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NEOPLASTIC PLEURAL EFFUSIONS. OUR THERAPEUTIC PROGRESS
C. Arrigoni, E. Tisi, D. Ballabio, E. Cassina, M .Costa Angeli, *P. Lissoni, C. Benenti Department of Thoracic Surgery - San Gerardo Hospital – Monza - Italy. *Department of Radioterapy - San Gerardo Hospital – Monza - Italy.
Primitive and secondary malignant pleural effusion are still an unresolved medical problem. Many different therapeutic strategies have been proposed, however a commonly accepted protocol still has to be defined. Until 1981,we performed pleuro-pneumonectomy in diffusive pleural mesothelioma , limited to Boutchart’s stage I., with poor results.(average surv. 12 months).In the following 10 years, we obtained excellent results in terms of quality of life using pleurectomy and palliative anti-effusive decortication. (average surv.13months). The most significant change in our therapeutic approach to mesothelioma and all secondary malignant pleural effusions has occurred more recently, since we decided to attempt local therapy by intra-pleural rIL2 .In the period from 1992 through December 1997 ,we treated 95 patients with multi-recidive malignant pleural effusion(45 primary,50 secondary) immediately after thoracoscopic diagnosis, by intrapleural infusion of Euro Cetus human rIL2( 9 millions UI, once or twice ) , until achievement of stable X-ray appearance. We evaluated the therapeutic response according to Paladine’s criteria(CR 47 - PR 40 cases).We observed an excellent tolerability, no complication and stable effusion during a follow up period of 6 months. The observed better efficacy of rIL2, compared to other cytokines , could be ascribed to endogenous production of TNF and interferon.
To date, malignant pleural effusions, both primitive and secondary, remain an unsolved problem in clinical practice. Several strategies have been proposed, but a consensus has not yet been reached over a reliable treatment protocol. From an historical point of view, literature data regarding primitive pleural malignancies (mesotheliomas) show that surgery has been the earliest approach to the disease: extrapleuropneumonectomy, as radical as possible, has been proposed as a single treatment, aimed at the ablation of the whole macroscopically detectable tumoral mass. Nevertheless, such surgical approach has been associated with a high perioperative mortality and with a marked incidence of sequelae, with an extremely low survival rate at 2 years. All patients that did not meet the above selection criteria were only eligible for radiation therapy or chemotherapy, alone or variably combined. Later on, in consideration of all these data, the surgical approach became less aggressive, even though extrapleuropneumonectomy has not been completely abandoned in mesotheliomas, and it has been generally confined to I.M.I.G. stage I. Surgical approach was limited to total parietal pleurectomy, or, more often, subtotal parietal pleurectomy, associated with visceral pleural stripping (lung decortication) and, in selected cases, to excision of sections of the diaphragm pericardium and lung. This procedure, although exclusively palliative, appears to be the best option for mesothelioma patients. Since it maintains lung integrity, pleurectomy does not have the same limits as pleuro-pneumonectomy. It carries an immediate relief for the patient, by decreasing dispnoea and pain, and by controlling effusion recurrence even at long term. In our experience, a dramatic change of the therapeutic strategy for malignant pleural mesothelioma occurred in recent years, concomitantly with clinical trials which tested the use of rIL2 in advanced pulmonary malignancies. This same strategy has been consequently extended to all kinds of malignant pleural effusions. Advances in technical acquisition of thoracoscopy and its expanding indications to diagnosis and staging of all kinds of malignant pleural effusions, led us to test a topical therapy with intrapleural rIL2 early after diagnosis. Several cytokines, namely alpha-Interferon, beta-Interferon, TNF and IL2 seem to offer an alternative option in the palliative care of such malignant pleural effusions, both because of their antitumoral activity and their ability of inducing fibrosis. IL2 is a glycoprotein produced by T-cells and it also influences other cellular lines, such as NK-cells and B-lymphocytes. IL2 is secreted mainly by T-cells with co-operative phenotype (CD4+); cytotoxic T-lymphocytes (CD8+) able to secrete low quantities of IL2 have been described too. The marked difference observed in the T-cells for the production of IL2 is related to the amount of specific mRNA. IL2 activity is related to its linkage with a specific receptor located on the cell wall (IL2-R). The interaction between IL2 and IL2-R induces, as a main effect, progression of cellular cycle from G1 to S phase (synthesis of DNA), with subsequent cellular mitosis. The most important biological activity of IL2 is the induction of proliferation of activated T-cells. This effect derives both directly from inducing the transition from G1 to S phase in the cellular cycle, and indirectly from inducing the production in the T-cells of other lymphokynes, particularly gamma-IFN. Moreover, IL2 directly stimulates NK-cells and cytotoxic cells which are activated by lymphokine (lymphokine-activated killer, LAK). Finally, IL2 also plays a direct role among B-cells, since activated B-cells have high affinity IL-R and interaction between IL2 and these cells increases antibody production. IL2, therefore, plays a central role in the interleukin network which modulate immunological response. Due to their antineoplastic action and to their stimulating effects in the process of fibrosis, cytokines represent a new possible palliative therapy of neoplastic effusions. Il2 appears to be the most interesting among all the cytokines eventually eligible as a treatment for effusions, both because it is the main factor associated with antineoplastic immunological response and because it has the property of inducing endogenous production of other cytokines, particularly Interferon and TNF. Both the latter cytokines are active against effusions. IL2 therefore appears to have two potential actions: an antineoplastic action and a sclerotizing anti-effusive action. METHODS Efficacy of antieffusive treatment with intrapleural IL2 has never been related to lesion location nor to cancer hystotype (this holds true not only for mesotheliomas, but also for pleural effusions due to different malignancies: lung adenocarcinoma, breast cancer, ovarian cancer, cervical cancer etc.). Effective control of malignant effusions was observed in patients with persistent positivity for CTM in the pleural fluid. This observation demonstrates that the treatment with intracavitary IL2 avoids repeated accumulation of fluid, not only with an antineoplastic mechanism (debatable at low IL2 doses), but mainly inducing fibrosis processes. Clinical response has been evaluated according to Paladine’s criteria: - Complete response (CR): fluids do not reaccumulate during the first 30 days; - Partial response (PR): recurrence of a small amount of effusion which does not need to be drained in the first 30 days. - No response (PD): recurrence of effusion which needs to be evacuated. Initially a thoracoscopy is performed in order to confirm diagnosis and staging. At the end of thoracoscopic procedure, a double lumen drainage tube is left in place. Subsequently an intrapleural infusion is started with rIL2 9 millions UI (Euro-Cetus, Amsterdam-Holland) diluted in 3 ml D5W + 0.5 ml of 20% human albumin. This mixture is again diluted to 20 ml with normal saline. After clamping the pleural drainage, the patient rests in various decubitus for 2 hours in order to homogeneously spread IL2 all over the pleural cavity. The pleural tube is unclamped after 24 to 36 hrs and any eventual effusion is drained and measured. Independently from the amount of drained fluid, a second dose of rIL2 at the same dilution is then administered. After 2 or 3 days the drainage tube is opened again and effusion is measured. If the drained fluid exceeds 200 ml/day, a third administration of rIL2 is given, otherwise the treatment is considered complete and the patient is enrolled in the follow-up phase. The only detected sign of toxicity was a transient temperature increase to 38°-40°. Transient reactive eosinophylia may occur. In our experience, neither nausea and vomiting nor cardiovascular accidents due to this treatment ever occurred, and this is in agreement with data from literature. Unsuccessful intrapleural treatment with rIL2 is due to conditions which do not allow lung reexpansion, such as bronchial obstructions and massive pachypleuritis involving visceral pleura. The latter is scarcely detectable with lung CT scan, and it is more easily identified during thoracoscopy. Pulmonary reexpansion is therefore a necessary condition for pleurodesis. Moreover, it should be noticed that malignant pleural effusions, when not recently formed, may possibly lead to plurilobular collection pockets, requiring lysis during thoracoscopy. CASE REPORTIn the first phase of our experience an attempt in controlling secondary malignant pleural effusions with negative prognosis had been made administering intrapleurally substances with adhesive properties, such as tetracycline, bleomycine, interferon etc. Recurrence of effusion was avoided only for limited periods of time and this method was associated with side effects such as severe thoracic pain, particularly after intrathoracic introduction of tetracycline. In diffuse pleural mesothelioma, until to 1981, we diagnosed primitive malignant pleural effusion in 10 patients, 6 of which were eligible for surgical treatment. In 2 cases surgery was limited to explorative thoracotomy, while 4 patients underwent extrapleuropneumonectomy. In this group, mean survival time was 12 months for patients who underwent surgery, and only 5 months for patients without surgical treatment. In our experience, as well as in most Authors’, this kind of procedure, largely demolitive and functionally inhabilitating, doe not modify long term prognosis. Survival rate in this group is not significantly different from survival rate among patients without surgical treatment, considering that most of them were at a pre-terminal stage when diagnosed. The poor results of the radical treatment led us to the conviction that prognosis was impossible to improve; thereafter, from 1982 to 1991, we turned to a palliative surgical treatment, expanding the indications for treatment and aiming only to improve the patients’ quality of life through relief from pain and recurring effusions, which are the factors leading, in turn, to dispnoea. In this second phase, we performed parietal pleurectomy associated to lung decortication as first choice surgical treatment, obtaining a satisfactory control of effusion recurrence and of pain for a reasonable interval of time, in 40 patients with malignant pleural mesothelioma. This surgical approach can be performed in all the cases in which a large infiltration of lung parenchyma is not detectable after thoracotomy, because such condition would not allow decortication and therefore would interfere with an adequate lung reexpansion. Average survival time in the 40 patients who underwent surgery in this phase was 13 months, with satisfactory control of pleural effusions. 30 patients, in the same years, were not surgically treated and their average survival time was 5 months. In the third and most recent phase of our experience, from 1992 to 1997, 95 patients with malignant pleural effusion, both primitive (45 pts) and secondary (50 pts) underwent topical treatment with IL2. This method included intrapleural infusion of recombinant IL2 9 millions UI Euro-Cetus (Amsterdam, Holland) in 2 or more consecutive administrations: - 2 administrations were performed in 85 patients, for a total of 18 millions UI rIL2 per - patient; - 4 consecutive administrations were performed in 3 patients, for a total of 36 millions UI - rIL2 per patient; - 5 consecutive administrations were performed in 2 patients, for a total of 45 millions UI - rIL2 per patient; - in 2 patients, after the first 2 administration, 2 more administration of 9 millions UI rIL2 - were performed after an average interval of 3.1 months due to reoccurrence of the effusion. Therapeutic response was assessed according to Paladine’s criteria: - No response (PD): 8 patients (7.6%) - Partial response (PR): 40 patients (38%) - Complete response (CR): 47 patients (44.6%) Tolerability was optimal in all patients and no side effects were observed, except for fever in 1 case and eosinophylia in 1 other case; both effects were transient. X-ray follow-up showed no progression of the effusion for an average interval of 6 months. The 8 unsuccessful cases occurred at the beginning of the protocol, and we may hypothesise that an insufficient standardisation of the technique had a central role (inactivation of the active compound due to 72 hrs conservation of the parent solution). In the subgroup of patients with mesothelioma who underwent intrapleural treatment with IL2, despite the paucity of data, we observed an average survival time similar to that one of palliative parietal pleurectomy: 12-14 months (for all stages). For primitive pleural effusion, during this phase, we restricted pleurectomy/decortication procedures to stage I according to I.M.I.G., obtaining an average survival time of 20 months in this subgroup of patients (10 pts.). CONCLUSION To date, the only realistically feasible target in malignant pleural effusion, both primitive and secondary, remains pain control and control of pleural effusion. In our experience, secondary malignant pleural effusion are well controlled by topical treatment with IL2, which we use as first choice treatment. Approach to mesothelioma is more complex: radiation therapy or chemotherapy, isolated or in association with surgery don’t seem to modify significantly survival rate in these patients. Palliative surgical procedures of pleurectomy/decortication adequately controls the most severe sequelae of the disease, such as pleural effusion and pain. Currently, pleuro-pneumonectomy does not seem to be a feasible option, since it is largely demolitive, it is associated to high morbidity and mortality and its efficacy is retrospectively similar to the palliative procedure. It still holds true that a longer lasting control of pain and of recurrence of pleural effusion can be obtained with surgical procedures of pleurectomy/decortication, but the same target, in our experience, can be reached with intrapleural administration of IL2. In our cases, in fact, survival time, recurrence of pleural effusion and control of pain resulted similar to those obtained with pleurectomy/decortication. Therefore we believe that this palliative treatment for pleural effusions, both primitive and secondary, is the most reliable among the techniques in use at our institution, and that it is the least risky and aggressive therapy which is able to provide improvement of the patient’s quality of life.
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