1. Trattamento integrato neoadiuvante delle neoplasia polmonari non microcitoma (NSCLC) localmente avanzoate: rationale, criteri di eleggibilità e scheda di somministrazione in uso presso l’U.O.D. di radio-terapia oncologica del complesso ospedaliero S. Giovanni-Addolorata – Ascarelli
2. The treatment of lung cancer in Victoria, Australia. A survey of current practice - Ball
3. A prospective review of field placement in the radical radiation treatment (RT) of non-small cell lung cancer (NSCLC) using electronic portal imaging (EPI) - Davis
4. Preoperative chemo-radiotherapy in stage III non-small cell lung cancer: impact of total dose, dose intensity, and fractionation schedule on therapy outcome - Choi
5. Gemcitabine and cisplatin for unresectable non-small cell lung cancer (NSCLC): preliminary results - Garcia Carbonero
6. Randomized phase III trial of the southern Italy oncology group study (G.O.I.M.) of mitomycin C plus vindesine and cisplatin (MVP) versus vinorelbine and cisplatin (PV) in stage III-IV non-small cell lung cancer - Gebbia
7. Mediastinal lymph node dissection in a multimodal approach to the management of lung cancer - Grannis
8. Assessment of chromosome breaks in oncogene sites in T lymphocites among the population of a radionuclide-contaminated zone around the Siberian chemical plant after a radiation accident on April 6,1997 - Ilyinskikh
9. 1) Monitoring NSCLC patients after operation and adjuvant therapym with the use of serum cyfra 21-1 tumor maker -Kozlowski
10. 2) Adjuvant therapy after operation of stage IIIa non-small cell lung cancer - Kozlowski
11. Weekly cisplatin + epidoxorubicin + medroxuprogesterone acetate + R-interleukin-2 in advanced (stage IIIb-IV) lung cancer (NSCLC). Preliminary results of a dose-finding study - Mantovani
12. Thorascopic ultrasound staging of lung cancer – Mezzetti
13. The interaction between gene P53 and oncogene mdm2 in human lung glandular cancer cell line GLC-82 – Ping
14. Comparison of CEA and TPS levels in serum samples from peripheral blood and pulmonary vessels in patients with lung cancer - Staniszewski
15. Prognostic implications of pulmonary satellite nodule: are the 1997 staging revisions apropriate? - Urschel
16. IIIa/b NSCLC: Quickly alternating, radical radio-/chemo-therapy with few side effects - Von Briel
17. Debulking operation for stage IIIa, IIIb non-small cell lung cancer - Wu
18. Vindesine with cyclophosphamide-epirubicin-cisplatin in the treatment locally advanced non-small cell lung cancer - Yanping

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TRATTAMENTO INTEGRATO NEOADIUVANTE DELLE NEOPLASIE POLMONARI NON MICROCITOMA (NSCLC) LOCALMENTE AVANZATE: RATIONALE, CRITERI DI ELEGGIBILITÀ E SCHEDULA DI SOMMINISTRAZIONE IN USO PRESSO L' U.O.D DI RADIO-TERAPIA ONCOLOGICA DEL COMPLESSO OSPEDALIERO S.GIOVANNI-ADDOLORATA

A.M. SCAPATI, P GIOVANNI, R PECCHIA, A.A. ASCARELLI

Unità Operativa Dipartimentale di Radioterapia Oncologica, Complesso Ospedaliero S.Giovanni- Addolorata, Roma

Le neoplasie polmonari non microcitoma (NSCLC) costituiscono circa la metà dei casi diagnosticati ogni anno. Approssimativamente un quarto dei tumori del polmone non microcitoma localmente avanzati presentano coinvolgimento linfonodale ipsilaterale o controlaterale alla sede primitiva di malattia indipendente dall'istotipo.
Stante l'efficacia non ancora ben definita delle chemioterapia da sola nel trattamento neoadiuvante di questa patologia, ed i limiti legati al dosaggio della radioterapia esclusiva neoadiuvante, da molti anni l'integrazione delle due metodiche terapeutiche è in uso presso la maggior parte dei centri oncologici.
Pur non essendo ancora numerosi i dati provenienti da studi randomizzati, è ormai evidente che la radiochemioterapia concomitante incrementa in modo significativo il numero dei pazienti condotti al tavolo operatorio, apportando un importante contributo sia al target fondamentale del management terapeutico del NSCLC che resta la chirurgia, sia al controllo locale. Presso l'U.O.D di Radioterapia Oncologica dell'Ospedale S.Govanni-Addolorata di Roma è in atto un protocollo di teapia neoadiuvante realizzato sulla base delle esperienze del Fox Chase Cancer Center di Philadelphia (USA)

Si presentano rationale, criteri di eleggibilità e schedula di trattamento

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THE TREATMENT OF LUNG CANCER IN VICTORIA, AUSTRALIA. A SURVEY OF CURRENT PRACTICE

G. RICHARDSON, V. THURSFIELD, G. GILES, D. BALL

Lung Study Committee of the Victorian Cooperative Oncology Group and the Victorian Cancer Registry, Anti Cancer Council of Victoria, Carlton Victoria 3053 Australia

Peter MacCallum Cancer Institute, Locked Bag 1 A’Beckett Street, Victoria 3000 Tel: 61 3 9656 1111 Fax: 61 3 9656 1424 email: dball@petermac.unimelb.edu.au

Purpose: To survey the patterns of practice in the management of lung cancer in the state of Victoria during a seven month period in 1993.

Methods: The study population consisted of all patients with primary lung cancer diagnosed between 1/1/93 and 31/7/93 that had been registered with the Victorian Cancer Registry. The treating doctor in each case was identified and sent a questionnaire which included questions concerning the method of diagnosis, extent of disease, first line and subsequent treatment modalities, and outcome.

Results: 1054 cases of primary lung cancer were identified pre-mortem and completed questionnaires were received for 869 (82%). The population consisted of non-small cell lung cancer 635 (73%), small cell lung cancer 124 (14%) and no histology 107 (12%). First line therapy consisted of surgery, radiotherapy or chemotherapy either alone or in combination in 654 (75%) patients but 215 patients (24.7%) were offered no treatment at all. In patients with non small cell lung cancer there appeared to be little influence of UICC stage on choice of treatment with some patients in every stage grouping receiving one or all three treatment modalities.

Conclusions: This study confirms the results of surveys of clinician attitudes to the management of hypothetical cases of non small cell lung cancer and indicates a lack of consensus on what constituted best practice in Victoria in 1993. The results also suggest that a significant number of patients may have received inadequate treatment.

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A PROSPECTIVE REVIEW OFFIELD PLACEMENT IN THE RADICAL RADIATION TREATMENT (RT) OF NON-SMALL CELL LUNG CANCER (NSCLC) USING ELECTRONIC PORTAL IMAGING (EPI)

S. DAVIS, K. HATHERLY, K. NASH

William Buckland Radiotherapy Centre, Melbourne Australia

With increasing interest in conformal therapy and dose escalation in RT for NSCLC, we have investigated daily field placement using EPI in these patients.

All patients in this group are planned using computerized tomography (CT) scans transferred to a 3D planning computer (Nucletron PlatoR). Customized shielding blocks are manufactured and at simulation, adequate coverage of the tumour volume during respiration is determined in the lateral and longitudinal directions using fluoroscopic screening, and in the AP direction using the CT option on a Varian XimatronR radiotherapy simulator.
Standard radiotherapy treatment of these patients in our unit is 60 Gy given in 30 fractions, 5 per week, with patients treated supine, immobilized usually in a customized Vac-FixR and arms-up positioning system. Routine field position verification consisted of portal imaging at the beginning of the treatment course.
Using EPI on Varian linear accelerators, we collected daily images of patients and analyzed the tumor position on the obtained images, using digitized films taken at simulation for reference. A total of 1236 data points on twelve patients were analyzed. Assessment for variation in the lateral, longitudinal and rotational directions was made, and the shift (in millimeters) from the reference plotted.

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PREOPERATIVE CHEMO-RADIOTHERAPY IN STAGE III NON-SMALL CELL LUNG CANCER: IMPACT OF TOTAL DOSE, DOSE INTENSITY, AND FRACTIONATION SCHEDULE ON THERAPY OUTCOME

N.C. CHOI, M.D., Director Of Thoracic Radiation Oncology

MGH Thoracic Oncology Center, Department Of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, MA

Purpose: A new opportunity for trials in preoperative chemotherapy or chemo-radiotherapy followed by surgery for marginally resectable stage IIIA and selected IIIB non-small cell lung cancer (NSCLC) became available with the advent of cisplatin-based chemotherapy in the early 1980s. However, what the standard preoperative therapy should be remains controversial. The purpose of this study was to evaluate the importance of radiation in preoperative chemo-radiotherapy for stage III NSCLC and present a robust hypothesis for clinical trials.

Methods: The current literature (1985-1997) on this subject, most from phase I/II studies, was reviewed for the toxicities, therapy response and survival outcome. The majority of these studies used a variety of chemotherapy regimens, different sequences in combining radiation therapy with chemotherapy and surgery, and variable radiation dose schedules. Representative studies were grouped according to the modality of preoperative therapies, chemotherapy regimens, and dose fractionation schedules of radiation. The effectiveness of the preoperative therapies was assessed and compared by using pertinent endpoints: Toxicities, the rate of complete resection, frequencies in obtaining pathological complete response, the rate of tumor downstaging, median survival time (MST) and 3-5 year survival rate.

Results: The role of chemotherapy (cisplatin-based regimen) in preoperative therapy for stage IIIA NSCLC has been established by 2 small phase III studies. However, the magnitude of the gain in survival by such preoperative chemotherapy remains undetermined because of the small sample size in both studies.

Phase II studies in preoperative chemotherapy alone for stage IIIA (N2) NSCLC showed a complete resection of 7% to 65% and 5-year survival rate of 17% to 29% by using 2-3 cycles of intensive cisplatin plus vindesine (PV), cisplatin, fluorouracil, and leucovorin (PFL), mitomycin, vindesine, and cisplatin (MVP) and mitomycin, ifosfamide, and cyclophosphamide (MIC) regimens. Phase II studies in preoperative chemo-radiotherapy demonstrated a complete resection rate of 32%-88% and 5-year survival rate of 18%-37%. The chemotherapy regimens in these studies included 2-4 cycles of cyclophosphamide, doxorubicin, and cisplatin (CAP), cisplatin and fluorouracil (PF), PF plus etoposide (PFE), PF plus vinblastine (PFVIb), carboplatin plus etoposide (CarbE), and cisplatin plus etoposide (PE) regimens. Toxicities of these treatments were comparable between the two approaches. Some of these preoperative chemo-radiotherapy trials included patients with stage IIIB disease. Preoperative chemo-radiotherapy resulted in complete resection and survival rates higher than those obtained with preoperative chemotherapy alone.

A progress in the innovation of radiation dose schedule in preoperative chemo-radiotherapy has been made in an attempt to improve the complete resection and survival rates by an increase in total radiation dose and dose-intensity. With once a day (QD) radiation schedule in preoperative chemo-radiotherapy, the total radiation dose was escalated up to 60 Gy/3O F/6 wks with encouraging results and acceptable toxicities.

Twice daily (BID) radiation was administered at total doses ranging from 42 Gy/28 F/4 wks (10-day rest after 21 Gy) to 45 Gy/3 F/3 wks in conjunction with concurrent chemotherapy. This BID radiation schedule resulted in a higher complete resection and survival rate than that of QD radiation schedule with acceptable toxicities. The main dose limiting toxicity of this BID radiation schedule was acute esophagitis.

A hybrid dose schedule of standard QD radiation combined with concurrent BID radiation as concomitant boost for 6-10 days during chemotherapy cycles was tested in patients with stage IIIB NSCLC. With this hybrid QD and BID schedule, two levels of radiation doses, 45 Gy/25 F/5 wks to the initial volume (gross tumor plus adjacent lymph node bearing region) and 54-60 Gy to the gross tumor, were administered by using concurrent boost radiation for a dose of 9-15 Gy in 1.5 Gy/F, as a second fraction of the day for 6-10 days during the chemotherapy cycles (wk. I and wk. 5). The toxicities were moderate and the preliminary results were very encouraging.

Conclusion: The current results of phase II trials in preoperative chemo-radiotherapy in stages IIIA and IIIB NSCLC support a hypothesis that preoperative chemo-radiotherapy will result in a significant gain in survival over either preoperative chemotherapy alone or preoperative chemotherapy and postoperative radiotherapy. Significant progress has also been made in innovating radiation dose schedule in preoperative concurrent chemo-radiotherapy for stage III NSCLC. The hybrid dose schedule of mixed QD and BID radiation needs to be studied further for its potential in administering and modulating total dose and dose intensity within the constraint of the normal tissue tolerance. An exploration of chemo-radiation interaction by using both new chemotherapy agents and either BID or hybrid QD and BID radiation schedule also remains a fertile ground.

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GEMCITABINE AND CISPLATIN FOR UNRESECTABLE NON-SMALL CELL LUNG CANCER (NSCLC): PRELIMINARY RESULTS

G. CARBONERO, J.L. GONZALEZ LARRIBA, J. SASTRE, M. ORUEZABAL, P.PEREZ, E. DIAZ-RUBIO

Department of medical Oncology, Hospital Clinico San Carlos, Madrid, Spain

Objective: To evaluate the efficacy and toxicity of cisplatin plus gemcitabine in patients with unoperable or unresectable NSCLC. To determine survival and time to progression (TTP).

Method: twenty-two patients received cisplatin (100mg/m2) on day 1, and gemcitabine (1000-1200mg/m2) on days 1, 8, and 15, every 28 days, until progression or unacceptable toxicity.

Patients' characteristics: sex M/F 19/3; median age: 65 year (49-79 y); median PS:

90 (60-100); histology: adenocarcinoma: 68%, squamous: 18%, non small-cell 9%. Stage III-B: 27%, stage IV: 68%, and stage I(unoperab1e): 4% (1 patient).

Results: Total number of cycles administered: 75; median number of cyc1es/patient: 3 (1-6); median dose intensity: cisplatin 20mg/m2/week (14.6-25mg/m2/w), gemcitabine 600mg/m2/week (244-840mg/m2/w). 4 patients are not evaluable for response because of short follow-up. Among evaluable patients the overall response rate was 44% (CR: 11%, PR: 33%), progression was observed in 44% of the patients, and stabilization in 11% of the patients. With a median follow-up of 10 months (2-18m), median survival was 7 months (3-14m+), and median TTP 7 months (2-13m). Grade-III-IV toxicity: Trombopenia 25%, neutropenia: 25%, anemia: 6%, emesis: 1.3%, mucositis: 1.3%, nefrotoxicity: 1.3%, ototoxicity: 1.3%, neurosensory: 2.6%. Grade I-II toxicity: Trombopenia: 13%, neutropenia: 9.3%, anemia: 44%, ototoxicity: 1.3%, and neurosensory: 2.6%. There were no toxic deaths.

Conclusion: Chemotherapy with cisplatin and gemcitabine in NSCLC has a promising activity (44%RR) and a mild toxicity, mainly hematological which leads to the reduction/omission of some gemcitabine doses.

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RANDOMIZED PHASE III TRIAL OF THE SOUTHERN ITALY ONCOLOGY GROUP STUDY (G.O.I.M.) OF MITOMYCIN C PLUS VINDESINE AND CISPLATIN (MVP) VERSUS VINORELBINE AND CISPLATIN (PV) IN STAGE III - IV NON SMALL CELL LUNG CANCER

V.GEBBIA, D. GALETTA, F. RICCARDI, C. GRIDELLI, A. TESTA, E. DURINI, N. GEBBIA, G. COLUCCI

G.O.I.M. Chemotherapy Unit, University of Palermo; Division of Medical Oncology, Oncological Inst., Bari; Medical Oncology Unit, Tricase; Division of Medical Oncology, Oncological Institute, Naples; Division of Medical Oncology, Cardarelli Hospital, Naples.

To date cisplatin (CDDP) plus vinorelbine (VNR) represent a combination regimen widely employed in the treatment of inoperable and/or metastatic non-small cell lung cancer (NSCLC). Although this combination regimen is able to induce a nearly 40% overall response rate, however no prospective randomized phase III trial has compared the CDDP + VNR regimen to "standard" polychemotherapy combinations such as the MVP regimen. Therefore between January 1996 and December 1997 a multicentric randomized phase III study was carried out by the G.O.I.M. to compare the CDDP (100 mg/m2 q 28 days) + VNR (25 mg/m2 i.v. on day 1,8 q 28 days) to the MVP regimen (mitomycin C 8 mg/m2 d 1., vindesine 3 mg/m2 d 1,8,15, CDDP 100 mg/m2 d 1 q 28 d). A total of 247 pts with stage III-IV NSCLC have been centrally registered at the Univ. of Palermo and were randomized accordingly to stage and PS. Overall 134 pts had stage III NSCLC and 113 pts stage IV. Pts were well balanced between the two arms in terms of age, sex, histology, stage, PS distribution, sites of disease and number of metastatic sites. 122 pts received CDDP+VNR and 125 pts MVP. Pts were re-staged after 3 cycles. Response rates were reported accordingly to an inten-to-treat fashion. In stage III response rate was identical in both arms (46%), while in stage IV was 36% and 31 % for PN and MVP respectively. Although follow-up is not fully completed, no statistical difference in time to progression and survival has been detected to date. CDDP+VNR is associated with a higher rate of phlebitis, while the MVP with a higher incidence of myelosuppression. Above-reported data suggest that the combination of CDDP + VNR is as active as the MVP regimen in terms of objective response, time to progression and survival, but with a lesser toxicity.

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MEDIASTINAL LYMPH NODE DISSECTION IN A MULTIMODAL APPROACH TO THE MANAGEMENT OF LUNG CANCER

E. SHAUGHNESSY, K. CLARKE, T. ODOM MARYON, N. VORA, L. WAGMAN, F. GRANNIS, JR.

City of Hope National Medical Center, Duarte, CA.

Resection and radical mediastinal lymph node dissection (MLND) have been employed in the management of NSCLC for the past ten years at the City of Hope, with the addition of radiotherapy for N1 N2 node positive disease. A retrospective analysis of over 150 patients diagnosed and treated between 1987 and 1996 examined patterns of failure, perioperative patient and tumor characteristics, as well as morbidity, mortality and survival. 15 (10%) patients were found to be unresectable at surgery, leaving over 125 evaluable patients resected by lobectomy(s) or pneumonectomy and systematic MLND by one surgeon (FG). Pre operative radiotherapy was provided only to patients with superior sulcus tumors; patients with N1 or N2 nodal disease underwent postoperative radiotherapy. Two patients received neoadjuvant chemotherapy on protocol. Median follow up was 20.3 mos (range 0.2 99.2 mos). The stage distribution as well as five year overall and disease free survivals can be found in the following table:

Actuarial 5 year OS was 32% for patients with N2 NSCLC and 39% for patients with T3 NSCLC. There were no survivors with T3N2 stage IIIA NSCLC. Local control remained high for all resected, ranging 56.3 73.1%. The degree of metastatic mediastinal involvement, in terms of lymph node number and nodal stations, significantly correlated with OS, as did the status of the surgical margin. These factors also correlated with DFS. Perioperative morbidity (34%) included arrthymia (14%), pneumonia (4%), pulmonary edema (2%), and empyema (1%). 60 day mortality was 2.4%, occurring in patients who underwent pneumonectomy for stage III disease. 24% received transfusions, but none required re operation for hemorrhage. Median hospital stay was 8 days, with a median 2 days in the ICU.

The inclusion of systematic MLND in the surgical management of NSCLC, combined with radical resection, appears to be safe and without long term adverse effects. In the context of a multimodal approach, resection with MLND plus radiotherapy for N1 N2 nodal disease improves survival in NSCLC patients as compared to historical controls.

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ASSESSMENT OF CHROMOSOME BREAKS IN ONCOGENE SITES IN T LYMPHOCYTES AMONG THE POPULATION OF A RADIONUCLIDE-CONTAMINATED ZONE AROUND THE SIBERIAN CHEMICAL PLANT AFTER A RADIATION ACCIDENT ON APRIL 6, 1993

N.N. ILYINSKIKH, I.I. IVANCHUK, A.V. DUBACOV, I.N. ILYINSKIKHY, E.N. ILYINSKIKH

Siberian Medical University, 634050, Tomsk-50, a/ya 808, Russia, E-mail:root@ecogen.tomsk.su

The aim of the present study was to investigate the level of chromosome aberrations in fragile sites in peripheral blood lymphocytes among the population of an area contaminated with radionuclides following an accident at the Siberian Chemical Plant (SCP). Cytogenetic monitoring of 1246 persons who inhabited in the radiation-contaminated area was conducted. We also examined 40 patients with non-small cell lung cancer (one of the ordinary cancer in the Tomsk region) and chronic bronchitis with stage II - III of epithelial dysplasia. Also 86 individuals from a non-contaminated area were used as the control group. Chromosome breaks and exchanges predominantly occurred in individuals with genome instability and lung cancer (the sites of 3p14 - 3p25 and 6p23). There was a tendency towards predominant affliction of the sites q21-q25 of chromosome 6 in patients with lung cancer and chronic bronchitis as well. Specific damage in some chromosome sites was observed in both the radiation-exposed persons and patients with lung cancer. Most of these chromosome aberrations were located near oncogene loci which can be implicated in genome instability and the development of lung cancer among radiation-exposed individuals.

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1.) MONITORING NSCLC PATIENTS AFTER OPERATION AND ADJUVANT THERAPY, WITH THE USE OF SERUM CYFRA 21-1 TUMOR MARKER

A. KURZYNA, M. FURMAN, M. KOZLOWSKI

Department of Thoracic Surgery, Bialystok Medical School, Poland

Introduction: Tumor markers are very useful in malignancies, particularly in diagnosis, prognosis and treatment monitoring. Cytokeratins (CK) construct cytoskeleton of epithelial cells and are found to be good markers in lung cancer. Among several markers connected with cytokeratins (TPA, TPAcyk, TPS) CYFRA 21-1 is the most specific for CK 19. Many authors found CYFRA 21-1 to be a good marker for lung cancer in terms of diagnosis and prognosis. Unfortunately there is still little information about it's role in patients' monitoring, especially after operative treatment. Aim: We wanted to estimate CYFRA 21-1 role in 18-30 months monitoring of NSCLC patients, that were operated on and given adjuvant chemotherapy.

Material and methods: In 1995-1996 we operated on 80 patients for NSCLC. All patients were performed R0 resection (stage I-IIIA) and survived early postoperative period. 50% of them was given chemotherapy (4 cycles every 28 days, each with cisplatin 100mg/m2 and etoposide 3x100mg/m2). Patients with and without chemotherapy were randomized. Serum CYFRA 21-1 was taken before the surgical procedure and after it every 3 months for 1,5 year after operation. The serum concentration was measured by IRMA (Cis bio International). Results more than 3,6ng/ml were regarded as elevated.

Results: Before the operation 57% of patients had elevated CYFRA 21-1 levels. Operation diminished the marker level in all patients (below the point of cut in 96%). There were 5 types of monitoring curves during the observation period, when response to operation and chemotherapy as well as recurrence were considered. Recurrence was observed in 25% of patients(16 without and 4 with chemotherapy). CYFRA 21-1 preceded metastasis or recurrence onset for 2-6 months in 64% of them. The clinical recurrence onset was earlier in patients without chemotherapy ( disease free period: mean 9,8 vs15,3 months).

Conclusions: CYFRA 21-1 is a useful marker in lung cancer monitoring. It can precede cancer recurrence without any predilection to postoperative chemotherapy. The question, whether elevated serum CYFRA 21-1 before clinical signs of recurrence can make us introduce the treatment in such a case, is discussible.

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2) ADJUVANT THERAPY AFTER OPERATION OF STAGE IIIA NON SMALL CELL LUNG CANCER

S. KILUK, M. KOZLOWSKI, M. FURMAN, M. KILUK, A. KURZYNA, K. FURMAN

Department of Thoracic Surgery, Bialystok Medical School, Poland

The aim of our study was discussion of supplementary treatment after operation of stage IIIa non small cell lung cancer. The supplement of surgical treatment by radio- and/or chemotherapy were used in case T3N0-1Mo and T1-2-3N1-2M0 (after statement of metastasis to hilar and mediastinal lymph nodes) and it was depended to the histology of the tumors and general condition of the patients. Radiotherapy was used in squamous cell carcinoma, to total of 48-50 Gy/T, daily fractions of 2 Gy/T were delivered through two opposite fields, 5 fractions a week. The chemotherapy (DDP+VP 16; 2-3 courses) was used in adenocarcinoma or large carcinoma in the beginning and after that prophylactic radiation of daily fractions of 1,8 Gy/T, 5 fractions a week to total 25 Gy/T was delivered on the brain through two opposite fields Concurrent radio- and chemotherapy was used in mixed cancer - squamous and adenocarcinoma. In the group of 95 patients operated in stage IIIa (46,6% all resection for lung tissue) after supplementary treatment 62 (63,3%) survived 1 year, 32 (33,9%) - 2 year and 25 (25,8%) - 3 year. The supplement of the operation by radio- and/or chemotherapy is the procedure at choice in the treatment of the advanced stage lung cancer. The supplementary treatment improve distant results.

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WEEKLY CISPLATIN + EPIDOXORUBICIN + MEDROXYPROGESTERONE ACETATE + R-INTERLEUKIN-2 IN ADVANCED (STAGE IIIB-IV) LUNG CANCER (NSCLC). PRELIMINARY RESULTS OF A DOSE-FINDING STUDY

MANTOVANI G.*, MACCIÒ A., LAI P., GHIANI M., MUDU M.C., DESSÌ D., MULAS C., SUCCU G., MASSA E., MASSIDDA S., ARESU P., MANCA O., VERSACE R.1 and PISANO M.1

Department of Medical Oncology and Internal Medical Sciences, University of Cagliari and Division of Thoracic Surgery, "R. Binaghi" Hospital, Cagliari, Italy.

Several cytokines, mainly interleukin (IL)-1, IL-2, IL-6 and tumor necrosis factor a (TNF a), are involved in the pathogenesis of anorexia/cachexia syndrome. In a previous study (Eur. J. Cancer, 33, 602-607, 1997) we reported the effect of MPA on PBMC from 10 cancer patients (pts) in advanced stage of disease. Our study provided evidence that MPA is able to hinder the activity of some of the above mentioned cytokines, such as IL-lb , IL-6 and TNFa , by inhibiting their production and/or release. These experimental results prompted us to perform a phase I study to evaluate toxicity (dose-limiting toxicity - DLT; maximal tolerated dose - MTD) and efficacy of a weekly schedule of a combination of Cisplatin (CDDP) i.v., Epidoxorubicin (EPI) i.v., Medroxyprogesterone acetate (MPA, 1g/day p.o.) and recombinant Interleukin 2 (rIL-2, 1.8 MIU d2-d7 s.c.) plus G-CSF support (300 m g d2-7 s.c.) in pts with advanced (IIIB-IV) inoperable lung cancer. Methods. Administration of MPA started one week before the first cycle. Dose escalation was: CDDP 30 mg/m2/w + EPI 25 mg/m2/w (1st level: 2 pts), CDDP 30 mg/m2/w + EPI 33 mg/m2/w (2nd level: 2 pts), CDDP 40 mg/m2/w + EPI 33 mg/m2/w (3rd level: 5 pts), CDDP 40 mg/m2/w + EPI 40 mg/m2/w (4th level: 4 pts). After 6 weekly cycles, an evaluation of clinical response and of toxicity was done. If become operable, pts underwent surgery, if not, 3 further cycles were administered. After 9 cycles, if operable, pts underwent surgery, if not, 3 further cycles were administered.

Patients. Inclusion criteria were: histologically confirmed primary lung cancer without brain metastases, ECOG PS 0-1, normal cardiac function (LVEF³ 60%, normal Echo). All pts gave written informed consent. From March to October 1997, 13 pts (M/F 11/2, mean age 59 years, range 42-68) were enrolled: all 13 were evaluable for toxicity and 11 of them for response. Eleven pts had NSCLC (2 pts had stage IV disease, 7 pts stage IIIB, 1 pt stage IIIA and 1 pt stage II, the last 2 pts were evaluated only for toxicity); 2 pts had SCLC (1 ED and 1 LD). Results. Clinical response after 6 cycles: 7 PR (63.63%), 3 SD (27.28%) and 1 PD (9.09%) out of 11 pts were found with an ORR of 63.63%.

Toxicity. Only hematological toxicity was observed. Maximal toxicity per patient was as follows: 1 grade I (leukopenia) and 1 grade II (anemia) at 1st level (23 cycles evaluated); 1 grade II and I grade III (both anemia) at 2nd level (20 cycles evaluated); 1 grade I (anemia), 1 grade II (anemia and leukopenia) and 2 grade III (1 anemia and 1 leukopenia) at 3rd level (31 cycles evaluated); 1 grade I (anemia), I grade II (anemia) and 2 grade III (1 anemia and I leukopenia) at 4th level (29 cycles evaluated). One pt died while being in PR for non toxicity-related causes. Conclusions. Our preliminary results show that this regimen and schedule are effective (7/11 PR and 3/11 SD at 6 cycles) and feasible. Hematological (mainly anemia) is clearly the main toxicity. No cardiac toxicity was seen. DLT (hematological) was seen at 4th level. MTD will be assessed. The study is still ongoing. Work supported by CNR., Rome, A.P. 'A.C.R.O.'; Contract No. 96.00588.PF39

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THORACOSCOPIC ULTRASOUND STAGING OF LUNG CANCER

M. MEZZETTI, R. SANTAMBROGIO, P. BIANCHI, A. MANTOVANI, F. GHELMA

Clinica Chirurgica - Università di Milano - Ospedale San Paolo - via A. di Rudinì 8 - 20142 MILANO

Key Words: Thoracoscopic staging; non small cell lung cancer; intraoperative ultrasound

To assess the extent of tumor invasion in lung cancer, we start a study protocol to use intraoperative ultrasonography in addition to preoperative roentgenography, computed tomographic scanning and other standard procedures. High-resolution (7.5 MHz) intraoperative ultrasonography allow for a real-time assessment of direct cardiovascular invasion of tumor and lymph node metastasis. Immediately after thoracoscopic inspection but before tissue dissection, operative ultrasound enabled delineation and evaluation of the vessels and the heart behind or within the tumor and detection of regional lymph nodes. A diagnosis of cardiovascular invasion was made when ultrasound revealed that the vessel wall or heart wall was distorted or destroyed by tumor. Lymphadenopathy detected by ultrasound was judged possibly malignant according to the following criteria: round shape; sharp, distinct bordes; hypoechoic texture; and a short-axis diameter greater than 10 mm. Throacoscopic ultrasound was used during lung cancer operations in 12 patients. The ages ranged from 45 to 73 years with a mean age of 63.3 years. Ten patients were men and 2 were women. In 1 patient thoracoscopic ultrasound revealed an unsuspected direct invasion of the tumor to the aorta, while in another case thoracoscopic exploration visualized a chest wall involvement. In 12 ultrasound evaluation of lymph nodes, 3 patients were judged to have lymph node metastasis according the above-mentioned criteria. Eight patients were submitted to an open thoracotomic lobectomy, 2 patients to a thoracoscopic lobectomy and 2 others only to a biopsy. So, 10 patients were submitted to a standard node sampling and 6 were found to have metastatic lymph nodes: in 3 cases, already identified by the above-mentioned ultrasonical criteria, while in other 3 cases they were judged to be negative for metastasis (false negative) by ultrasound. In conclusion, thoracoscopic ultrasound adds useful information in patients with lung cancer. Further investigations are now needed before the role of thoracoscopic ultrasound in the staging of lung cancer can be considered firmly established.

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THE INTERACTION BETWEEN GENE P53 AND ONCOGENE MDM2 IN HUMAN LUNG GLANDULAR CANCER CELL LINE GLC-82

L. PING, R. GUOZHOU, C. YUNCHUN, D. ZHENRUO, R. IIQIANG, Y. WENBIN

Department of Molecular Biology, Xijing Hospital, The 4th Military Medical University, Xijan 710032, P.R.China

Key words: wp53, mdm2, GLC-82, interaction

Background. The wild-type p53(wp53) tumor suppressor gene is commonly inactivated in human malignancies, either by mutations or by loss of expression. An additional proposed mechanism for inactivation of wp53 id amplification of the murine double minute 2 (mdm2) gene and overexpression of the mdm2 protein, which binds to p53 and eliminates its tumor suppressor function. To study the relationship and interaction between oncogene mdm2 and wp53 in human lung glandular cancer cell line GLC-82.

Methods. By means of lipofectamine-mediated DNA transfection, wp53 and mdm2 were transfected separately or co-transfected into GLC-82 cells via retrovival vector PDOR-neo which was the carrier of wp53 and mdm2.

Results. Wp53 blocked the growth of GLC-82 cells and inhibited their DNA synthesis; the rate of colony-forming in soft agar culture and the tumorigenicity in nude mice decreased, but mdm2 antagonized the function of wp53.

Conclusion. After the recombinant vectors PDOR-mdm2 were transfected into GLC-82 cells which contained wp53 previously, it turned out that mdm2 can partially deprive wp53 of its function to inhibit the growth of GLC-82 cells.

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COMPARISON OF CEA AND TPS LEVELS IN SERUM SAMPLES FROM PERIPHERAL BLOOD AND PULMONARY VESSELS IN PATIENTS WITH LUNG CANCER

J. KOLODZIEJ1,4, A. HARLOZINSKA-SZMYRKA2, P. SEDLACZEK2, A. STANISZEWSKI3 , M. MARCINIAK1, A. RZECHONEK4

1Dept. of Thoracic Surgery, 2Dept. of Tumour Immunology, and 3Dept. of Family Medicine, Wroclaw University of Medicine; 4 Dept. of Thoracic Surgery, Lower Silesian Center for Tuberculosis and Pulmonary Diseases; Grabiszynska 105, 53-439 Wroclaw, Poland; Tel. (+48-71) 621515, 621029

The difficulty in clinical assessment of patients with lung cancer (L.C.) has led to a search for more sensitive tumour markers. In this study carried out between 1993 and 1997, we evaluated the potential role of two tumour markers (i.e. carcinoembryonic antigen, CEA, and tissue polypeptide specific antigen, TPS) in diagnosis and prognosis of L.C.

In 44 patients (36 men, 8 women) aged 39-71 (median 60 years) who underwent thoracotomy for non-small cell L.C. at various stages, CEA and TPS levels were determined by an enzyme-linked immunoasssay (ELISA) method. The blood samples were taken intraoperatively from the vascular supply of a malignant tumour, the efferent vessels, and the peripheral vein.

Results:

Although further research is indicated, this study suggests that TPS may be a promising marker in the clinical management of lung cancer patients.

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PROGNOSTIC IMPLICATIONS OF PULMONARY SATELLITE NODULES: ARE THE 1997 STAGING REVISIONS APPROPRIATE?

J.D. URSCHEL, D.M. URSCHEL, T.M. ANDERSON

Dept of Thoracic Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York, 14263-0001, USA. Fax (716) 845-7692

In the 1992 AJCC and 1993 UICC staging systems, primary lobe satellite nodules increased the T designation of the primary by one level and ipsilateral non-primary lobe satellite nodules raised the T status to T4. The recent (1997) UICC and AJCC staging revisions assign a T4 (IIIb) designation to satellite nodules in the primary lobe, and a Ml (IV) designation to satellites in ipsilateral non-primary lobes. There is abundant evidence showing that satellite nodules are negative prognostic factors, but their inclusion in stage IIIb and IV may not be appropriate.

The English-language medical literature was searched for papers reporting survival after surgical resection of NSCLC with satellite nodules (primary and non-primary ipsilateral lobe locations). Nine articles were retrieved and their data pooled for analysis. Of 465 resected patients with satellite nodules, reported actuarial 5-year survival was 18%. Four articles gave separate survival data for satellite nodules in primary vs. non-primary lobes. All four articles showed better survival for satellite nodules in the primary lobe.

Satellite nodules in the primary lobe have a better prognosis than those in non-primary ipsilateral lobes. Overall survival of resected NSCLC with satellite nodules is better than that usually associated with T4 (IIIB) or Ml (IV) disease. The 1997 staging revisions for satellite nodules may not be appropriate.

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III A/B NSCLC: QUICKLY ALTERNATING, RADICAL RADIO-/CHEMO-THERAPY WITH FEW SIDE EFFECTS

CH. VON BRIEL1, D. BETTICHER2, H.B. RIS3 ,R.H. GREINER1

I) Dep. Radiation Oncology, 2) Inst. Med. Oncology, 3) Dep. Thoracic-, Heart- and Vascular Surgery, Inselspital, University Bern, Switzerland

Purpose: Feasibility study of quickly alternating radio-/chemotherapy for patients with unresectable non-small cell lung cancer with intention of local tumor control, probably by final tumor resection

Methods: 39 pat. have been treated between March 92 and August 96, 6 (16%) female and 32 male pat. Median age was 63 yrs (40-75). 22 (58%) pat. were classified as stage IIIA, 16 as stage IIIB. 24/38 (63%) pat. had a squamous cell carcinoma. Ch-Th was given d1, Cis-Platinum 60 mg/sqm and Vinblastin 6 mg/sqm and repeated 5x every 3 weeks. R-Th was applied first time on d 8-I 2, twice 160 cGy daily, 10 fx weekly, and repeated 3x every 3 weeks, always the week after Ch-Th. Since April 94 the pat. were restaged after 3 cycles Ch-Th and 48 Gy (3x16 Gy) regarding for resectability.

Results: 35 out of 38 pat. reached the planned dose of R-Th, median dose for unoperated pat. 58 Gy (24 -64), for operated pat. 48 Gy (48-56). 178 (90%) out of 198 planned Ch-Th cycles could be applied. 10 out of 17 pat. with resectable tumors have been operated. After a median FU-time of 36 months, 23/38 pat. are dead, the death in 20/23 pat. caused by tumor. 13/15 pat. are alive with NED. 13/38 pat. developed a local progression (2-22 months), 16/38 pat. developed metastases (I -28 months). The MS is 23 months with 28% of pat. alive after 3 years. There is a difference (p=O.07) between the operated and the not operated pat. with stage IIIA tumor but no difference between the total numbers of pat. with stage IIIA and stage IIIB.

This R-Th treatment scheme was extremely well tolerated. With no treatment interruption due to acute side effects. 4/38 pat. suffered from esophagitis G II and 3 pat. from skin reactions G 11.3 pat. developed radiologically diagnosed pneumonitis. 2 pat. came into a leucopenia G III/IV, 1 pat. showed a thrombocytopenia GIII.

Conclusion: The treatment scheme of quickly alternating, radical radio-/chemotherapy with twice daily 160 cGy, applied in 4 weeks with 3 weeks interval each, is feasible, extremely well tolerated and also highly efficient as preoperative treatment measure.

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DEBULKING OPERATION FOR STAGE IIIA, IIIB NON-SMALL CELL LUNG CANCER

Y. WU, Z. HUANG, T. RONG

Department of Thoracic Surgery, Tumor Hospital, Sun Yat-sen University of Medical Sciences, Guangzhou, P. R. China Tel:(+86-20)87774384; Fax:(+86-20)87754506; E-mail: gzyilong@pub.gz.gdpta.net.cn

Key words: lung neoplasms/surgery debulking operation survival analysis

Objective To assess effectiveness and influencing factors of debulking operation for non-small cell lung cancer are presented.

Method The cumulative survival and its influencing factors were analyzed and compared by the Kaplan-Meier and COX model of SPSS FOR WINDOWS in 244 patients received debulking operation and 364 received thoracotomy.

Results The 1,3,5-year cumulative survival of patients treated with debulking operation was 56.9%, 20.6%, 17.5% respectively while that received thoracotomy was 41.1%, 7.8%, 5.3%, respectively (debulking vs. thoracotomy, Breslow=27.55, p=0.0000). The result of cumulative survival rates of 244 cases with debulking operation for different postoperative treatment was seen in below:

Conclusion: Tumor debulking operation is an important treatment for stage IIIa and IIIb non-small cell lung cancer. With postoperative adjuvant chemoradiotherapy better survival can be achieved.

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VINDESINE WITH CYCLOPHOSPHAMIDE-EPIRUBICIN-CISPLATIN IN THE TREATMENT LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER

H. YANPING, K. YUHUA, F. XIAOYU

Hubei Cancer Hospital, Wuhan, P.R.China

Key Words: Chemotherapy, Locally advanced NSCLC

From May 1994 to October 1997, 48 previously untreated patients with Stage a and b non-small cell lung cancer(NSCLC) were enrolled into this trial to evaluate the addition of vindesine to a Cyclophosphamide-Epirubicin-Cisplatin(CAP) regimen. Patients characteristics were the following: the median age was 52 years; the median performance status was 1; there were 15 Stage a and 33 Stage b; there were 38 adenocarcinoma, 8 squamous cell carcinoma and 2 large cell carcinoma. In this report, all patients were treated with vindesine(2mg/m2 , on day1 and day 8), cyclophosphamide (0.6/m2, on day1), epibubicin (40mg/m2, on day1) and cisplatin (60mg/m2, on day1) every 3 or 4 weeks. The only significant side effect was myelosuppression, with 10.4% of patients having Grade 4 toxicity. Three achieved a complete response (6.3%), 20 achieved a partial response (41.7%), 13 had stable disease, and 13 had progressive disease. A clinical improvement was in 36 of 48 patients. In conclusion, the vindesine with CAP regimen for the treatment of locally advanced NSCLC achieved a higher response and was less toxic.