Malignant pleural mesothelioma, stage T3-T4 - Consideration of a case study

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Published on Monday, 19 May 2014

Malignant pleural mesothelioma, stage T3-T4 - Consideration of a case study.M.D. Achille Norsa - Malignant pleural mesothelioma, stage T3-T4. Consideration of a case study - Hospital Ospedale Civile Maggiore, Verona

 

 

 

 

Preliminary remarks and observations related to a series of cases of pleural Mesothelioma

The Achille Norsa’s work, introduced and documented below, describes in detail a therapeutical case and its related case study. It has already allowed the author to draw significant conclusions, moreover the collected data offer the possibility to make wider considerations and useful comparisons.

For this reason they can be merged with the data of other health professionals in a case study whose extent can make incontestably plausible a comparison of survival between patients treated with MDB, chemotherapy, radiotherapy, other treatment methods and non-treated patients.

However we consider useful to give here a first partial example of statistical verification.

For this reason the verified and verifiable data of Achille Norsa’s work have been merged with those of another single case of a second health professional (hereinafter referred to as “B”), who has treated only a patient with pleural mesothelioma throughout his working experience with DBM. This explains why we use the word “case studies”, which both in the case of A and in the case of B are based on an absolutely random flow of patients, not preselected by health professionals.

All the 7 nonsurgically treatable cases (6 of A and 1 of B) described here were accepted as patients had not been previously treated with chemotherapy or radiotherapy. The pretreated cases referred to A health professional (M.D. Achille Norsa) were removed from the evaluation and the same was done for other two cases of the above mentioned health professional: the former because the patient didn’t start the treatment at all, the latter because the patient didn’t wait the time necessary for the treatment to fully work.

Although - as you can see - the study case is extremely small, two kinds of evaluations were made. For the comparison we considered the result obtained working out the average of the median survivals of 10 works selected among the 19 most recent articles proposed by MEDLINE. The selection was made based on:

  1. The immediate and transparent evidence of the data;
  2. The kind of therapy (chemotherapy).

The value mentioned above was compared with the median survival of the patients randomly referred to A and B, which was calculated starting from the date of the observation, i.e. the approximate therapy start date.

The same value was compared also with the median survival calculated from the diagnosis. This was done because it is necessary to take into account that there is usually a minimum time latency between the date of the diagnosis and that of the start of official therapies.

This is not the case of the DBM, which is often required in articulo mortis because of the huge difficulties in finding timely information and experienced health professionals. We used the mentioned comparison standard because of such significant gap.

The results were the following:

 

On 1 April 2000, the group of 7 patients showed (from the start of the therapy):

 

On the same date the same group showed (from the diagnosis):

 

As regards the literature, we referred to the following:

  1. Kasseyet S, Astoul P, Boutin C. - Results of a phase II trial of combined chemotherapy for patients with diffuse malignant mesothelioma of the pleura. Cancer. 1999 Apr 15;85(8):1740-9;
  2. Byrne MJ, Davidson JA, Musk AW, Dewar J, van Hazel G, Buck M, de Klerk NH, Robinson BW. - Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol. 1999 Jan;17(1):25-30 (see and/or download below complete publication);



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  3. Andersen MK, Krarup-Hansen A, Mårtensson G, Winther-Nielsen H, Thylen A, Damgaard K, Olling S, Wallin J. - Ifosfamide in malignant mesothelioma: a phase II study. Lung Cancer. 1999 Apr;24(1):39-43;
  4. Metintas M, Ozdemir N, Uçgun I, Elbek O, Kolsuz M, Mutlu S, Metintas S. - Cisplatin, mitomycin, and interferon-alpha2a combination chemoimmunotherapy in the treatment of diffuse malignant pleural mesothelioma. Chest. 1999 Aug;116(2):391-8 (see and/or download below complete publication);



  5. Vogelzang NJ, Herndon JE 2nd, Miller A, Strauss G, Clamon G, Stewart FM, Aisner J, Lyss A, Cooper MR, Suzuki Y, Green MR. - High-dose paclitaxel plus G-CSF for malignant mesothelioma: CALGB phase II study 9234. Ann Oncol. 1999 May;10(5):597-600 (see and/or download below complete publication);



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  6. van Meerbeeck JP, Baas P, Debruyne C, Groen HJ, Manegold C, Ardizzoni A, Gridelli C, van Marck EA, Lentz M, Giaccone G. - A Phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer. 1999 Jun 15;85(12):2577-82 (see and/or download below complete publication);



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  7. Nakano T, Chahinian AP, Shinjo M, Togawa N, Tonomura A, Miyake M, Ninomiya K, Yamamoto T, Higashino K. - Cisplatin in combination with irinotecan in the treatment of patients with malignant pleural mesothelioma: a pilot phase II clinical trial and pharmacokinetic profile. Cancer. 1999 Jun 1;85(11):2375-84;
  8. O'Reilly EM, Ilson DH, Saltz LB, Heelan R, Martin L, Kelsen DP. - A phase II trial of interferon alpha-2a and carboplatin in patients with advanced malignant mesothelioma. Cancer Invest. 1999;17(3):195-200;
  9. Maksymiuk AW, Marschke RF Jr, Tazelaar HD, Grill J, Nair S, Marks RS, Brooks BJ, Mailliard JA, Burton GM, Jett JR. - Phase II trial of topotecan for the treatment of mesothelioma. Am J Clin Oncol. 1998 Dec;21(6):610-3;
  10. Samuels BL, Herndon JE 2nd, Harmon DC, Carey R, Aisner J, Corson JM, Suzuki Y, Green MR, Vogelzang NJ. Dihydro-5-azacytidine and cisplatin in the treatment of malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B. Cancer. 1998 Apr 15;82(8):1578-84 (see and/or download below complete publication);



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The median survivals reported in the single works are the following:

for a total of 2597 days and an average of 257.7 days equal to 8.59 months (assuming a 30-day month).

Although the small study case doesn’t allow to make a final conclusion, the comparison seems to show the efficacy of DBM. The survival of 4 months (if calculated starting from the diagnosis), in particular, is significant for this group of patients.

Also in this case, even if with the huge limits derived from the starting point conditions, it is necessary to point out that there are the prerequisites to continue, improve and plan research, which even only under a first partial approach, clearly shows the favourable results that can be obtained properly applying the DBM.

 

Abstract

According to the poor results in survival of malignant pleural mesothelioma after classic therapeutic approaches, suggest a new therapeutic step as the DBM (Di Bella Method) for the treatment of the malignant disease. DBM treatment has proved a survival benefit, even linked with talc pleurodesis.

 

Introduction

Mesothelioma is a relatively rare cancer that can occur in a localized or diffuse form and is characterized by an inauspicious prognosis quickly.

The incidence of this cancer has gradually increased in recent decades and this has been put relation with the greatest exposure to asbestos.

From the histological point of view are distinguished an epithelial form, a sarcomatous form and a mixed.

The differential diagnosis with metastatic adenocarcinoma is difficult and it is necessary to analyze biopsy material of a discrete entity.

Mesothelioma manifests clinically with chest pain accompanied by dyspnea.

The prognosis depends on “the performance status”, the staging, the blood platelet count, age, and histological type.

Surgical treatment, radiotherapy and chemotherapy used in combination do not give sensitive increases in survival compared to the absence of any treatment.

Staging is difficult in the classification of this neoplasia: but for convenience we distinguish stages 1-2-3-4, referring mainly to the extension of the neoplasia, and the infiltration of the chest wall, mediastinal structures and diaphragm and the compromising of the lymph nodes in the mediastinum.

Overall, the median survival reported by varius AA, varies between 9 and 12 months, taking into consideration especially the early stages, and without any reference to coenaesthesia of these patients.

There are few references on the survival of the more advanced stages (3 and 4), which clearly proved small.

Given that current therapies have proved incapable of significantly increasing the survival for this neoplasia, everyone is hoping on research on new therapeutic strategies more effective [3].

The purpose of this work is to report the results of medical treatment according to the methodology DBM (Di Bella Method) in a number of patients affected by pleural mesothelioma in stage 3 and 4 to the majority who voluntarily have undergone themselves to this method having previously undergone themselves without success to various treatments (chemotherapy-radiotherapy-surgery), or to any of the same therapies.

According to our experience DBM sometimes in association with palliative surgical treatments such as talc pleurodesis, confers a significant advantage in survival and coenaesthesia of these patients, especially when they have not been previously subjected to standard therapies.

 

Materials and methods

During the period 12/Oct/1996 - 16/Aug/2000 were observed 14 cases of pleural mesothelioma, who voluntarily have undergone themselves to biological therapy according to the treatment. The ages of the patients ranged from 55 to 73: 11 were males and 3 females.

The interval between diagnosis and initiation of therapy DBM is varied from 2 to 11 months, said interval has been filled by an approach to chemo or chemo plus radiotherapy in 6 cases, which led to a further evolution of the disease. The other 8 cases had not followed any program chemo-radio.

Twelve cases were classified T3-N2 while the other 2 cases were classified as T4-N3. Nine patients presented themselves to the visit in terminal conditions, and of these, respectively, 1 is still alive improved clinically and radiologically a distance of 5 months and 1 survived two months. The remaining are deceased in a period varying from 2 to 10 days.

Of the other 8 cases not undergoing chemo-radio, 1 has come to the observation in severe heart failure and died the next day without even starting the therapy, 1 died after 8 days for pulmonary embolism, 2 others have survived two months, one 6 months and one 10 months from the beginning of biologic therapy. One case is alive clinically and radiologically healed at 18 months, and 1 case was improved and stabilized at a distance of 46 months!

Lastly, the case of 1 patient who had previously followed a chemotherapy treatment for 3 months, after which she had an initial progression of the disease (spilling-infiltration of the mediastinum with mediastinal syndrome) with increase of the mass, the induction of a diabetic syndrome by cortisone, a pulmonary eterolateral metastatization and a bone diffusion in the sternal, which is living and clinically improved after 5 months of biological therapy.

Regarding surgical therapy associated to this particular experience, we were able to observe the results of surgical treatment performed in some of these patients at our Division: the pleuro-pneumonectomy performed in one patient immediately after the diagnosis was complicated by pleural empyema secondary to a main bronchus fistula 3 months after chemotherapy, probably induced by immune depression, characterized by anemia, leukopenia, and piastropenia. The patient has undergone DBM treatment only after 5 months after surgical intervention open drainage of the chest wall, by now in extreme conditions, and died after 8 months of starting therapy.

Commenting on this case, we can say that the pleuro-pneumonectomy was almost certainly compromised by chemotherapy, and DBM was adopted only at the end as a last resort, and this is an attitude to be avoided. In fact, a second patient undergoing the same surgery pleuro-pneumonectomy, which does not follow any chemo-radio, undergoing to the DBM immediately after surgery has survived 6 months.

We were able to perform a simple pleurectomy surgery to a patient, but this was subsequently subjected to chemo-radio: there was a further evolution of the disease, characterized by a syndrome of the inferior vena cava, accompanied by a massive ascites and edema the lower limbs. The same patient has voluntarily subjected to DBM only belatedly, and survived only 20 days from the date of the observation.

The intervention of talc pleurodesis associated with the DBM was performed in three cases: the first case (T3-N2), not subjected to chemo-radio, had a survival than 2 months; the second (T3-N2) also did not undergo chemo-radio, survived 10 months, and a third patient has improved and stabilized to 46 months after the beginning of the DBM without chemo-radio.

In conclusion, despite the limited number of patients observed, we can say in general that patients suffering from mesothelioma stage T3-N2 to T4-N3, came to our attention presented themselves with the extreme stage of the disease.

The chemo and radiotherapy used did not have any improving effect in the disease, and the best results with the application of DBM were observed in those patients who had not previously been treated with chemotherapy or radiotherapy.

Regarding the surgical experience, the talc pleurodesis proved the measure that has enabled us to achieve the best results in association with DBM, while the pleuro-pneumonectomy, according to our opinion should be evaluated from time to time and also always associated from the outset with DBM.

 

Discussion

Pleural mesothelioma is a rare neoplasia, for which the major risk factor is represented by the exposure to asbestos. Considering that the latency of the disease from exposure to asbestos to its clinical expression is 25-30 years, it would take time to see the results of the reduction of exposure to this element of the workers engaged [2].

In the last 10 years there has been an improvement in diagnostic tools, staging and study of the biology of this tumor, however, the treatment remains controversial, as well the indications for palliative treatment only and that more aggressive [1].

There are some types of staging, such as Butchart, and more recently IMIG (International Mesothelioma Interest Group) classification.

The most important prognostic factors are represented from the stage of the disease, histologic type, the performance status of the patient.

Current therapies used until now (surgery, chemotherapy, radiotherapy) have not shown significant increases in survival [3]. Radical surgery, such as pleuro-pneumonectomy has been considered useful only in the early stages of the disease. The monochemotherapy and polychemotherapy have not clearly shown any significant advantage in survival and improving the quality of life of patients. Radiotherapy most of the times has no indication, for the extension of the lesions, and the proximity of the same to vital organs, such as lung and heart. And finally, the systemic or intracavitary immunotherapy appears to be particularly dangerous for its toxicity, especially for the occurrence of infectious complications [4 - 5]. In any case, the average survival of patients with this neoplasia is 9 months [6 - 7].

Regarding the surgery, the impression of the various AA is that thoracoscopy with talc pleurodesis represents the measure most suitable, not only for the confirmation of the diagnosis of the disease, but also as a therapeutic measure can always improve the symptom dyspnoea [8].

 

Conclusions

In general, when dealing with a neoplastic disease, it is necessary to consider that it always originates from a biological context depressed from the immune point of view.

Famously current therapies (chemotherapy and radiotherapy-immunotherapy) have the effect of further inhibit the immune mechanisms, and prevent cell mitosis, fast-growing, then the tumor cells in particular; however there is no selectivity in this mechanism, and consequently, there is also the repression of the multiplication of cells essential for maintaining the biological balance (e.g. white cells, blood cells, and platelets).

The therapy proposed here represents a therapeutic choice for certain respects the body's ability to implement its valid defense mechanisms, and can be summarized as follows: no more indiscriminately destroy everything that multiplies quickly, but on the contrary would should create an organic unsuitable environment for growth of cancer cells, exploiting and strengthening the defense mechanisms against neoplastic disease, which are inherent in the body.

 

Final reflections

The paucity of the material that we were lucky to pick up does not allow us to emphasize and generalize the results.

However we had the impression that even for this type of cancer, practically incurable with current treatments, under certain conditions you can get results much higher than those reported in the literature. Of the three cases treated in the most favorable conditions for our method, one is clinically and radiologically healed after 18 months of therapy, and another case is alive and has always had a normal life, including an intense working activity, even in the presence of disease, though it has reduced considerably in the last four years.

 

Translated by: Maria Pia Biffi and Roberta Martello

 

 

Bibliography

  1. Rusch VW. - Clinical features and current treatment of diffuse malignant pleural mesothelioma. Lung Cancer. 1995 Jun;12 Suppl 2:S127-46;
  2. Kjaergaard J, Michelsen EV. - Malignant mesothelioma: incidence, survival and relative risks in selected municipalities 1943-1992. Ugeskrift for Laeger [1997, 159(31):4756-4761];
  3. Ruffié P, Lehmann M, Galateau-Sallé F, Lagrange JL, Pairon JC. - Standards, Options, and Recommendations for the management of patients with malignant mesothelioma of the pleura. Fédération Nationale des Centres de Lutte Contre le Cancer. Bull Cancer. 1998 Jun;85(6):545-61;
  4. Gross-Goupil M, Ruffié P. - Malignant pleural mesothelioma. Bull Cancer. 1999 Oct;Suppl 3:43-54;
  5. Von Bültzingslöwen F, Siemon G. - Therapy of malignant pleural mesothelioma--a permanent dilemma. Pneumologie. 1999 May;53(5):266-75;
  6. Boylan AM. - Mesothelioma: new concepts in diagnosis and management. Curr Opin Pulm Med. 2000 Mar;6(2):157-63;
  7. Alberts AS, Falkson G, Goedhals L, Vorobiof DA, Van der Merwe CA. - Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers. J Clin Oncol. 1988 Mar;6(3):527-35 (see and/or download below complete publication);



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  8. Charvat JC, Brutsche M, Frey JG, Tschopp JM. - Value of thoracoscopy and talc pleurodesis in diagnosis and palliative treatment of malignant pleural mesothelioma. Praxis (Bern 1994). 1998 Mar 4;87(10):336-40.