, and there were no serious complications. Panpleuropneumonectomy was performed 14±1.2 days after TIPHC, and the mean operation time was 280±35 min, the blood loss was 620±89 ml. One patient with pathological N2 developed liver metastases 8 months after surgery and died. The other four patients are living and have not experienced any recurrence to date. The mean survival time is 19 months, and the longest is 32 months. Our new treatment modality is feasible and seems to provide a possibility for safe and effective radical local tumor control for patients of lung cancer with advanced carcinomatous pleuritis.
Key Words: Hyperthermic chemotherapy; Lung cancer; Carcinomatous pleuritis; Malignant effusion; Panpleuropneumonectomy; Cisplatin
Non-small cell lung cancer with malignant pleural effusion and pleural dissemination has a very poor prognosis, and many attempts to treat the disease including the surgery have not met with success. Therefore, surgical therapy alone is generally not recommended [1]. In order to improve prognosis, more extensive surgical procedures, such as pleuropneumonectomy and adjuvant chemotherapy, have been attempted, but no ‘gold standard’ for therapy has yet been established [2,3]. Recently, Kodama et al. reported good results using a combination of intrapleural hyperthermic chemotherapy and lung resection in patients in whom pleural dissemination without malignant effusion was first detected at thoracotomy. Interest has now focused on the usefulness of intrapleural hyperthermic chemotherapy as a novel type of adjuvant pleural therapy [4,5]. However, similar trials of multimodality treatment in patients with more advanced disseminated lung cancer, and major malignant effusion have yet to be conducted, and whether this treatment might offer such patients a chance of cure remains to be determined [3,5]. The present study evaluates the feasibility, early and mid-term results of an aggressive, locoregional two-stage approach combining intrapleural perfusion hyperthermic chemotherapy and panpleuropneumonectomy as our pilot study in phase I trial for the management of lung cancer with carcinomatous pleuritis.
Five patients, including three men and two women, ranging in age from 50 to 67 years (mean, 58 years), were enrolled in the study. Eligibility criteria for study treatment included the following: (1) confirmation after detailed evaluation of lung cancer with stage cN0–1M0; (2) age 70 years or younger; (3) no coexistence of cardiac complications; and (4) adequate performance status. This study was approved by the Institutional Review Board of Takarazuka Municipal Hospital for a phase I study. Additionally, the potential risks of treatment, standard and alternative treatment modalities were explained to each patient, and written, informed consent was obtained prior to treatment. The primary tumors in all five patients were lobar lesions, and the histological type was adenocarcinoma in four patients and adenosquamous carcinoma in one patient. The mean tumor diameter was 3.4 cm (range, 2.0–4.5 cm). Four of the five patients who had major malignant pleural effusion (>300 ml, E2) were undergoing thoracic drainage, and were diagnosed with carcinomatous pleuritis before surgery. One patient had minor malignant pleural effusion first detected at the time of surgery (E1), but numerous dissemination was proven by the intraoperative cytodiagnosis (D2). The degree of dissemination was classified as follows: D1, less than 10 visible dissemination nodules; D2, more than 11 visible disseminated nodules; D0, no visible nodules but cytology-positive effusion. The combined treatment regimen was planned first with thoracoscopic intrapleural perfusion hyperthermic chemotherapy, followed by a second stage with panpleuropneumonectomy as radical surgery. The specific procedures are described below. 2.1. Thoracoscopic intrapleural perfusion hyperthermic chemotherapy (TIPHC) Intrapleural perfusion hyperthermic chemotherapy was performed in general accordance with the method as previously reported [5]. However, we performed all procedures completely under thoracoscopic guidance without the use of open surgery (thoracoscopic intrapleural perfusion hyperthermic chemotherapy; TIPHC). TIPHC was started with three trocar ports placed. After pleural biopsy was performed, a temperature probe was positioned under the intercostal pleura. Then two tubes for irrigation inlet and drainage outlet were inserted and connected to a specially devised circuit (heat exchanger, roller pump, reservoir: CP FOUR BCP, Mera, Tokyo, Japan). Physiologic saline (2000 cm2) was perfused, and with an intrathoracic temperature of 43 °C confirmed, then cisplatin (CDDP) 200 mg/m2 was injected and perfused through the circuit for 2 h. Additionally, a thoracic drain was placed to complete the surgical procedure.Before the second operation, cytological examination of pleural effusion for tumor cells from a thoracic drain was performed at least twice, and the negative results were confirmed. Then, panpleuropneumonectomy, as local radical surgery, was scheduled about 2 weeks after TIPHC. 2.2. Panpleuropneumonectomy (Full-thoracotomy approach) Each patient was placed in a lateral decubitus position. A slightly longer posterior incision was made. Four ribs and intercostal muscles were cut along the mid-axillary line. Incisions were also made dorsally in the 4th intercostal and ventrally in the 9th. Two rib spreaders were positioned as shown in Fig. 1. This approach was performed in all patients for panpleuropneumonectomy with resection of the pericardium and diaphragm. For postoperative management, cricothyrotomy was performed the day after surgery using a Mini-Trach II Kit (Mini-Trach II; SIMS Portex Ltd., Kent, England) to prevent pneumonia.
This surgical procedure was evaluated with respect to operation time, intraoperative blood loss, length of postoperative ICU stay, duration of thoracic drainage, and postoperative complications. Usefulness of the combined treatment regimen was evaluated based on survival time and on serum carcinoembryonic antigen (CEA) levels before and after TIPHC and panpleuropneumonectomy.
Table 1 summarizes the clinical characteristics including E and D factors. The pleural findings at the time of TIPHC showed two patients in the E2D1 and E2D2 category, respectively, and one patient in the E1D2 category. Treatment was completed in all patients as expected.
After TIPHC, two patients experienced nausea and one patient each had mild nephrotoxicity and bradycardia, but there were no serious adverse reactions associated with the procedure. The results of cytological examinations of pleural effusion after TIPHC showed negative in all cases including four cases with major malignant effusion before the treatment. Table 2 shows the operative results with panpleuropneumonectomy by full-thoracotomy approach. Two patients in the E2D2 category showed the whole lung adhered severely to the chest wall, so their pleural findings during the surgery could not be obtained. However, those of the remaining three patients revealed no visible disseminated nodule (D0). The mean operation time was 280±35 min, the blood loss was 620±89 ml, and the length of ICU stay was 1.2±0.5 days. Postoperative complications included supraventricular arrhythmias in two patients and acute pulmonary embolism in one patient. There was no worsening of symptoms, and all improved with conservative management. There were no other complications, and all patients improved and were discharged from the hospital. One patient with pathological N2 (patient 3) developed liver metastases 8 months after surgery and died. The other four patients are living and have not experienced any tumor recurrence to date. The mean survival time is 19 months, and the longest (patient 1) is 32 months.
Assessment of changes in CEA levels before and after treatment showed high baseline levels preoperatively in all patients, with a mean value of 36.8±9.2 ng/ml (upper limits of normal for CEA, 5.0 ng/ml). CEA markedly decreased in all patients after TIPHC, and with the exception of one patient (patient 3), completely normalized after panpleuropneumonectomy (Table 3).
The treatment strategy for disseminated non-small cell lung cancer with malignant pleural effusion but no distant metastases is often perplexing and remains controversial but the major challenge for the thoracic surgeons [6]. Patients with non-small cell lung cancer and carcinomatous pleuritis are generally not considered suitable candidates for surgery, and palliative treatment modalities such as pleurodesis are common in these patients. A recent multicenter collaborative study reported a poor prognosis in non-small cell cancer with malignant pleural effusion and dissemination when treated by lung resection alone [7]. Then, some medical centers are now combining chemotherapy with more radical surgical procedures in selected patients [3,8]. On the other hand, good results have been reported with the use of adjuvant intrapleural hyperthermic chemotherapy. In patients with non-small cell lung cancer and carcinomatous pleuritis, Matsuzaki et al. reported a mean survival time of 20 months using a combination of lung resection and hyperthermic chemotherapy but only 6 months without combined treatment [5]. However, in their study, these combined treatments were used only in patients with disseminated lung cancer at a stage with no or minor pleural effusions and relatively early dissemination first detected at thoracotomy. Effective treatment regimens have not been evaluated in lung cancer with more advanced dissemination and major malignant pleural effusions [6]. Before this study, we had applied TIPHC to these E2D2 category cases with advanced pleural spread; however, in these cases, TIPHC alone could not provide long-term survival for the patients and we had experienced a high incidence of local recurrence with them (data not shown). Therefore we devised the present strategy of a second stage of therapy with panpleuropneumonectomy, as radical surgery, after induction therapy of the disseminated lesions with intrapleural perfusion hyperthermic chemotherapy. Although several studies have reported the use of panpleuropneumonectomy in carcinomatous pleuritis [9,10], some believe that panpleuropneumonectomy is difficult in carcinomatous pleuritis with advanced dissemination because disseminated lesions are difficult to completely remove, thus predisposing to postoperative local recurrence, and due to advanced dissemination, parietal pleurectomy in areas involving the pericardium and diaphragm is difficult, thus contributing to increased blood loss and surgical mortality [9,11]. We used intrapleural perfusion hyperthermic chemotherapy, as induction adjuvant therapy, to improve local tumor eradication with the following objectives: (1) to reduce or eradicate the disseminated lesions as much as possible; (2) to prevent intraoperative (radical surgery) lesion re-dissemination by subpleural treatment; and (3) to improve overall prognosis. Some mild adverse effects occurred with hyperthermic chemotherapy, but there were no serious problems, and panpleuropneumonectomy could be performed in all patients 2 weeks later. In performing panpleuropneumonectomy, the first consideration is how best to minimize surgical invasiveness because the major problem in carcinomatous pleuritis is that it is a highly invasive procedure associated with significant intraoperative bleeding and surgical related deaths [10,11]. Our surgical approach in all patients was a full-thoracotomy. The extent of the skin incisions and bony thorax involved with this approach makes it seem like a highly invasive procedure, but the wide access with view of the thoracic apex, along the diaphragm, and area around the pericardium, is advantageous for this surgical procedure in terms of reliability and safety [12]. As a result, as shown in Table 2, the mean blood loss was 620 ml and the mean operation time was 280 min with this approach. These results are significantly better than previously reported [9], thus demonstrating this to be a safe and reliable surgical procedure. Concerning these favorable results, the effects and contribution of hyperthermic chemotherapy should also be considered. Because of parietal pleural thickening affected by hyperthermic chemotherapy, parietal pleurectomy, including the disseminated lesions, could more easily be performed. In addition, the excellent field of view in all patients made it possible to perform pericardial and diaphragmatic resection without any problems. One of the biggest concerns in the immediate postoperative period is the development of pneumonia because of decreased sputum expectoration in immuno-suppressed conditions after adjuvant chemotherapy using high dose of CDDP. To prevent this serious problem, we performed a mini-tracheostomy (Mini Trach II) in all patients on the day after surgery and respiratory complications, including pneumonia, were not observed in any patients. One patient on postoperative day 18 developed a pulmonary embolus in the remaining lung. However, anticoagulant therapy immediately after onset of symptoms prevented exacerbation, and the patient had an uneventful recovery. Four of the five patients are still living and have had no tumor recurrence, but one patient with pN2 died within a year of treatment. In a study evaluating panpleuropneumonectomy in carcinomatous pleuritis, Yokoi et al. reported long-term survival only in stage N0 and N1 patients [13]. In another study investigating the effects of visceral pleural invasion (VPI) on prognosis in lung cancer, Manac'h et al. proposed a pathway of dissemination of lesions by subpleural lymph flow, mediastinal lymph node drainage, and flow through the jugular vein, thus leading to systemic metastases [14]. Based on these findings, it may be reasonable to assume that in patients with pleural dissemination but no distant metastases, including in the mediastinal lymph nodes, that metastases are limited to pleural carcinomatosis [6,13]. Our evaluation of CEA levels showed that in all four patients who are currently alive, CEA levels normalized after treatment. There was persistent elevation of the CEA only in patient 3 with pN2. In an investigation of changes in serum CEA before and after surgery in patients with early staged lung cancer, Sawabata et al. found serum CEA to be a significant prognostic factor [15]. We observed similar results in the present study. Accordingly, the results of evaluation of lymph node metastases can suggest that in the four patients with CEA levels normalized after the surgery, metastases may be limited to pleural carcinomatosis. In other words, the N factor may be the most important factor in determining which patients are suitable candidates for our combined treatment regimen. Postoperative adjuvant therapy included the use of systemic chemotherapy in all patients. It has previously been reported that lung cancer patients with pleural dissemination are prone to development of distant metastases [4,5]. Therefore, the use of systemic chemotherapy after radical local tumor control is important in providing complete treatment. The present study has limitations due to the small number of patients (5) and relatively short follow-up period. Therefore we should be careful in drawing early conclusions that our results seem to provide a good chance for safe and effective cancer treatment and better prognosis. However, our findings suggest that in patients with carcinomatous pleuritis in whom metastases may be limited to pleural carcinomatosis, treatment with ‘combined surgery of intrapleural perfusion hyperthermic chemotherapy and panpleuropneumonectomy’ may have a possibility for the radical local tumor control. Patients with carcinomatous pleuritis and malignant effusions should be carefully considered as candidates for this treatment regimen in order to investigate the clinical usefulness in a larger number of cases. doi:10.1016/S1569-9293(03)00197-X
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Abstract
1. Introduction