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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 REPORT
In
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. BIBLIOGRAFIA: 1) Astoul P.;Viallat
J.;Laurent J.;Brandley M.;Boutin C. Intrapleural recombinant IL2 in passive
immunotherapy for malignant pleural effusion. Chest 1993;103:209-213 2) Astoul P.;Peres B.;Durand A.;Catalin J.;Vignal F.;Boutin C. Pharmacokinetics of intrapleural recombinant IL2 in immunotherapy for malignant pleural effusion. Cancer January 15,1994,volume 73,n°2 3) Barni S.,Lissoni P.,Ardizzoia A.,Crispino S.,Tisi E.,Angeli M.,Arrigoni C.,Cassina E.,Tancini G. Efficacy of IL2 in the palliative therapy of neoplastic effusions. Eur.J.Cancer,27(suppl 3):S71(abstr),1991 4) Boutin C.,et al. The role of thoracoscopy in evaluation and management of pleural eeffusions. Lung 1990,168:1113-1121 5) Doria G.,Adorini L. Immunologia generale Casa Ed. Ambrosiana Milano II edizione 1991;194-197 6) Konrad MW.,Hemstreet G.,Hersh EM.,Mansell PWA.,Mertelsmann R.,Kolitz J. et al. Pharmacokinetics of recombinant IL2 in Humans.Cancer Res 1990;50:2009-2017 7) Kosei Y.,Takeshi O. Intrapleural application of recombinant IL2 in patients with malignant pleurisy due to lung cancer. Biotherapy,3:345-349,1991 8) Lissoni P.,Barni S.,Ardizzoia A.,Olivini G.,Brivio F.,Tisi E.,Tancini G.,Characiejus D,Kothari L. Cancer immunotherapy with low-dose IL2 subcutaneous administration:potential efficacy in most solid tumor Histotypes by a concomitant treatment with the pineal hormone melatonin. J.of Biological and Homeostatic Agents 1993;7:121-125 |
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