Download Naples, Italy

SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
1.
MOLECULAR DIAGNOSIS IN THORACIC ONCOLOGY
G. BEVILACQUA
Department of Oncology, Division of Pathology, University of Pisa
2.
NEOADJUVANT TREATMENT AND SURGERY FOR EARLY STAGE AND STAGE
IIIA LUNG CANCER
F. SARTORI, L. BORTOLOTTI, M. GRAPEGGIA, D. CALLEGARO, M. LOY, F. REA AND A.
FAVARETTO
Division of Thoracic Surgery, University of Padua
3.
POSTOPERATIVE COMPLICATIONS IN RELATION WITH INDUCTION THERAPY
FOR LUNG CANCER.
P. FUENTES, C. DODDOLI, G. ROLLET, P. THOMAS, R. GIUDICELLI.
Department of Thoracic Surgery. Sainte-Marguerite Hospital, Marseille, France
4.
ADJUVANT TREATMENT IN LUNG CANCER: NEW ISSUES
M. TONATO, MD
Medical Oncology Division, Policlinico Hospital, Perugia, Italy
5.
TREATMENT OF ADVANCED LUNG CANCER (III B- IV) - TWO OR THREE DRUG
TREATMENT
V. IAFFAIOLI
Medical Oncology, University of Cagliari, Italy
6.
TUMOR MARKERS: A ROLE OF TUMOR MARKERS IN THE DIAGNOSIS AND
PROGNOSIS OF LUNG CANCER
C. CECERE, S. ELIA, G. FERRANTE, P. PAPA^, A. DI CARLO*, A. MARIANO°, V. MACCHIA°
Chair of Thoracic Surgery, Medical School, University “Federico II”, Naples, Italy
^Division of Bronchopneumology, General Hospital, Avellino, Italy
*Department of Experimental Pathology, Medical Biotechnologies, Epidemiology and
Infectious diseases, University of Pisa, Italy
°Chair of Clinical Pathology, Department of Biology, Cellular and Molecular Pathology
University Federico II, Naples, Italy
NAPLES 2000 http://members.xoom.it/naples2000/
1
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
MOLECULAR DIAGNOSIS IN THORACIC ONCOLOGY
G. Bevilacqua
Department of Oncology, Division of Pathology, University of Pisa
Cancer can be considered a “disease of cell proliferation” and a “genetic disease”. One of two
definitions focuses on the fact that cancer is consequence of the deregulation of the mechanisms of cell
growth control, the other on the fact that relevant events conditioning the neoplastic transformation and
the progression of the disease consist in modifications of the genome. In addition, sometimes the genomic
alterations can be inherited; in this case, cancer is a genetic disease also in the sense that it represents an
inheritable disease.
The natural history of a malignant tumor can be considered divided in three main phases: initiation,
promotion and progression. A cell is initiated when, after a series of specific mutations, acquires the
neoplastic genotype. Initiation is considered a common event, but, fortunately, in a very large number of
cases it does not give origin to a tumor; in facts, the transformed cell is eliminated through the normal
mechanisms of defense, that recognize it as “different”. The neoplastic growth starts if the entire cell
compartment of which the transformed cell is part is stimulated (promoted) to proliferate; in human
cancer, promoting agents belong to two main types, chronic inflammation and hormones. The growth
factors produced by chronic essudates represents a strong stimulus on cell proliferation; this takes place,
for example, in two human cancer models, as squamous lung cancer and squamous cervical cancer. On
the other hand, steroid hormones exert a powerful promotion on the mammary epithelial cells and
represent the main promoting agents for breast carcinoma. Progression is the last and longest phase of the
life of cancer and can be defined as the whole of the neoplastic steps from the beginning of cell growth to
the eventual acquisition of the metastatic phenotype; its early phase consists in all the degrees of in situ
epithelial proliferation (hyperplasia, atypical hyperplasia of different grade, in situ carcinoma), infiltrating
cancer is the intermediate phase of tumor progression and metastasis is the late one.
Genes involved in initiation and progression belong mainly to three categories: oncogenes, suppressor
genes and genes of the DNA repair, also called mutator genes. The physiological role of the genes of the
first two groups is to stimulate and to inhibit cell proliferation, respectively; their mutations bring to an
uncontrolled growth, essence of cancer disease. The genes of the “repair” play a role that is fundamental
for the surviving of the single individual and for the preservation of the species; as example, they repair
the damage that sunrays cause in the DNA of the cells of epidermis during the summer tanning.
Mutations of this class of genes increase greatly the mutation rate of the entire genome, giving origin to
the so called “genomic imbalance”, to the disarray indispensable for the origin of the cell clones provided
of all the necessary characteristics for the “full malignancy”. Without the role of the mutator genes, the
already long process of tumor progression (that can last for decades) would be too long to be completed
during the life of a human being; in this case, cancer would represent an exceptionally rare event.
As many genes are involved in oncogenesis, many other genes are involved in cancer progression; to
the neoplastic pathway with its genes (oncogenes, suppressor genes, mutator genes) corresponds a
metastatic pathway with its genes, sometimes not euphonically named “metastogenes”. Oncogenes
stimulate cell to proliferate and are considered dominant genes, in that one mutant allele is able to exert a
trasforming effect. Proteins codified by oncogenes belong to several types: growth factors and growth
factor receptors, signal transducing molecules, nuclear transcription factors, cyclins, cyclin-dependent
kinases. All these proteins can be qualitatively or quantitatively altered, following modifications of both
structure and function of oncogenes: point mutations and chromosomal rearrangements produce a
structural damage with a consequent abnormal activation of the gene, whereas gene amplification
increases the quantity of the proteic product.
Suppressor genes inhibit cell proliferation and are considered recessive, in that a neoplastic effect
requires that both allele are mutated. Products of suppressor genes are nuclear transcription factors,
proteins controlling the cell cycle, signal transduction molecules, cell surface receptors. Because these
proteins exert an inhibitory effect on cell proliferation, an oncogenic effect takes place if the gene is in
some way mutated, from a point mutation to its complete loss; unlike oncogenes, the involvement of both
alleles is necessary.
NAPLES 2000 http://members.xoom.it/naples2000/
2
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
In addition, genes that regulate apoptosis, the programmed cell death, have to be mentioned as another
class of genes involved in cancerogenesis. Some of them, as bcl-2, play a protective role against
apoptosis, whereas others favor it. Their overexpression or their mutation can have a tumorigenic effect.
Mutated genes of this class can have both a dominant or a recessive behavior.
All this information represents the background for a clinical application of molecular genetics. The
knowledge of the molecular events characterizing the several steps of the life of a malignant tumor can be
used for several purposes in clinical oncology: early diagnosis, prognostic evaluation, research of
micrometastasis. Moreover, molecular biology can modify the pathological classification of tumors, in
that it clarifies relevant aspects of their natural history.
Focusing on thoracic oncology, molecular analysis can be of help in several fields:
a. Early diagnosis: lung cancer is often diagnosed when in an advanced stage; unfortunately, available
techniques, such as the cytological examination of the sputum, do not allow a real early diagnosis. The
fact that some genetic alterations represent early events in the progression of lung carcinoma can be used
as a tool for a very early demonstration of the presence of a malignant tumor. A modern version of the
classic “cytology” is the molecular analysis of the sputum, by looking at p53 or k-ras gene mutations or at
the presence of microsatellite instability. This kind of approach gives excellent results in both
retrospective and prospective studies, demonstrating a false negative cytological diagnosis in more than
30% of cases.
b. Diagnosis of micrometastasis: there is a large consent on the fact that the presence of
micrometastasis in lymph nodes or in bone marrow represents a relevant parameter of prognosis and can
influence the therapeutic strategy; unfortunately, it should be well known that about 30% of histological
diagnosis of N0 are wrong. Immunohistochemical analysis of lymph nodes and bone marrow can reduce
the number of errors even dramatically, but still requires a long and tedious histological work. The search
of tumor related gene modification or of the expression of genes not expressed in normal lymph node or
bone marrow cell population is able to increase the percentage of correct diagnosis of about 30%.
c. Prognostic evaluation: several genetic alterations can be studied in the attempt to give useful
prognostic information, such as those of p16, p53, k-ras, cyclin D1, RB, NM23. Very interesting results
are obtained by the evaluation of telomerase activity. Anyway, a correct strategy seems to be the
contemporary evaluation of the status of several genes.
d. Natural history: the study of their genetic modifications can be of great help in clarifying relevant
aspects of the pathogenesis of some kind of tumors. For example, the analysis of genes as FHIT, p53, and
k-ras is useful for a molecular classification of bronchioloalveolar carcinomas, whereas the analysis of
FHIT and p53 can help in understanding the pathogenesis of lung adenocarcinoma in non-smoking
patients.
Today, molecular biology cannot resolve all our clinical or theoretical problems; on the
other hand, it is reasonable to believe in a very near “molecular future”. In any case, the
establishment of a “molecular culture” is an essential requisite for a modern medical class.
References.
1. Ahrendt SA, Chow JT, Xu LH, Yang SC, Eisenberger CF, Esteller M, Herman JG, Wu L,
Decker PA, Jen J, Sidransky D: Molecular detection of tumor cells in bronchoalveolar
lavage fluid from patients with early stage lung cancer. J Natl Cancer Inst 91: 332-9, 1999
2. Culp LA, Lin WC, Kleinman NR, Campero NM, Miller CJ, Holleran JL: Tumor
progression, micrometastasis, and genetic instability tracked with histochemical marker
genes. Prog Histochem Cytochem 33: 329-48, 1998
3. Dobashi K, Sugio K, Osaki T, Oka T, Yasumoto K: Micrometastatic P53-positive cells in
the lymph nodes of non-small-cell lung cancer: prognostic significance. J Thorac
Cardiovasc Surg 114: 339-46, 1997
NAPLES 2000 http://members.xoom.it/naples2000/
3
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
4. Fu XL, Zhu XZ, Shi DR, Xiu LZ, Wang LJ, Zhao S, Qian H, Lu HF, Xiang YB, Jiang GL:
Study of prognostic predictors for non-small cell lung cancer. Lung Cancer 23: 143-52,
1999
5. Huncharek M, Muscat J, Geschwind JF: K-ras oncogene mutation as a prognostic marker in
non-small cell lung cancer: a combined analysis of 881 cases. Carcinogenesis 20: 1507-10,
1999
6. Marchetti A, Buttitta F, Pellegrini S, Chella A, Bertacca G, Filardo A, Tognoni V, Ferreli F,
Signorini E, Angeletti CA, Bevilacqua G: Bronchioloalveolar lung carcinomas: K-ras
mutations are constant events in the mucinous subtype. J Pathol 179: 254-9, 1996
7. Marchetti A, Buttitta F, Pellegrini S, Bertacca G, Chella A, Carnicelli V, Tognoni V,
Filardo A, Angeletti CA, Bevilacqua G: Alterations of P16 (MTS1) in node-positive nonsmall cell lung carcinomas. J Pathol 181: 178-82, 1997
8. Marchetti A, Doglioni C, Barbareschi M, Buttitta F, Pellegrini S, Gaeta P, La Rocca R,
Merlo G, Chella A, Angeletti CA, Dalla Palma P, Bevilacqua G: Cyclin D1 and
retinoblastoma susceptibility gene alterations in non-small cell lung cancer. Int J Cancer 75:
187-92, 1998
9. Marchetti A, Pellegrini S, Sozzi G, Bertacca G, Gaeta P, Buttitta F, Carnicelli V, Griseri P,
Chella A, Angeletti CA, Pierotti M, Bevilacqua G: Genetic analysis of lung tumours of nonsmoking subjects: p53 gene mutations are constantly associated with loss of heterozygosity
at the FHIT locus. Br J Cancer 78: 73-8, 1998
10. Marchetti A, Pellegrini S, Bertacca G, Buttitta F, Gaeta P, Carnicelli V, Nardini V, Griseri
P, Chella A, Angeletti CA, Bevilacqua G: FHIT and p53 gene abnormalities in
bronchioloalveolar carcinomas. Correlations with clinicopathological data and K-ras
mutations. J Pathol 184: 240-6, 1998
11. Marchetti A, Bertacca G, Buttitta F, Chella A, Quattrocolo G, Angeletti CA, Bevilacqua G:
Telomerase activity as a prognostic indicator in stage I non-small cell lung cancer. Clin
Cancer Res 5: 2077-81, 1999
12. Ohta Y, Nozawa H, Tanaka Y, Oda M, Watanabe Y: Increased vascular endothelial growth
factor and vascular endothelial growth factor-c and decreased nm23 expression associated
with microdissemination in the lymph nodes in stage i non-small cell lung cancer. J Thorac
Cardiovasc Surg 119: 804-813, 2000
13. Passlick B, Kubuschok B, Izbicki JR, Thetter O, Pantel K: Isolated tumor cells in bone
marrow predict reduced survival in node-negative non-small cell lung cancer. Ann Thorac
Surg 68: 2053-8, 1999
14. Pellegrini S, Bertacca G, Buttitta F, Bevilacqua G, Marchetti A: Lung tumours from nonsmoking subjects: A p53-related genetic instability in a subset of cases. Int J Mol Med 4:
419-24, 1999
15. Shackney SE, Smith CA, Pollice A, Levitt M, Magovern JA, Wiechmann RJ, Silverman J,
Sweeney L, Landreneau RJ: Genetic evolutionary staging of early non-small cell lung
cancer: the P53 --> HER-2/NEU --> ras sequence. J Thorac Cardiovasc Surg 118: 259-67,
1999
16. Somers VA, Pietersen AM, Theunissen PH, Thunnissen FB: Detection of K-ras point
mutations in sputum from patients with adenocarcinoma of the lung by point-EXACCT. J
Clin Oncol 16: 3061-8. 1998
17. Somers VA, van Henten AM, ten Velde GP, Arends JW, Thunnissen FB: Additional value
of K-ras point mutations in bronchial wash fluids for diagnosis of peripheral lung tumours.
Eur Respir J 13: 1120-4, 1999
NAPLES 2000 http://members.xoom.it/naples2000/
4
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
NEOADJUVANT TREATMENT AND SURGERY FOR EARLY STAGE AND STAGE IIIA
LUNG CANCER
F. Sartori, L. Bortolotti, M. Grapeggia, D. Callegaro, M. Loy, F. Rea and A. Favaretto
Division of Thoracic Surgery, University of Padua
Surgery remains the only curative treatment for patients with non-small cell lung cancer (NSCLC): it
offers the best chance of long-term survival and cure providing the tumor is confined to the chest and is
resectable.
Surgery is the best treatment for early stage disease, but it is important to adopt the appropriate
procedure to remove the tumor and the loco-regional nodes. The survival for stage I and II resected
disease ranges from 38% to 76%. In a multicenter Phase II trial with T2N0, T1-2N1, and T3N0-1 NSCLC
treatment consisted of induction chemotherapy followed by surgery and additional cycles of
chemotherapy major responses occured in 56%; no increased or unexpected toxicity or surgical morbidity
have been observed. Depierre et al. in a recent study suggested that neoadjuvant chemotherapy could
improve survival in Stage I-II NSCLC. One focus for research is the earlier stages of disease, in which
induction chemotherapy may also have a role.
The optimal treatment for patients with locally advanced NSCLC, which accounts for about 40% of
cases of NSCLC, remains open to debate. Since a large number of patients have stage III disease, even
small improvements in treatment can reduce the high rate of mortality recorded for lung cancer. Surgical
results with stage IIIA (N2) patients are unfavorable and surgery is not considered as a standard treatment
for this group of patients. Though there is a chance of long-term survival in selected patients with N2
disease, e.g., patients who had lower mediastinal node metastases confined to a single nodal station (30%
five-year survival rate after complete resection), but they represent only a quarter of all patients with N2
disease. By contrast the prognosis for stage IIIA patients who have bulky or multi-level N2 disease is so
poor that surgical resection is no longer considered appropriate initial therapy.This has led to
investigations on the potential role of preoperative induction (neoadjuvant) chemotherapy, either alone or
with radiotherapy. For N2 clinical disease, both local control and overall survival were influenced by
radiation but 50% to 80% of patients developed distant metastases during or shortly after treatment,
emphasizing the need for systemic therapy in stage III NSCLC. The rationale is that the addition of
chemotherapy will control micrometastases as well as reduce the size of the primary tumor to facilitate
the local control achieved by resection.
There are numerous reports on the successiful use of neo-adiuvant chemotherapy for downstaging
locally-advanced NSCLC. Many Phase II trials have investigated the use of pre-operative chemotherapy
as part of the treatment plan for Stage IIIA patients and have demonstrated what appear to be improved
median survival time and prolonged 5-year survival as compared to historical controls. Several Phase II
trials have analized the use of preoperative chemoradiotherapy as an induction protocol; concurrent
chemotherapy and radiation has the theoretical advantage of synergy: this approach emphasizes both the
importance of local control as well as distant metastatic control in the cure of patients with Stage III
disease. There are three randomized Phase III trials indicating that neoadiuvant cisplatin based
chemotherapy in Stage IIIA disease improves survival.
The main goal of pre-operative therapy is to prolong survival. However, there are useful surrogate
markers that can be used to evaluate the likelihood of new approaches achieving this aim. These include
resection rate, tumor downstaging by elimination of mediastinal lymph node disease, and improvement in
pathologic complete response rate.
Trials on neo-adjuvant therapy have demonstrated the faesibility of combined modality treatment in
Stage III NSCLC; in all trials reported to date, however, the most common form of relapse has been
distant metastatic disease, which emphasizes the need for more effective systemic treatment.
With neoadjuvant therapy there is an increased risk of postoperative complications. Various
chemotherapetic agents are associated with potential perioperative problems, e.g., the risk of exacerbating
cisplatin induced nephrotoxicity by volume depletion. It is important to avoid fluid overloading in
patients whose pulmonary vascular bed may be compromised by preoperative therapy (at risk of ARDS
due to mitomycin or radiation). Moreover, resection after preoperative therapy can be extremely difficult
NAPLES 2000 http://members.xoom.it/naples2000/
5
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
and hazardous beacause of the fibrosis that often results as a response to such therapy. Intraoperatively, it
is often impossible to determine whether there is any residual active tumor within an area of dense
fibrosis and difficult decisions must be taken as to the extent of bronchopulmonary resection. Finally,
preoperative treatment increases the risk of surgical complications affecting the bronchial stump and
anastomoses.
Locally advanced NSCLC is a systemic disease requiring a multimodality approach to its
management. The optimum chemotherapy and radiotherapy integration schedule remains to be
determined. These combined-modality programs are now being included in early stage disease trials.
Despite numerous studies addressing preoperative therapy, whether chemotherapy alone or combined
with radiation therapy, the question as to the role of surgical resection in the outcome of patients with N2
disease remains unanswered. To date there have been no conclusive studies to demonstrate that surgery is
superior to radiation therapy in controlling local disease in such patients, but at present surgery is an
important part of multimodal treatment in Stage IIIA NSCLC.
References.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Kaiser RL, Friedberg JS. The role of surgery in the multimodality management of non-small cell
lung cancer. Semin Thorac Cardiovasc Surg 1997; 9:60-79.
Sartori F, Bortolotti L, Michelon M et al. The role of surgery in integrated therapies for non-small
cell lung cancer. Ann Oncol 1999; 10 (Suppl.5):S73-S76.
Rosell R, Felip E. Role of multimodality treatment for lung cancer. Semin Surg Oncol 2000; 18:143151.
Rea F, Loy M, Bortolotti L et al. Morbidity, mortality, and survival after bronchoplastic procedures
for lung cancer. Eur J Cardio-Thorac Surg 1997; 11:201-205.
Martini N, Kris M, Flehinger BJ et al. Preoperative chemotherapy for stage IIIA (N2) lung cancer:
the Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993; 55:1365-74.
Burkes RL, Ginsberg RJ, Shephard FA. Induction chemotherapy with mithomycyn, vindesine, and
cisplatin for stage III unresectable non small cell lung cancer: results of the Toronto phase II trial. J
Clin Oncol 1992; 10:580-586.
Elias AD, Skarin AT, Gonin R et al. Neoadiuvant treatment of stage IIIA non-small cell lung cancer.
Am J Clin Oncol 1994; 17:26-36.
Skarin A, Jochelson M, Sheldon T et al. Neoadiuvant chemotherapy in marginally resectable stage
IIIA M0 non-small cell lung cancer: long term follow-up in 41 patients. J Surg Oncol 1989; 40:26674.
Kirn DH, Lynch TJ, Mentzer SJ et al. Multimodality therapy of patients with stage IIIA N2 nonsmall cell lung cancer. J Thorac Cardiovasc Surg 1993; 106:696-702.
Strauss GM, Hernodon JD, Sherman DD et al. Neoadiuvant chemotherapy and radiotherapy followed
by surgery in stage IIIA non-small cell carcinoma of the lung: report of a cancer and leukemia Group
B Phase II study. J Clin Oncol 1992; 10:1237-44
Rosell R, Gomez-Codina J, Camps C et al. A randomized trial comparinng preoperative
chemotherapy plus surgery with surgery alone in patients with non-small lung cancer. N Engl J Med
1994; 330:153-158.
Roth JA, Fossella F, Komaki R et al. A randomized trial comparinng perioperative chemotherapy and
surgery with surgery alone in resectable stage IIIA NSCLC. J Natl Cancer Inst 1994; 86:673-80.
Pass HI, Pogrebniak HW, Steinberg SM et al. Randomized trial of neoadjuvant therapy for lung
cancer: interim analysis. Ann Thorac Surg 1992; 53:992-998.
Albain KS, Rusch VW, Crowley JJ et al. Concurrent cisplatin/etoposide plus chest radiotherapy
followed by surgery for stages IIIA (N2) and IIIB non-small cell lung cancer: mature results of
Southwest Oncology Group phase II study 8805. J Clin Oncol 1995; 18:1880-1892.
Thomas M, Rube C, Semik M et al. Impact of preoperative bimodality induction including twicedaily radiation on tumor regression and survival in stage III non-small cell lung cancer. J Clin Oncol
1999; 17:1185-93.
NAPLES 2000 http://members.xoom.it/naples2000/
6
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
POSTOPERATIVE COMPLICATIONS IN RELATION WITH INDUCTION THERAPY FOR
LUNG CANCER.
P. Fuentes, C. Doddoli, G. Rollet, P. Thomas, R. Giudicelli.
Department of Thoracic Surgery. Sainte-Marguerite Hospital, Marseille, France
Objective. The patients with locally advanced non-small cell lung cancer are referred to as having
stage III disease. Some of patients in this category benefit from operation or from oncological medical
treatment or from combined modality therapy that includes operation. The purpose of this study was to
evaluate the risk of lung cancer surgery, following induction chemo and/or radiotherapy.
Methods. This retrospective study included 69 patients treated from January 1990 to January 1998 for
a primary lung cancer in whom surgery had been performed after induction treatment. There 60 were
males and 9 females. The median age was 57 years (±11). The histologic type was squamous cell
carcinoma in 30 patients, adenocarcinoma in 25, undifferentiated carcinoma in 14. Surgery had not been
considered initially for the following reasons: N2 disease (n=25), temporary functional impairment (n=4);
doubtful resectability (n=40). The medical regimen resulted in combined radio-chemotherapy in 43
patients who received 2 to 4 sessions of chemotherapy (average=2. 9±0. 8 sessions) and 43±8 Gy (20 to
60 Gy), or chemotherapy alone in 26 patients (3±0. 7 sessions).
Results. Indications for subsequent surgery resulted from a salvage related to a complication of this
medical treatment (n=4), or an adjuvant treatment (n=65). Thirty five patients had a objective response
and 30 had no response. The surgery was performed from 4 to 8 weeks after the induction therapy.
Exploratory thoracotomy was performed in 4 patients (6%). There were 33 pneumonectomies, 1
bilobectomy, 23 lobectomies and 8 lung sparing resection. Complete resection was possible in 59 patients
(87%). For the 6 remaining patients (7%), 3 had a macroscopic residual tumour and 3 had a microscopic
residual tumour found on specimen analysis.
The in-hospital mortality was 9% (n=6), from respiratory origin in all cases. There were 3 pneumonia,
2 acute respiratory distress syndrome, and 1 acute respiratory failure without diagnostic.
There were 4 reoperations (6%): 3 for bronchial fistula and 1 for bleeding. Thirty five patients (51%)
required blood transfusion (4. 5±3. 8 cell packs). The incidence of early and delayed bronchial fistula
after pneumonectomy was 15%. These 5 fistula occurred all at the right side. So the rate after a right
pneumonectomy was 23%. Reinforcement of the bronchial stump was performed in all cases. Three
patients had a pleural flap and 1 had a intercostal pedicle flap. Thirteen patients had a postoperative
pneumonia (19%). Twelve patients (17%) had a major complications and 17 (25%) a minor. Type of
resection (lobectomy or pneumonectomy) and neoadjuvant treatment (RTCT or CT) are not mortality,
pneumonia or major complication predictive factors. The rate of bronchial fistula is more important when
a RTCT was performed, but the difference is not significantly (p=0. 36). The incidence of bleeding is
significantly higher when the induction was only CT (p=0, 001).
Conclusion. Surgery for lung cancer after induction chemo and/or radiotherapy is associated with an
increased risk. If the mortality seems "acceptable", the morbidity rate however is high. To decrease this
morbidity we have to review the protocols and the drugs used.
References.
1.
2.
3.
Fowler WC, Langer CJ, Curran WJ, Keller SM. Post operative complications after combined
protoadjuvant treatment of lung cancer. Ann Thorac Surg 1993; 55: 986-90.
Regnard JF, Icard P, Deneuville M et coll. Lung resection after high doses of mediastinal
radiotherapy (sixty grays or more). Reinforcement of bronchial healing with thoracic muscle flaps
in nine cases. J Thorac Cardiovasc Surg 1994; 107: 607-10.
Martini N, Kris MG, Flehinger BJ, et coll. Preoperative chemotherapy for stage IIIA (N2): the
Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993; 55: 1365-74.
NAPLES 2000 http://members.xoom.it/naples2000/
7
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
4.
5.
6.
Rusch VW, Albain KS, Crowley JJ et coll. Neoadjuvant therapy: a novel and effective treatment
for stage IIIB non-small cell lung cancer. Ann Thorac Surg 1994; 58: 290-5.
Rusch VW, Benfield JR,. Neoadjuvant therapy for lung cancer: a note of caution. Ann Thorac
Surg 1993; 55: 820-1.
Macchiarini P, Chevalier AR, Monnet I et coll. Extended operations after induction therapy for
stage IIIB (T4) non-small cell lung cancer. Ann Thorac Surg 1994; 57: 966-73.
NAPLES 2000 http://members.xoom.it/naples2000/
8
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
ADJUVANT TREATMENT IN LUNG CANCER: NEW ISSUES
M. Tonato, MD
Medical Oncology Division, Policlinico Hospital, Perugia, Italy
Lung cancer continues to be the leading cause of cancer deaths in the United States and in Europe.
Approximately 85% of lung cancer patients will have a non-small cell histologic diagnosis (NSCLC) for
which surgical treatment offers the best chance of cure. Despite this, the 5-year survival rate of patients
with NSCLC who undergo complete surgical resection is only 40-69%, depending on the stage (1).
Since 1970 it has been well known that distant metastatic disease is the dominant site of recurrence in
such patients and this observation served as the basis for trials of postoperative systemic therapy (2,3).
The rationale for these studies was based not only on a high rate of distant failure, but also on the
hypothesis that distant micrometastatic disease was present at the time of resection and that, therefore,
systemic chemotherapy might result in complete eradication of it and, consequently, in a longer survival.
The earliest trials of adjuvant chemotherapy, which consisted on single alkylating agents, could not
achieve this goal or, even worse, showed a detrimental effect of chemotherapy on survival.
The introduction of more active drugs, such as cisplatin and vinca alkaloids, a better diagnostic
evaluation and surgery technique, plus an improved methodology in conducting clinical trials, made it
possible to obtain more promising results in terms of delayed recurrence of the disease. This was mainly
the experience of the Lung Cancer Study Group (4) using the CAP regimen, not always confirmed by
European and Japanese researchers.
However, a recent meta-analysis including all randomized trials with accrual from January 1965 to
December 1991 showed that the absolute risk of death was reduced by 3% at two years and by 5% at 5
years for patients who were treated with postoperative cisplatin-containing regimens compared with
patients who were treated with surgery alone (P= 0.8) (5).
Although the results of this meta-analysis suggest that cisplatin CT regimens given postoperatively
may result in a slight survival improvement, it should be noted that the number of patients is rather small
for a meta-analysis (1,394 patients in the cisplatin-treated group), their characteristics rather
heterogeneous, and the difference in survival is of borderline statistical significance.
For all these reasons, adjuvant CT in NSCLC cannot be considered a standard therapy and it is
important that large, carefully conducted, randomized trials be performed in this group of patients.
In this perspective an Intergroup adjuvant trial (EST 3590) that accrued 482 patients has recently been
completed in the US. In TI-T3 NI completely resected patients it compares postoperative RT (50Gy)
versus the same RT plus 4 cycles of CT (cisplatin and VP16). The trial is important because of the rather
large number of patients, the inclusion of all histologies and the complete lymph node dissection. Its
preliminary results have been recently presented without evidence of any advantage for the CT arm (6).
Four large randomized trials are now being conducted in Europe. The first is the ALPI - EORTC
(Adjuvant Lung Project Italy) trial that compares, in completely resected stage I-III NSCLC patients, the
MVP regimens versus control, with RT being optional, according to the declared policy of each
participating center. About 1200 patients have been included and the accrual was closed in Dec. 1998 (7).
The other European trial (IALT), extended to the five continents, compares, in the same category of
patients, different CT regimens (cisplatin + VP16 or cisplatin + vinca alkaloids) versus control, with RT
being again optional.
This study has a planned accrual of 3000 patients with more than 1600 already included (8).
The third European trial is the ANITA trial which compares, in completely resected patients, cisplatin
and navelbine vs control and for which the accrual so far is about 700 patients. Finally, the BLT trial of
the MRC is investigating the role of adjuvant CT in different settings (postoperatively, after RT etc.)
Unfortunately, the accrual of this study is rather slow (9).
A trial very similar to the IALT is ongoing in Canada. It compares cisplatine + navelbine versus no
treatment in T2 N0, TI-2 NI completely resected patients with a planned accrual of 640.
Another North-American study is evaluating the use of new active drugs. The CALGB study is
comparing carboplatin/paclitaxel to observation only, following resection of T2 N0 NSCLC. This
regimen has been selected for analysis in an adjuvant setting because it has been associated with high
NAPLES 2000 http://members.xoom.it/naples2000/
9
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
response rate and long survival in phase II studies (10). Other regimens have been shown to be active in
advanced disease such as the combination of cisplatin and gemcitabine (11,12). The toxicity profile of
this new combination is sometimes also favorable.
It would thus be reasonable to see in the near future these new regimens compared with the standard
ones if the results of the ongoing trials confirm their efficacy in prolonging survival in operated patients,
making possible, consequently, a trial design without a no-treatment arm (13).
Possible future developments in adjuvant therapy of NSCLC will include better patient selection
(stage and prognostic factors), better integration of CT with RT and also the possibility of new forms of
treatment such as adoptive immunotherapy, gene therapy, chemoprevention and use of tumor
angiogenesis inhibitors (14). With these perspectives the participation of clinical investigators in national
and international trials will probably improve and the solution of the dilemma "adjuvant CT in NSCLC,
yes or no" will be closer.
References.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Mountain CF. A new international staging system for lung cancer. Chest. 1986; 89: (suppl 4) 225S233S.
Matthews MJ, Kanhouwa S, Pickren J et al. Frequency of residual and metastatic tumor in patients
undergoing curative surgical resection for lung cancer. Cancer Chemother Rep. 1973; 4: (suppl) 6367.
Feld R, Rubinstein LV, Weisenberger TH. Sites of recurrence in resected stage I non-small-cell lung
cancer: a guide for future studies. J Clin Oncol. 1984; 2:1352-1358.
Holmes EC. Adjuvant therapy for stage I, II and resectable IIIA disease-the North American
experience. Lung Cancer 1994; 11: (suppl 2) 47-48.
Stewart LA, Pignon JP. Chemotherapy in non-small-cell lung cancer: a meta-analysis using updated
data on individual patients from 52 randomized clinical trials. Br Med J. 1995; 311:899-909.
Keller SM, Adak S, Wagner H et al. Prospective randomized trial of postoperative adjuvant therapy
in Patients with completely resected stages II and IIIa non –small cell lung cancer: an intergroup trial
(E3590).Lung Cancer. Lung Cancer. 1999;465a.
Torri V, Flann M, Tinazzi A on behalf of ALPI participants. Randomized study of adjuvant
chemotherapy for stage I-II-IIIA non-small cell lung cancer: Report of the ALPI. Perugia
International Cancer Conference VI. Chemotherapy of non-small cell lung cancer: ten years later.
1998; pp18-21. (abstract).
Thierry. Le Chevalier, Personal communication.
Richard Stephens, personal communication.
Langer CJ, Leighton JC, Comis RL, et al. Paclitaxel and carboplatin in combination in the treatment
of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin
Oncol. 1995; 13:1860-1870.
Crinò L, Scagliotti G, Marangolo M, et al. Cisplatin-Gemcitabine combination in advanced nonsmall-cell lung cancer: A phase II study. J Clin Oncol. 1997; 15:297-303.
Abratt RP, Bezwoda WR, Hacking DJ. Weekly gemcitabine with monthly cisplatin: effective
chemotherapy for advanced non-small-cell lung cancer. J Clin Oncol. 1997; 15:744-749.
Bonomi P, Penfield Faber L. Postoperative and preoperative chemotherapy for non-small-cell lung
cancer. Cancer Control 1997; 4:297-306.
Tonato M. Adjuvant chemotherapy in Europe. Ann Oncol. 1998; (Suppl. 4) 9:3. (abstract).
NAPLES 2000 http://members.xoom.it/naples2000/
10
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
TREATMENT OF ADVANCED LUNG CANCER (III B- IV) - TWO OR THREE DRUG
TREATMENT
V. Iaffaioli
Medical Oncology, University of Cagliari, Italy
The lack of screening methods, the tendency for precocius spread and the inability to cure metastatic
disease minimize the cure rate for lung cancer. That’s still low and about 14%. Short median survival
times and rare long-term survivals characterize stage III or IV disease, wich represents more than half of
all NSCLC patients.
Nevertheless, therapeutic nihilism is no longer justified. The results of randomized clinical trials and
meta-analyses now support the conclusion that platinum based chemotherapy improves survival,
symptom control, and quality of life compared with best supportive care alone in stage IV disease, and
that platinum-containing chemoradiotherapy programs result in superior survival compared with
radiotherapy alone in stage III patients.
The increasing acceptance of chemotherapy as a reasonable standard of care for selected patiens with
III B/IV stage NSCLC stimulates new therapeutic approaches because of considerable inconvenience and
toxicity associated with cisplatin-based chemotherapy.
Chemotherapy regimens induce only 30% to 50% responses in previously untreated patients and
oncologists have few ways of predicting responses.
Consequently, patients are often exposed to drug toxicity without harvesting their benefits.
First of all, we must consider prognostic variables that can predict response to chemotherapy and
survival.
Regardless of the treatment used, three definitive predictors – P.S., stage of disease, and weight loss –
are recognized as well as a number of possible predictors, such as lactate dehydrogenase and albumin and
several new molecular markers.
Pharmacogenomic research is needed, but we at present know, for example, that key tumor suppressor
genes as MG MT and ML M1 can be involved in cisplatin resistance and DNA has recently been obtained
from the serum of patients at any time.
Interesting correlations have been found between transcriptional status of p53, protein MA4
microtubule associated and taxol binding.
Taxol citotoxicity is related to Bcl-2 and Raf-1 phosphorylation and taxol efflux is impaired in cells
that overexpresse Bax. These studies will provide a rationale for the future customized design of
combination therapy. This promising future for better and better designed study rationales is strongly
conflicting with the amount of some even debated problems.
1) Platinum compounds remain the “ backbone” of current chemoterapy and it has even been unclear
whether combination chemoterapy regimens in advanced NSCLC were superior to cisplatin or
carboplatin alone in terms of survival.
2) The addition of other chemoterapeutic agents to a platinum compounds showed increased response
rates without improving significantly survival.
3) Of the so-called “old drugs” only cisplatin, carboplatin, ifosphamide and mitomycin are still
frequently used.
While the consensus about drugs like etoposide, teniposide, vinblastine, vindesine rapidly decreases,
during the last 5 years the introduction of drugs with a different cytotoxic mechanism was given a warm
welcome.
The taxanes, taxol and docetaxel, the topo-isomerase inhibitors, and novel analogs (gemcitabine and
vinorelbine) in phase II trials, alone in combination with cis-carboplatin or with each other, have reported
impressive response and survival data. Notoriously, phase II results can be influenced by patient selection
factors and may be overly optimistic.
Phase III trials comparing new agent-platinum combinations to cisplatin alone or to “older” platinum
combinations have generally confirmed this point: the degree of improvement in survival for new agentplatinum combinations resulted less favourable than that predicted by phase II studies.
NAPLES 2000 http://members.xoom.it/naples2000/
11
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
4) In these phase III studies the quality of life, toxicity and the cost-effectiveness are evaluated and
stressed more than response rates.
Therapeutic index, the ratio of efficacy to toxicity, and even convenience produce considerations in
the choice and selection of new regimens.
The main question remains: phase III trials comparing new drug-platinum regimens with standard
combinations or even cisplatin alone have shown consistently higher response rate with new schedules
but no demonstrable improvement in survival. It may reflect a greater cell kill of only the chemosensitive
populations and focuses the necessity of innovative approaches to chemotherapy designed to eliminate
resistant subpopulations with the introduction of truly novel therapeutic agents and/or promising
sequential treatments.
NAPLES 2000 http://members.xoom.it/naples2000/
12
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
TUMOR MARKERS: A ROLE OF TUMOR MARKERS IN THE DIAGNOSIS AND
PROGNOSIS OF LUNG CANCER
C. Cecere, S. Elia, G. Ferrante, P. Papa^, A. Di Carlo*, A. Mariano°, V. Macchia°
Chair of Thoracic Surgery, Medical School, University “Federico II”, Naples, Italy
^Division of Bronchopneumology, General Hospital, Avellino, Italy
*Department of Experimental Pathology, Medical Biotechnologies, Epidemiology and Infectious
diseases, University of Pisa, Italy
°Chair of Clinical Pathology, Department of Biology, Cellular and Molecular Pathology University
Federico II, Naples, Italy
Nowaday the cancer is the leading cause of death among men and women. Even in face of enormous
research effort a significant increases in mortality (>15%) have occurred in lung cancer (1). The number
of new lung cancer cases is significantly increased. The early detection and more effective treatment,
combined with prevention by decreasing smoking could greatly reduce mortality rate of cancer in the
future. Nevertheless, the risk of lung cancer remaines markedly elevated for up to 15 years after smoking
cessation (2), this trends in smoking suggest that the prevalence of and mortality from the disease will
remain high during the next 10 to 20 years. At present, it is very important: a) to establish the assessment
of tumor aggressiveness, b) to settle strategies for early detection of malignant lesion in an attempt to
improve the poor prognosis associated with the disease. Such strategies involve a multimodal approach
such as the identification of biomarkers useful either in detection of the disease or in predicting tumor
behavior and prognosis.
Since in vitro lung cancer cells produce and release a variety of substances it has been suggested that
in vivo measurement of some of these may be useful for detection and diagnosis of neoplastic diseases as
well as the monitoring of their course especially during treatment.
At present, some substances have been found elevated in the serum of an high percentage of patients
with lang cancer (3). However, only few data are available on the simultaneous determination of markers
in serum, in tissue and in bronchoalveolar lavage (BAL) fluid. Therefore, in the last few years, we have
focused our research: 1) to assess the behaviour of the content of CEA, TPA, CA 15-3, CA 125 and Cyfra
21-1 in the serum and in the tumoral and peritumoral cytosol of surgically treated patients comparing the
obtained data with those of a control group; 2) to evaluate whether their combined determination
enhances their diagnostic accuracy; 3) to assess whether there is any correlation between tumor stage and
tissutal marker level and 4) to verify if the determination of CEA, TPA, Ca 125, Ca 15-3, NSE, TK,
ferritin, Cyfra 21-1 and sialic acid in bronchoalveolar lavage (BAL) fluid of patients with benign and
malignant lung disease my be useful in the detection of a neoplastic status.
In our casuistry, the mean level of serum CEA was significantly higher in both squamous cell
carcinoma and adenocarcinoma compared to normal subject and patients with benign lung disease. The
serum TPA concentration was increased in a relatively large number of patients either with cancer or
benign disease. As it concerns serum levels of CA 125 and CA 15-3 a slight increase has been observed at
a low percentage in patients with benign and malignant diseases. Finally the mean serum level of Cyfra
21-1 was significantly higher in squamous cell carcinoma and in adenocarcinoma compared to both
benign disease and normal subjects. However none of the markers studied correlated its serum levels with
histological type or with tumor staging or differentation grade. On the other hand, the simultaneously
determination of more than one marker such as Cyfra 21-1, TPA and CEA, increase the percentage of
positivity.
In addition CEA, TPA, CA 125 and CA 15-3 were measured in the tumoral and peritumoral cytosol.
The CEA and CA 125 content was much higher in the tumors than in the peritumoral tissues and the
levels of serum CEA correlate very well with cytosolic CEA levels in some lung neoplasias squamous
cell carcinoma. On the other hand the TPA and the Ca 15-3 values were only slightly higher in the tumors
than in peritumoral tisues. Furthermore also for tissutal tumoral markers no correlation between markers
content in the tissue and tumor staging or differentiation grade was found.
As it concerns the content of tumor markers in the bronchoalveolar lavage (BAL) fluid the results are
more difficult to interpret because no BAL from healthy subjects was available. So we can compare the
NAPLES 2000 http://members.xoom.it/naples2000/
13
SYMPOSIUM
THORACIC ONCOLOGY: AN UPDATE - PART ONE
CHAIRMAN: F Sartori (Padua, I)
CO-CHAIRMEN: AR Bianco (Naples, I) P Fuentes (Marseille, F)
data obtained with BAL from patients with benign and malignant disease. In this case we observed that
BAL CEA and Cyfra 21-1 values were higher in patients with neoplasia than in those with benign
disease. However, no correlation with histological type, tumor staging and differentiation grade was
observed. Finally no significant variation between benign and malignant disease was observed in the BAL
content of TPA, CA 125, CA 15-3, ferritin and sialic acid.
In conclusion, the data obtained in our study suggest that only the combined determination of more
than one marker or the determination not only in the serum can be useful to get information on the
diagnosis and on the evolution of the lung neoplasias.
References.
1.
2.
3.
Henderson BE, Ross RK, Pike MC. Toward the primary prevention of cancer. Science 254: 11311138, 1991
Gaffney M, Altshuler B. Examination of the role of cigarette smoke in lung carcinogenesis using
multistage models. J. Natl, Cancer Inst. 80: 925-931, 1988
Muller T, Marshall RJ, Cooper EH, Watson DA, Walker DA, Mearns AJ. The role of tumour
markers to aid the selection of lung cancer patients for surgery and the assessment of prognosis.
Eur. J. Cancer Clin. Oncol. 21: 1461-1466, 1985
NAPLES 2000 http://members.xoom.it/naples2000/
14