9TH WORLD CONFERENCE ON LUNG CANCER

Summary report and personal reflections

The International Association for the Study of Lung Cancer (IASLC, www.iaslc.org ) is the international scientific society that picks up the adhesion of lung cancer experts, independently of the specialty and the geographical area of affiliation. Obviously, it comprises many medical oncologists -with prevailing interest for thoracic tumors -, but also many pulmonary physicians, thoracic surgeons, radiation oncologists and experts of pain medicine and supportive care. Furthermore, since IASLC doesn’t limit his field of action to the purely medical aspects but spaces from epidemiology to prevention and from molecular biology to pathology, the specialties that are actually encompassed in its boundaries are truly numerous. Numerous are also the activities of the IASLC, including the organization of workshops on specific aspects of tumor biology and clinical management, the promotion of "staging" or "pathological" committees for the revision of the international classifications, the publication of the scientific journal of the Society -Lung Cancer-, and the carrying out its own general congress, the World Conference on Lung Cancer, perhaps the most important event in the life of the Society. The World Conference on Lung Cancer takes place every three years. It is organized in a location established through a regular rotation among countries of Asia, Europe and America: this year Tokyo hosted the congress, in 1997 Dublin was the host city, in 2003 it will be Vancouver (Canada). For a medical society dealing with only one illness, the numbers of the Tokyo Conference were truly significant (over 6000 participants and almost 1000 free communications, which must be added to the hundreds of lectures on matters of general interest commissioned to experts of undisputed value). I has honored of participating in the International Scientific Committee, with the charge to contribute to the definitive layout of the program. This circumstance allowed me to be aware of the program while it was taking form, proposal after proposal.

Tokyo 2000 have been above all a Congress of Chemotherapy and not for the wish of the organizers, but for the decision of the same delegates that sent 422 abstracts regarding chemotherapy, either alone or in combination with other therapeutic modalities. There is a giant interest that moves this sector. A possible success would be, in fact, a triumph for the medicine, but it would also be, with no doubt, a great business for the drug company that would have invested on... And, as everybody knows, a good part of the investments made by the various BMS, Eli-Lilly and Aventis consists of allowing -especially doctors that have something to say in favor of their products - to meet each other in places otherwise completely out of a normal portfolio! Any way, it is a matter of fact that a big ferment exists and it is, as we will see, enough justified.

The lines of development in the sector of chemotherapy are mainly three:

1. Integration of the so-called new "drugs" in the standard schemes of treatment;

2. Introduction into the clinical practice of new cytotoxic molecules, usually an evolution of those already known;

3. Development and preliminary clinical experiences on the crowd of chemical substances, modified viruses and antibodies that the research of the lung tumor biology of the last decade has recognized as potentially efficacious.

As far as the so called "new drugs" is concerned (i.e., gemcitabine, the taxans, vinorelbine, irinotecan, topotecan, and so on.), these are considered acquired, active in both small-cell lung cancer (SCLC) and in non-small-cell lung cancer (NSCLC), able to overcome in many cases the hemato-encephalic barrier (Abstracts no. 4, 8) and to replace drugs, up to yesterday considered irreplaceable, such as cisplatin (Abstracts no. 14,50,103,115,181). The neo-adjuvant chemotherapy with the "new drugs" is more and more often used in the preparation to the surgical intervention (Abstract no. 35). Many international cooperative groups are appraising whether it can be administered even to perfectly operable patients [among them, the South West Oncology Group, study SWOG 9901; the Lung Cancer Group of the MRC, study LU 22; a French group (Abstract no. 296), a Spaniard one, and two Italians, one of which directed from Bologna by Prof. L. Crinò, the other by Prof. U. Pastorino, in Milan]. The chemotherapy with the "new drugs" is more and more often used as a second line chemotherapy, after the failure of a prior treatment based on cis-platinum, and usually consists of a single cytotoxic agent (Abstract no. 15,67,97,101,104,152,190,193,202,240,242,244). Analogously, "new drugs" are more and more frequently employed in elderly and/or unfit patients (Abstract no. 100,111,184,185,203).

Contemporarily, other novel drugs are under clinical assessment. These include the anti-metabolite Premetrexed (MTA, Alimta ®, Abstracts no. 36,102,123,189) and new derivatives of platinum, among which there is Nedaplatino (Abstract no. 222,223,224), Oxaliplatino (Abstract no. 48) and, above all, ZD0473, a new compound drawn for overcoming the cellular mechanisms of resistance to platinum (Abstract no. 227). Other examples of really new cytotoxic drugs include the Amrubicina (SM-5887), a totally synthetic antracycline, and two new inhibitors of Topoisomerase I, the 9-AC and the DX-8951f, which has been already tested as a single agent in patients with NSCLC with declared percentages of objective response ranging 9 to 19%. The Tirapazamina (Tirazone ™) is a benzotriazine activated to free radical under conditions of ipoxia and capable to produce a specific increase of the alkylating action of cisplatin, as shown by the CATAPULT trial I and confirmed by the CATAPULT trial II (Abstract no. 87). According to T. Le Chevalier and his group of the Institute Gustave-Roussy in Paris, the addition of Tirapazamina to the standard chemotherapy with cisplatin and vinorelbine increases the percentage of objective responses with an "exciting impact on survival" (Abstract no. 113).

However, the most fascinating area is, without any doubt, that of the biological treatment, born by the bio-molecular research of the last 10-15 years. Medicines of these group doesn’t usually have the purpose to kill the cells of the tumor, but to prevent it to indefinitely multiply and migrate, colonizing the body. The classical example is that of the anti-neoangiogenetic drugs. There are over 50 molecules that are believed to block the tumor signals that produce the formation of new vessels (neo-angiogenesis) and there are different ways of stopping it. One method is using inhibitors of the metalloproteinase of the intercellular matrix. Among these, Thalidomide that still recalls to the mind the cases of phocomelia of almost half century ago. His effect, when given in addition to Paclitaxel, Carboplatin and radiotherapy, it is currently under evaluation in patients with advanced NSCLC in stage III. Also Prinomastat (AG3340) and Marimastat, other two powerful inhibitors of the metalloproteinase, are under clinical evaluation: with gemcitabine and cisplatin in the advanced disease, the Prinomastat; alone in the minimal residual illness, the Marimastat. Another approach to the inhibition of angiogenesis is based on the use of direct antibodies against the endothelial receptor for the vascular-endothelial growth factor (VEGF), the anti-VEGF Ab: this approach has already been evaluated with success in studies of phase II and it is quite probable that it will be will soon studied in randomized clinical trials. Not everything, however, is inhibition of the angiogenesis: there are at least two other biological alterations that represent a favorable target for a possible biological therapy. One is the inhibition of tumor growth factors; the other is the stimulation of apoptosis. Many ways of inhibiting the most known growth factor, i.e. the Epidermal Growth Factor (EGF), and its receptor have been explored. An antibody directed against the EGF receptor has been already developed (Herceptin), and it is currently under clinical evaluation in studies of phase II (Abstract no. 183) and III (Abstract no. 186). There are also two small molecules, the ZD1839 (Iressa ™, Abstract no. 229, 230,233) and the CP 358,744 (Abstract no. 208) that inhibit a specific tirosinchinase for the EGF and that are undergoing clinical evaluation. In Tokyo, three cooperative groups, two North Americans and one Japanese, have presented data about a pilot usage of Iressa (Abstract no. 229, 230,233). Around 30% of the adenocarcinomas show a mutation of the gene Ras that results in its continuous expression and in a consequent tumor growth stimulation and cellular dedifferentiation. The transfer of the signal, from the cellular membrane –behind which is attached the protein encoded by the Ras gene- to the intracellular organs, is catalyzed by the pharnesiltransferase. Some small molecules that inhibit the pharnesiltransferase, e.g. the SCH 66336, have shown to delay the cancer growth in preclinical models (Abstract no. 28), and in clinical studies (Abstract no. 205). It is esteemed that around 50-60% of NSCLC manifests a mutation of the gene p53, resulting in abnormality of the apoptosis. It seems that a decreased apoptosis is at the basis of the refractoriness to chemotherapy and radiotherapy. Many researchers are developing different methods to increase the apoptosis. One of the first strategies has been that of transfecting the tumor cells with a viral vector of p53, or to use the ONYX-015 (Abstracts no. 414,417), a mutant adenovirus for a deletion in the region E18, that confers a cytolytic effect in cells with non functioning p53 gene. Such strategy seems effective but it is limited by the necessity of recurring to local administrations (intra-tumor injections). For this reason, a notable effort is in progress with the objective to develop small pro-apoptotic molecules having the advantage of the systemic distribution. Some are already available, as the Exisulind (Abstract no. 248), inhibiting of the proteinkinase C, and the PKC412 (Abstract no. 262).

At the end of the long chapter of the chemotherapy, a personal reflection: it appears entirely evident that an epoch, in which so many medicines all potentially effective have materialized altogether in the clinical arena, has never be seen before. This is the time, indeed, to arrive to the discovery capable to revolutionize the treatment of the evil of the century! ...

Among the several others, the next most important topics were certainly mass screening (Abstracts no. 755,757,759,767,779,789,797,802,803,809,818,821,849,850,851,853) and Positron Emission Tomography (PET). On this technique, a unanimous consent about his being the most accurate non-invasive diagnostic method has been already coagulated (Abstract no. 309,822,839,861,862,868,869,871,915,917,920). An ample digression deserves the other of the two topics. To study the effectiveness of mass screening in the cancer of the lung, the National Cancer Institute sponsored, at the beginnings of the years ’70, an important project. Three of the most distinguished American Academic Institutions took part in the so-called Lung Project. They were the Mayo Clinic of Rochester, the John Hopkins Hospital of Baltimore and the Memorial Sloan Kettering Cancer Center in New York. The results of the Lung Project were made known, for the first time, in the occasion of the 4° World Conference on Lung Cancer (Toronto, 1985). Unfortunately, they went in a direction contrary to the expectations, and produced only a cooling of the enthusiasm ². For things starting to change, it was necessary to attend many years and the introduction of new radiological equipments. Among them, particularly decisive was the spiral-computed tomography (CT) that requires low dose of radiations, light and even mobile machinery, and short times of execution. The Japanese, first, started to do mass screening. Initially, at level of some local prefecture, then, within a vast national program, launched at the end of the years ‘80.³ They confirmed that it is possible to discover many asymptomatic tumors in a precocious phase when they are still susceptible of cure.³ They also showed that the spiral CT was much more sensitive than the standard chest radiography used previously.³ Today, an important North American experience has been concluded ⁴, while new projects are continuously launched around the world, among which that of the European Institute of Oncology in Milan and that of the Mayo Clinic, the same American institution that had participated in the first fruitless project of the years’70, deserve a mention. In Tokyo, novel important data regarding the mass screening have been presented. They originate from over 13 screening projects almost concluded in Japan and in the rest of the world. Perhaps, the most promising results are those of two different groups of Japanese researchers affiliated to the institute of Epidemiology and Prevention at the University of Okayama (Abstract no. 802) and to the Medical Cancer Center of the Osaka University (Abstract no. 809). Both were "case-control" studies, in that they compared mortality for lung cancer in two groups of subjects who only differed for having (cases) or not having been submitted to the annual screening (controls). Both the studies accomplished a notable reduction of the specific mortality (respectively, of 41% and of 60%).  Many other technical aspects, among which the minimally invasive surgery

 (Abstracts no. 470-474), the intra-operative pleural washing (Abstract no. 681,831,838,919) and

 the always-preponderant matters of tumor biology (Abstracts no. 586-711) were effectively discussed during the five days of congress.

 To conclude, I would like to underline the interesting English experience of the Lung Cancer Units (Abstracts no. 402,884,899,900) that could be a model for any worldwide reality. Following the indication of the British Thoracic Society⁵, multidisciplinary units are going to be formed in many English hospitals. Independently of the primary specialty, the expert with the greatest specific competence coordinates them. The Lung Cancer Unit seems to be the best answer to the changing and ever increasing demand for care of lung cancer.

5.  Anonymous. BTS recommendations to respiratory physicians for organising the expensive of patients with lung cancer - Introduction. Thorax 53 Suppls. 1:S1-S8, 1998.