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Scientific Results and New Research ProjectsCulCaSG investigates primary malignancy of the lung, posing questions on different clinical aspects of the diagnosis and treatment. The main areas of interest are tumor markers, pre-surgical staging of non-small cell lung cancer (NSCLC), chemotherapy of inoperable NSCLC, psychological aspects, and prognostic evaluation.
After a prelimary testing of different tumor markers (1,2), attention was focused on the Tissue Polypeptide Antigen (TPA), a substance whose serum concentration follows the burden of disease in a very strict fashion. It was shown that TPA may help clinicians in staging evaluations, disease monitoring, and prognostication (3). Large scale studies, examining separately each of these aspects, corroborated the evidence and provided a first quantitative assessment of the clinical yield of TPA (4-6, 32). Next steps have been to develop practical guidelines to use and interpret the TPA test. A clinical investigation, recently terminated, has shown that, although CT remains the gold standard for the pre-operative evaluation of NSCLC, it may significantly underestimate the real tumor extension. The addition of the easy and inexpensive TPA test is capable to correct this underestimation, and helps to decide whether to completely rely on CT or order additional clinical investigations (recent studies). With the likely exception of carcinoembryonic antigen (CEA), other tumor markers seem to have limited or null utility. So far, we have taken under consideration CEA (1,2,7,32), beta-chorionic gonadotropin (1), calcitonin (1), adrenocorticotropin hormone (1), lactate dehydrogenase (LDH) (1,2, 32), ferritin (8), and the soluble receptors of interleukin-2 (9). Recently, we have discovered a new, exciting clinical application of CEA. Based on our data (recent studies), in fact, the pre-operative CEA test might be superior to any other method in predicting early recurrences of radically resected NSCLC. The following steps will be taken to see whether the addition of a second marker will increase the clinical significance of TPA. The best candidate is, again, CEA, which is fairly well correlated with diverse tumor characteristics, but poorly linked to the serum TPA expression (1,2). A new derivative of TPA, Cyfra21-1, appears to have similar behavior and equal clinical momentum. In a preliminary comparison between CEA and TPA, major differences were not found (10,32)(see also recent studies). Neuron Specific Enolase (NSE) is universally accepted as the best marker for small cell lung cancers (SCLC). Elevated serum levels have been signaled, however, also in NSCLC. Tests have begun to assess NSE in patients with NSCLC and results are expected within two years. In the meanwhile, a recent review of our experience in SCLC with CEA, TPA and LDH (39) seems to suggest avoiding a routine CEA test in SCLC, because of the limited clinical utility, especially when compared with that of other markers. On the contrary, LDH should be maintained in the lab-routine of SCLC, in which also transaminases and alkaline phosphatase may have a significant value. Finally, data on TPA and other cytokeratin markers is still insufficient for advocating their use in this particular malignancy Preoperative NSCLC staging: Alternative methods to thoracic and upper abdomen computed tomography (CT) to preoperatively evaluate NSCLC patients have been investigated by members of the CuLCaSG since the mid-eighties. All were based on Nuclear Medicine techniques. The radiotracer considered first was Gallium-67 (11). However, this radionuclide was soon abandoned in favor of Indium-111 labeled F(ab')2 fragments of the anti-CEA monoclonal antibody FO23C5, which aapeared to offer a more specific radio-targeting. In a number of sequential studies, detection rates for the primary (12), overall staging potential (13), and mediastinal assessment capability (14,15) of the anti-CEA immunoscintigraphy resulted promising, but did not to supersede the conventional CT scanning. The focus is now on patients with small and peripheral adenocarcinomas, where the yield of anti-CEA immunoscintigraphy has been shown to be significantly higher (33).99mTc-tetrofosmin has recently emerged as a new radiopharmaceutical for cancer visualization. In a recent study, we investigated its ability to assess lung cancer dissemination and progression. The technique was found fairly, but not dramatically accurate (see recent studies). A different path of investigation, which is in the planning stages, is to evaluate the utility of the cortical adrenal scintigraphy with Iodine-131 NP59 in any CT-suspected case of adrenal metastasis. In a CuLCaSG's clinical investigation of the mid ninths (16), the praxis of doing cranial CT was evaluated in terms of unnecessary operations saved, and opened a new discussion (17).
CuLCaSG has been always conservative in choosing chemotherapy combinations to treat the locally advanced or metastatic NSCLC (18). Since the early eighties, the MACC regimen was used. Experience showed that this old non-platinum-based regimen had limited antineoplastic activity and acceptable toxicity (19). The use of MACC, except for non-responders after two or three test courses (20), caused a significant prolongation of the patients' life expectancy (21). These findings and a simultaneous review of the literature made a convincing argument for the use of chemotherapy in general (22,23). Recently, a classic platinum-based program, the MVP regimen (24) has been implemented. Interestingly both activity and toxicity profiles of MVP were similar to MACC (24). A formal randomized trial comparing MACC and MVP was published in 1997 (30). We are now evaluating newer drugs, such as the Taxanes, Irinotecan, Navelbine and Gemcitabine in several undergoing phase II studies. The first phase II study on Navelbine in unfit and elderly patients has been only recently concluded and published (34). Second line chemotherapy is becoming a common practice in many cancer centers. We have recently reviewed this topic (38). A first assessment of the psychological status of patients randomized to receive chemotherapy or no-chemotherapy dates back to the late eighties (20). Intrigued by the relativity of the psychological evaluations,comparison were made of treatment tolerance, physical well-being, and mental depression as judged by doctors, patients, and patients' relatives (25). More recently, we showed that several dimensions of the quality of life possess an independent prognostic significance (26), and, among them, a state of depression seems to be particularly unfavorable (31). Currently, evaluation are being made of how cancer patients, non-cancer patients, and healthy subjects judge the small benefits of a potentially harmful treatment (i.e., chemotherapy in certain tumors). This information should be very helpful in answering the frequently asked question: "Is chemotherapy worthwhile in inoperable NSCLC?". Preliminary data have been published in the year 2000 (35).
The clinical outcome of any disease depends on many known and unknown factors. In lung cancer, CuLCaSG has reviewed more than 100 factors claimed to be prognostically meaningful (27). However, unknown prognostic factors are certainly more. At the CuLCaSG, nearly 200 variables are recorded for each new patient seen. This has offered the opportunity to search for the potential prognostic value of rarely considered variables. For example, several plasma proteins, including transferrin, alpha-1-antitrypsin, alpha-1-acid glycoprotein, and haptoglobin were found prognostically significant (28) Also copper and zinc serum contents may be abnormal in non-small cell lung cancer, and this finding seems to be prognostically meaningful (36). It is likely that also subclinical thrombotic states correlate with shorter survivals. A first report has already confirmed this hypothesis (29), but continuous evaluation of clotting factors should give more insight on the matter (see recent studies). The stage of disease remains, however, the most important single factor of prognosis; however, the influence of the different TNM groupings in its prognostic capability is trivial or null (37). REFERENCES
In this short overview of the Group's scientific production, not all our publications have been commented. Several other clinical studies and review articles have been produced by our members and published in peer-reviewed international journals. To access to the full list of our publications, go to the page ALL OUR RECENT PUBLICATIONS To access to our most recently concluded studies (with full text available on line), go to the page RECENT STUDIES
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