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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1541-1548
Long-Term Follow-Up of the Italian Trial of Interferon- Versus
Conventional Chemotherapy in Chronic Myeloid Leukemia
By
The Italian Cooperative Study Group on Chronic Myeloid Leukemia*
 |
ABSTRACT |
Several prospective randomized studies have shown that the treatment
of chronic myeloid leukemia with interferon- (IFN-) prolongs the
survival by comparison with conventional chemotherapy. However,
although IFN- can induce cytogenetic responses, true complete
remissions are rarely achieved and information on the long-term effects
of IFN- treatment is limited. For that purpose, we updated and
analyzed a prospective comparative trial of IFN- and conventional
chemotherapy that was initiated in 1986. The first analysis of the
trial was already published, and showed a survival advantage for
IFN- (N Engl J Med 12:820, 1994). The observation period of
living patients now ranges between 95 and 129 months and we examined
the long-term effects of IFN- treatment, always by comparison with
conventional chemotherapy and according to the intention-to-treat
principle. The patients who were submitted to allogeneic bone marrow
transplantation (BMT) in chronic phase (38 of 322 or 12%) were
censored at the date of BMT. Seventy-three of the original 284 nontransplanted patients were alive, 56 (30%) in the IFN- arm and
17 (18%) in the chemotherapy arm. Forty-one patients overall (14%)
were still receiving IFN-. In the IFN- arm 9 patients were in
continuous complete cytogenetic remission and 11 were in major or minor
cytogenetic remission. Median and 10-year survival of low-risk patients
were 104 months (95% CI, 85 to 127 months) and 47% (95% CI, 36% to
59%) in IFN- arm versus 64 months (95% CI, 49 to 98 months) and
30% (95% CI, 16% to 44%) in chemotherapy arm (P = .03).
Median and ten-year survival of non-low-risk patients were 69 months
(95% CI, 56 to 76 months) and 16% (95% CI, 8% to 24%) in IFN-
arm versus 46 months (95% CI, 39 to 61 months) and 5% (95% CI, 0%
to 11%) in chemotherapy arm (P = .006). A low Sokal's
risk, hematologic response, and cytogenetic response were associated
with a longer survival. No major or unusual side effects were recorded
after the 5th year of IFN- treatment. Fourteen patients died in
chronic phase, 9 (4%) in IFN- arm and 5 (5%) in chemotherapy arm,
mainly of cardiovascular accidents (6 cases) and of other cancers (5 cases). We conclude that a policy of chronic treatment with IFN-
maintained a significant survival advantage over conventional
chemotherapy on a long-term basis and irrespective of the
risk. However, the great majority of the long-term survivors were in
the low-risk group. The question of treatment discontinuation was not
addressed in this study.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
INTERFERON- (IFN-) was reported to
be active in the treatment of chronic myeloid leukemia (CML) in
19831 and to induce cytogenetic remissions in
1986.2 In 1986 we enrolled 322 consecutive CML patients in
a prospective randomized study of IFN- versus conventional
chemotherapy. Our reports on cytogenetic response and on survival
appeared in 19923 and in 19944 and provided
confirmation to the findings5-7 that IFN- was able to
induce cytogenetic remissions and to the suggestion5 that
IFN- treatment prolonged survival as compared with conventional chemotherapy. Subsequently, the therapeutic role of IFN- in CML was
confirmed again in three prospective multicenter
trials.8-11 On the other hand the treatment is chronic, may
be required for a very long period of time, and can interfere with
other treatment procedures. The effect of IFN- on long-term
survival, the duration and the quality of the response, the late
treatment complications, and the compliance with chronic treatment are
all important issues that were described so far only in the patients
who were originally recruited at a single center at M.D. Anderson
Hospital (Houston, TX) because that center was the first to apply
IFN- to the treatment of CML on a large basis.5,12 We
report on these issues, based on an unselected multicenter series of
patients who were prospectively assigned to treatment with IFN- or
with conventional chemotherapy.
| |
MATERIALS AND METHODS |
Patients.
The recruitment for this study was opened July 1986 and was terminated
July 1988. Approval was obtained from the Institutional Review Boards.
Informed consent was provided according to the Declaration of Helsinki.
During that 2-year period, 322 patients were assigned at random, with a
ratio of 2:1, to receive either IFN- (218 cases) or conventional
chemotherapy (104 controls). In the IFN- arm, the drug was human
recombinant IFN-2a (Roferon-A; HoffmannLa Roche), 9 million IU
(mIU) daily for a minimum of 14 months and indefinitely in case of any
cytogenetic response, until tolerated or until progression to
accelerated or blastic phase. Chemotherapy could be used at any time in
case of poor hematologic control, and after 14 months in case of no
cytogenetic response. In the chemotherapy arm, first-line treatment was
hydroxyurea in 94 patients and busulfan in 10 patients.
Definitions.
Accelerated or blastic phase was defined by at least two of the
following predetermined criteria: (1) more than 10% blast cells or
more than 30% blast cells and promyelocytes in the peripheral blood;
(2) more than 15% blast cells or more than 50% blast cells and
promyelocytes in the marrow aspirate; (3) splenomegaly (>10 cm below
the costal margin) with a white blood cell (WBC) count of less than 25 × 109/L; (4) involvement of the central nervous system,
bone, lymph nodes, or other extrahematologic sites; and (5) trisomy Ph,
trisomy 8, or isochromosome 17. The cytogenetic response was evaluated after 8 and 14 months and yearly thereafter, based on a minimum of 10 evaluable metaphases, and was defined according to the percentage of Ph
negative metaphases as none, minimal (1% to 32% Ph neg), minor (33%
to 65% Ph neg), major (66% to 99% Ph neg), and complete (100% Ph
neg). The hematologic response was defined as complete if blood counts
were normal (hemoglobin > 110 g/L,
platelet < 500 × 109/L,
WBC < 10 × 109/L), if the differential leukocyte
count did not contain immature cells, and if the spleen was not
palpable. The formulation of Sokal et al13 was used to
categorize the patients by risk.
Statistical analysis.
Survival was calculated according to the method of Kaplan and
Meier14 from the date of randomization to the date of death or last contact. Follow-up information was available on all patients. At last contact (June 1997), the follow-up of living patients ranged
between 95 and 129 months (median, 112 months). During the chronic
phase, 38 patients underwent allogeneic bone marrow transplantation
(BMT) (12%) and 6 patients were autografted (2%). Allogeneic BMT was
allowed by the protocol, whereas autografts were protocol violations.
For that reason, all survival calculations and comparisons were made
either including, excluding, or censoring the patients who were
submitted to transplant. The results were always identical, and the
survival data that are reported hereforth include all randomized
patients, with censoring for allogeneic transplant. The time to the
progression to accelerated or blastic phase was calculated from
randomization, with censoring for allogeneic BMT and for death in
chronic phase. Analyses and comparisons were made by the chi-square
test and Student's t-test, by the log-rank method and by
logistic regression. The Cox proportional hazards model for covariate
analysis of censored data on survival15 was used whenever
appropriate. P values were two sided. All the calculations were
based on the intention-to-treat principle and always included all the
randomized patients. To avoid any bias from using time-dependent
variables like hematologic or cytogenetic response, landmark analysis
at specific time points was performed whenever appropriate.
| |
RESULTS |
Patients' status.
The status of the patients who were not transplanted is shown in Table
1. In the IFN- arm 56 of 188 patients
(30%) were alive and 16 of these patients (8%) maintained a complete
or a major cytogenetic remission. In the chemotherapy arm 17 of 96 patients (18%) were alive, with a minor cytogenetic response in one
case.
Treatment discontinuation and adjustment.
The number of the patients who discontinued the assigned treatment and
went off protocol before progression was 114 of 218 (52%) in the
IFN- arm and 37 of 104 (35%) in the chemotherapy arm. The
difference was due to the fact that 39 patients (18%) discontinued
IFN- because of the side effects that are listed in Table
2. The classic flu-like syndrome including
fatigue, fever, musculoskeletal pain, and headache covered 37% of
discontinuations, either early or late. Anorexia, nausea, and diarrhea
came second, but only during the first 3 years of treatment. Neurologic
side effects like depression, amnesia, lethargia, psychosis, reversible coma in one case, and polyneuropathy, mainly sensorial, developed during the first 5 years of treatment and were the third cause of
treatment discontinuation.
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Table 2.
IFN- Arm. Distribution by the Years of Treatment of
the Side Effects That Caused Treatment Discontinuation
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In the IFN- arm 84 patients overall (38%) also received
chemotherapy before progression to accelerated or blastic phase, either
because IFN- was discontinued for side effects (39 cases) or because
it was believed that IFN- was unable to control the disease (45 cases). In the chemotherapy arm, no option was provided for crossing
the treatment to IFN-, but IFN- was actually administered to 8 patients, 2 to 70 months after randomization. The overall survival of
these 8 patients was long, ranging from 96 to 129 months (median, 106 months), with 2 of 8 alive at last contact.
The dose of IFN- that was originally scheduled for this study was 9 mIU daily (corresponding to 63 mIU weekly) for 8 months, to be
maintained thereafter at maximum tolerated dose if any cytogenetic response was obtained. During the first year, the mean IFN- weekly dose was significantly higher in the patients who achieved any degree
of cytogenetic response than in the others (Table
3). Thereafter, in the majority of the
nonresponders the dose was decreased to 9 mIU weekly, as it was
prescribed by the protocol. In the responders the dose was also
adapted, according to tolerance, and from the 5th year on was about 20 mIU weekly (Table 3).
BMT.
The option for allogeneic BMT from an HLA-compatible family donor was
always open and was actually used during the chronic phase in 33 patients, 2 to 65 months after registration (median, 15 months). In
another 5 patients an allogeneic BMT was performed later (42 to 107 months after registration) from a matched unrelated or a partially
matched related donor. In summary, 38 of 322 patients of any age (12%)
and of 172 patients less than 51 years old (22%) received an
allogeneic BMT during the chronic phase. Sixteen of the 38 transplanted
patients (42%) died of transplant or transplant-related complications,
two are alive with leukemia, and the remaining 20 (53%) are alive and
in hematologic remission. Two additional patients, both in the IFN-
arm, were transplanted in blastic phase and died of transplant. Six
patients (4 in the IFN- arm and 2 in the chemotherapy arm) were
autografted in chronic phase. Three of them died of leukemia and three
are alive with leukemia. Ten patients (6 in the IFN- arm and 4 in
the chemotherapy arm) were autografted in accelerated or blastic phase.
Seven died of transplant or leukemia, and three are alive with
leukemia.
Survival and progression.
The median survival of the 218 patients who were assigned to IFN-
and of the 104 patients who were assigned to chemotherapy was 76 months
and 52 months, respectively (95% CI, 69 to 86 months and 43 to 66 months, log-rank test, P = .002) (Fig
1). The proportion of the patients who were
projected to be alive after 10 years was 29% (95% CI, 23% to 36%)
in IFN- arm and 17% (95% CI, 9% to 25%) in chemotherapy arm.
Figure 1 also shows the rate of the progression from chronic to
accelerated or blastic phase. The median time from diagnosis to
progression was 74 months with IFN- and 46 months for chemotherapy
(log-rank test, P = .0005).
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| Fig 1.
(A) Kaplan and Meier's plot of overall survival of all
randomized patients, irrespective of any protocol violation and of the
cause of death. The cases who were submitted to allogeneic BMT in
chronic phase were censored at the date of transplant. Log-rank test,
P = .002. The number of cases at risk at each year is shown
below the graph. (B) Time from randomization to progression to
accelerated or blastic phase. The cases who were submitted to
allogeneic BMT in chronic phase and the cases who died in chronic phase
were censored. Log-rank test, P = .0005.
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Figure 2 shows the survival and the
progression from chronic to accelerated or blastic phase of Sokal's
low-risk patients as a function of treatment. Figure
3 shows the same for Sokal's intermediate-
and high-risk patients. The difference was significant both in low-risk
patients (P = .03 for survival and .02 for progression) and
in intermediate- and high-risk patients (P = .006 for
survival and .002 for progression).
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| Fig 2.
Low-risk cases (Sokal's relative risk < 0.8).
Overall survival (A) and time to progression to accelerated or blastic
phase (B). P values are .03 and .02. Notice that 10-year
survival is 47% in IFN- arm and 30% in chemotherapy arm.
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| Fig 3.
Intermediate- and high-risk cases (Sokal's relative
risk  0.8). Overall survival (A) and time to progression to
accelerated or blastic phase (B). P values are .006 and .002. Notice that although IFN- patients fared significantly better than
chemotherapy patients, more than 80% of IFN- patients progressed
and died within 10 years as well.
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Deaths in chronic phase.
Fourteen patients died in chronic phase; nine of them had been assigned
to IFN- (4%) and five had been assigned to chemotherapy (5%)
(Table 4). The deaths occurred either early
(3 to 14 months after diagnosis), and were due to infection, cardiac
disease, or gastric bleeding; or late (32 to 99 months after
diagnosis), and were due to cardiac or vascular disease, or to other
cancers. Fatal cardiovascular events were slightly more frequent in
IFN- patients (5 of 218 or 2.3%) than in chemotherapy patients (1 of 104 or 1%). Cancers were slightly more frequent in chemotherapy patients (4 of 104 or 4%) than in IFN- patients (2 of 218 or 1%).
Among the nine IFN- patients who died in chronic phase, four were in
stable complete or major cytogenetic remission.
Prognostic factors.
Prognostic factors for survival were examined in all the patients and
in those who had been randomized to receive IFN- (Table 5). In all the patients, many factors were
associated with survival, but by multivariate analysis only treatment
arm remained statistically very significant, together with age, spleen,
and Sokal's score. In the patients who had been assigned to IFN-
the survival was significantly influenced by Sokal's score,
hematologic response, and cytogenetic response. Figure
4 shows a landmark survival analysis of the
patients who were assigned to IFN- according to hematologic response
and to cytogenetic response. Both responses were associated with a
substantial and very significant prolongation of survival.
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Table 5.
Results of Cox Proportional Hazards Model for Covariate
Analysis of Censored Data on Survival (P values)
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| Fig 4.
(A) Overall survival of the patients who were assigned to
receive IFN- and were alive and in chronic phase after 8 months,
when the hematologic response was assessed (landmark analysis). The
patients who achieved a complete hematologic response (n = 114)
survived more. Log-rank test, P = .0001. (B) Overall survival
of the patients who were assigned to receive IFN- and were alive and
in chronic phase after 24 months when the cytogenetic response was
assessed (landmark analysis). The patients who achieved a complete or
major cytogenetic response during the first 24 months (n = 34)
survived longer. Log-rank test, P = .001.
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Cytogenetic response in IFN- arm.
A cytogenetic response (Ph neg metaphases, 33% to 100%) was obtained
in 70 of 218 cases (32%). The best cytogenetic response was complete
(Ph neg, 100%) in 23 cases (10%), was major (Ph neg, 66% to 99%) in
23 cases (10%), and was minor (Ph neg, 33% to 65%) in the remaining
24 cases (11%). The time to achieve the first response ranged from
less than 1 year to 7 years (median, 1 year), but the time to achieve
the best response was even longer, with a median of 2 years. That was
mainly due to the fact that the majority of the complete cytogenetic
responses were detected rather late (4 after 1 year, 6 after 2 years, 5 after 3 years, and 8 after 5 years or more). Though many cytogenetic
responses were first recorded after more than 1 year, many responders
(48 of 70, 68%) received their first response within the first year of treatment, and other 14 patients (20%) were found to have some Ph neg
metaphases within the same period. Only 8 of 70 cases (11%) did not
show any Ph neg metaphases after the first year of treatment. One of
these patients achieved a complete and stable response later, whereas the other 7 achieved only a major or a
minor response, and that response was unstable and transient. Table
6 shows the course and the fate of 70 patients who achieved a cytogenetic response. Seven of them (10%) were
submitted to allogeneic BMT. Of the remaining 63 patients, 4 died in
chronic phase (6%), 34 (54%) are alive and in chronic phase, and the
remaining 25 (40%) progressed to accelerated or blastic phase and died
of leukemia or related complications. The proportion of the cases with
progression was negatively related with the quality of the cytogenetic
response (13% for complete response, 39% for major response, and 68%
for minor response, P = .005) (Table 6). In the 10 patients
who progressed to accelerated or blastic phase after a complete or a
major cytogenetic response, two modalities of progression were
observed: in 5 cases the loss of the cytogenetic response was rapidly
followed by an acute blast crisis, with a lymphoid phenotype in 4 of 5 cases; in the other 5 cases, the time from cytogenetic response loss to
progression was much longer, ranging between 17 and 73 months, progression to blastic phase was slow, and the terminal phenotype was
myeloid.
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Table 6.
IFN- Arm. Disease Course and Evolution of the
Patients Who Achieved a Cytogenetic Response (Ph neg metaphases
33%)
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| |
DISCUSSION |
The main purpose of this updated report of the Italian study is to
provide information on the long-term effects of a policy of chronic
IFN- treatment. The first point was to evaluate the effects of
IFN- on long-term survival, and more clearly to answer the question
if the survival benefit over conventional chemotherapy would continue
in the long term. This point was not settled in prior reports because
the difference between conventional chemotherapy and IFN- does not
concern the cure rate, but the cytogenetic response rate. In this study
complete and major cytogenetic responses occurred in 46 of 218 patients
(21%) and only 9 patients (4%) were still in complete cytogenetic
remission after more than 8 years. Although some of these patients were
found to be sometimes also in molecular remission, as defined by
nonquantitative reverse transcriptase polymerase chain reaction, and
although some cases of molecular remission were described by
others,16 in the great majority of the patients leukemia
cannot be cleared off by current IFN- treatment.17,18
Therefore, this study cannot provide evidence that IFN- can cure
CML, but shows that the survival benefit of IFN- over conventional
chemotherapy did not die out and was maintained in the long term either
in the low-risk patients or in the patients with a higher risk.
However, whereas the relative benefit of IFN- over chemotherapy was
independent of the risk, the absolute benefit was not, because nearly
all the long survivors were in the low-risk group (Figs 3 and 4). The
second point was to evaluate the long-term compliance and the long-term
side effects of chronic IFN- treatment. Late treatment-related
toxicity was neither more frequent nor different from early toxicity
(Table 2). In particular, no more cases of neurologic toxicity were observed. However, it should be noticed that the number of cases "at
risk" after 6 years was only 54 and that the mean dose that was
administered after that time was 3 mIU daily. Eight patients (4%) died
in chronic phase. In one case death was attributed to treatment-related
pancytopenia. In the other 7 cases, a direct responsibility of
treatment could not be established, but based on the causes of death
(Table 4), special attention should be paid to the chronic
administration of IFN- to patients with established risk factors for
cardiac or vascular disease. The development of other cancers was of
concern, but the proportion was not different in the two treatment arms
(1% with IFN- and 4% with conventional chemotherapy).
This study was planned in 1985 and was started in 1986 with the aim of
evaluating if IFN- would prolong the survival over conventional
chemotherapy. The design was not conceived with the purpose of
answering other questions like the prediction, the kinetic, and the
duration of the response. However, because these questions are
important, the data were examined retrospectively and the results
suggested that the cytogenetic response to IFN- was predicted by
Sokal's risk and by hematologic response, and that the great majority
of the cytogenetic responses were achieved within 1 year of treatment,
though in many cases the responses improved significantly with time.
The results also suggested that when the best cytogenetic response was
only minor (Ph neg, 33% to 65%), the response was unstable and of a
short duration, whereas the median duration of complete and major
responses (Ph neg, 66% to 100%) was of about 60 months. These data
fit with the observations from the M.D. Anderson Hospital
trial.5,12,19
The treatment protocol prescribed a daily IFN- dose of 9 mIU,
corresponding to 63 mIU weekly to be administered for at least 14 months and indefinitely in the case of any cytogenetic response. The
doses that were actually administered ranged widely, with a mean value
decreasing from 50 mIU weekly during the first year to about 20 mIU
weekly from the 5th year and continuing for the remainder of the
study. These data are the result of a treatment policy
that was targeted to the maximum tolerated dose and do not answer the
questions regarding whether lower doses of IFN- can be more
cost-effective8,9,11,19,20 and if the treatment should be
continued forever or could be discontinued once a durable complete or
major cytogenetic response has been achieved, as suggested by the
observations from M.D. Anderson Hospital.12,19,21
Evaluating and discussing the long-term effect of IFN- treatment
raises two main problems. The first problem is how to improve the
cytogenetic response rate and how to prolong survival even more. The
addition of low-dose arabinosyl cytosine was shown to be effective in
one study22 and is currently being tested by our group. The
second problem concerns the relationship with BMT. Autologous BMT can
help to improve survival but there is no evidence of a
cure,23,24 and although it is conceivable that the longer the time from diagnosis, the worse the results,25,26
pretreating with IFN- does not prevent from successful
autografting.24-27 Pretreating with IFN- does not
prevent from allogeneic BMT either, although delaying the transplant
would probably increase transplant-related mortality.28 One
study raised the suspicion that IFN- treatment may specifically
adversely affect transplant outcome,29 but more studies
showed that this was not the case.30-33 Allogeneic BMT from
an HLA-identical sibling is currently considered as the first
therapeutic option in the management of CML for patients under the age
of 60, and CML is the first in the list of the indications for an
allogeneic transplant from a matched unrelated donor.34,35 This is conceivable because allogeneic BMT is the only procedure that
can cure CML.19,28,34-36 However, CML is no longer a
rapidly fatal disease and about 50% of the cases present with low-risk features. In this study, the 10-year survival of the low-risk patients
who were assigned to IFN- is 47% (95% CI, 36% to 59%) for all of
the 91 patients and 64% (95% CI, 47% to 80%) for the 36 patients
who achieved a cytogenetic response. It should not be overlooked that
these are not the best results that can be obtained at a single
specialized center, but rather, are the results of a nationwide
multicenter study that pioneered the introduction of IFN- in Italy.
| |
FOOTNOTES |
*
Writing Committee: Sante Tura, Gianantonio Rosti, Antonio de Vivo,
Francesca Bonifazi, Mauro Fiacchini: the Institute of Hematology and
Clinical Oncology "L. and A. Seràgnoli," Bologna
University; Michele Baccarani, Domenico Russo, Renato Fanin: the
Division of Hematology and the Department of Bone Marrow
Transplantation, Udine University; Eliana Zuffa: the Division of
Hematology, Ravenna Hospital; Enrico Montefusco: the Institute of
Hematology, Roma "La Sapienza" University.
Submitted September 29, 1997; accepted May 1, 1998.
Supported by the National Research Council, Italy, Progetto Finalizzato
Applicazioni Cliniche della Ricerca Oncologica; and by AIRC, Milano,
Italy.
Address reprint requests to Michele Baccarani, MD, Division of
Hematology, University Hospital, 33100 Udine, Italy; e-mail: ematologia{at}Drmm.Uniud.it.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
APPENDIX |
The active members of the group for this study were: N. Testoni, M.D.
Zamagni, G. Martinelli: University of Bologna; D. Damiani, M. Michieli:
University of Udine; A. Zaccaria, Ospedale Ravenna; G. Specchia, V. Liso: University of Bari; M. Lazzarino, C. Bernasconi: University of
Pavia; E. Montefusco, G. Alimena, F. Mandelli: University La Sapienza,
Roma; P. Leoni, S. Rupoli, M. Candela: University of Ancona; A. Nosari,
L. Gargantini: Ospedale Niguarda Cà-Granda, Milano; I. Majolino,
S. Tringali: Ospedale Cervello, Palermo; A.M. Liberati, F. Grignani, A. Tabilio, M. Martelli: University of Perugia; F. Paolino, M. Bertini:
Ospedale Molinette, Torino; A. Di Tucci, G. Broccia: Ospedale
Oncologico Businco, Cagliari; F. Leoni, S. Ciolli: University of
Firenze; L. Luciano, B. Rotoli: University of Napoli; R. Perricone, A. Cajozzo: University of Palermo; A. Montuoro, A. De Laurenzi: Ospedale
San Camillo, Roma; F. Palmieri, E. Volpe: Ospedale Avellino; A. D'Emilio, E. di Bona: Ospedale Vicenza; A. Capucci, T. Izzi: Ospedale
Brescia; G.L. Scapoli, G.L. Castoldi: University of Ferrara; M. Lombardo, L. Ruberto: University of Chieti; S. Sica, G. Leone:
Università Cattolica, Roma; C. Delfini, G. Nicolini: Ospedale
Pesaro; F. Papineschi, E. Benedetti: University of Pisa; F. Gualandi,
A.M. Marmont: Ospedale San Martino, Genova; D. Dini, G. Torelli:
University of Modena; L. Mangoni, V. Rizzoli: University of Parma; M. Girino, E. Ascari: University of Pavia; C.A. Bodenizza, M. Carotenuto: Casa Sollievo della Sofferenza, San Giovanni Rotondo; A. Di Francesco, D. Quaglino: University of L'Aquila; S. Nardelli, F. Ciccone: Ospedale
Latina; E. Miraglia, R. De Biasi: Ospedale Nuovo Pellegrini, Napoli; D. Ferrero, A. Pileri: University of Torino; A. Rambaldi, T. Barbui:
Ospedale Bergamo; S. Morandi, C. Bergonzi: Ospedale Cremona; C. De
Rosa, R. Cimino: Ospedale Cardarelli, Napoli; F. Ronca, F. Nobile:
Ospedale Reggio Calabria; M. Cantonetti, S. Amadori: Università
Tor Vergata, Roma; A. Gallamini, E. Gallo: Ospedale Cuneo; C. Musolino,
G. Squadrito: University of Messina; A. Capaldi, M. Aglietta: Ospedale
Mauriziano Umberto I, Torino; G. Pinotti, A. Venco: Ospedale Varese; V. Zagonel, A. Pinto: Centro Regionale di Riferimento Oncologico, Aviano;
I. Gentilini, P. Coser: Ospedale Bolzano; P. Guglielmo, R. Giustolisi:
University of Catania; M. Pizzuti, F. Ricciuti: Ospedale Potenza.
| |
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Abstract
Introduction
Abstract