close

Вход

Забыли?

вход по аккаунту

?

149

код для вставкиСкачать
1599
Front-Line Chemotherapy with Cisplatin and
Etoposide for Patients with Brain Metastases from
Breast Carcinoma, Nonsmall Cell Lung Carcinoma, or
Malignant Melanoma
A Prospective Study
Vittorio Franciosi, M.D.
Giorgio Cocconi, M.D.
Maria Michiara, M.D.
Francesco Di Costanzo,
Vinicio Fosser, M.D.
Maurizio Tonato, M.D.
Paolo Carlini, M.D.
Corrado Boni, M.D.
Sofia Di Sarra, Ph.D.
M.D.
Medical Oncology Units of Parma, Terni, Vicenza,
Perugia, Roma, and Reggio Emilia, Italy.
This study was conducted by the Italian Oncology
Group for Clinical Research (GOIRC), Parma, Italy
(G. Cocconi, Chairman).
Supported by Associazione Italiana per la Ricerca
sul Cancro (AIRC) and by the Finalized Project of
CNR ACRO.
The authors thank Andrea Manni for his critical
review of the article and Anna Quadretti for her
secretarial assistance.
Address for reprints: Vittorio Franciosi, M.D., Medical Oncology Division, Azienda Ospedaliera di
Parma, Via Gramsci, 14, 43100 Parma, Italy.
Received May 4, 1998; revision received October
1, 1998; accepted November 16, 1998.
© 1999 American Cancer Society
BACKGROUND. The conventional treatment of brain metastases not amenable to
surgery is most often radiotherapy. Until now, pharmacologic issues related to the
blood brain barrier (BBB) prevented a wide evaluation of chemotherapy. The
authors previously reported that the combination of cisplatin (P) and etoposide (E)
had strikingly high activity in patients with brain metastases from breast carcinoma. The purpose of this study was to assess, in a larger prospective study, the
front-line activity of that combination against brain metastases from breast carcinoma (BC), nonsmall cell lung carcinoma (NSCLC), and malignant melanoma
(MM) in patients previously untreated with radiotherapy.
METHODS. From December 1986 to July 1993, 116 patients received P 100 mg/m2
on Day 1 and E 100 mg/m2 on Days 1, 3, and 5 or on Days 4, 6, and 8 every 3 weeks.
An insignificant change in the E schedule using the same dose on a random basis
assured the prospective enrollment and the registration of all cases. Six patients
were not eligible and three patients were excluded from the analysis because they
were lost to follow-up shortly after the date of registration. One-hundred seven
patients were considered for analysis. The distribution according to the primary
tumor site was BC in 56 patients (52%), NSCLC in 43 (40%), and MM in 8 (8%). The
first evaluation of response was performed after two cycles. In cases of no disease
progression, chemotherapy was continued to a maximum of six cycles.
RESULTS. Among the 56 patients with BC, 7 achieved complete response (CR) (13%),
14 achieved partial response (PR), 12 had no change (NC), 15 had progressive disease
(PD), and 8 had insufficient treatment or response was not assessed. The CR plus rate
was 38%. Among the 43 patients with NSCLC, 3 achieved CR (7%), 10 achieved PR, 15
had SD, 7 had PD, and 8 had insufficient treatment or response was not assessed. The
CR plus PR rate was 30%. None of the eight patients with MM achieved an objective
response. The median survival was 31 weeks for patients with BC (range, 0–287), 32 for
patients with NSCLC (0–3921), and 17 for patients with MM (2–48).
CONCLUSIONS. The combination of P and E is effective for patients with brain
metastases from BC and NSCLC. In this study, the response rate was of the same
order as that reported for disseminated disease without central nervous system
involvement. The survival figures compare favorably with some others reported in
the literature for patients given radiotherapy. A randomized study is warranted to
compare this chemotherapy followed by radiotherapy with radiotherapy alone for
patients with brain metastases from BC or NSCLC not amenable to surgery or
radiosurgery. Cancer 1999;85:1599 – 605. © 1999 American Cancer Society.
KEYWORDS: brain metastases, breast carcinoma, nonsmall cell lung carcinoma,
melanoma, chemotherapy.
1600
CANCER April 1, 1999 / Volume 85 / Number 7
B
rain metastases (BM) account for 5–15% in the
clinical series and 14% in the autopsy series of
intracranial tumors. About 20 – 40% of patients with
solid tumors present with BM, and two-thirds of them
become symptomatic during their lifetimes.1
BM are a major clinical problem for patients with
breast carcinoma (BC), occurring in 10 –20% of these
patients,2 and they are associated with a poor prognosis.3 Nonsmall cell lung carcinoma (NSCLC) is complicated by BM in 16 – 65% of the patients.4 Malignant
melanoma (MM) metastasizes to the brain in 12–20%
of the cases in the clinical series and in 36 –54% in the
autopsy series, with a very short average survival.5
Patients with inoperable BM from solid tumors have
been traditionally treated with radiation combined with
corticosteroids. A median survival of 3–6 months and a
1-year survival rate of 15% were reported.6 For a long
time, the idea existed that systemic chemotherapy could
not be effective against central nervous system tumors
because the blood brain barrier (BBB) would preclude
the non-lipid-soluble antineoplastic drugs to reach the
central nervous system. However, it is currently accepted
that the integrity of the BBB is impaired or absent in
large areas of the tumor vasculature.7
In the early 1980s, a few reports suggested that
chemotherapy was effective in the treatment of BM
from solid tumors.8 –12 A Phase II study conducted by
our group demonstrated strikingly good activity of the
cisplatin (P) and etoposide (E) combination in BM
from BC (CR, 23%; CR and PR, 55%).13 Indeed, the PE
combination, which was initially designed to treat
small cell and nonsmall cell lung carcinoma, was demonstrated by our group to be very active even against
systemic nonbrain metastases from BC.14 P is active
against MM, and its combination with E was demonstrated to be synergistic in experimental studies.15 For
these reasons, we decided to conduct a large, multicentric, prospective study in which this combination
would be given as front-line treatment to consecutive
patients with BC, NSCLC, and MM.
PATIENTS AND METHODS
Patient Selection
From December 1986, consecutive patients with recently diagnosed BM from BC, NSCLC, or MM not
amenable to surgery and not pretreated with radiation
therapy were enrolled in this prospective trial. They
were from nine institutions affiliated with the GOIRC
group. Patients considered not amenable to surgery
were those with extracranial visceral disease, more
than two brain metastases, or metastases in inoperable cerebral sites, or those who refused surgery.
The eligibility criteria were as follows: diagnosis of
brain metastases measurable or evaluable by computed
tomography (CT) scan, normal bone marrow and renal
function, no additional primary tumors, lack of severe
cardiac disease, no prior treatment with PE, no prior
treatment with any chemotherapy after the diagnosis of
BM, and no prior radiation therapy to the brain.
Prior to therapy, all patients underwent complete
staging, which included clinical examination, chest Xray, bone isotope scan and/or X-ray, liver ultrasound or
CT scan, complete blood count, and routine biochemistry. CT scan of the brain with contrast enhancement was
made prior to chemotherapy, after the second course,
and at every other course thereafter. Oral informed consent was obtained from each patient.
Treatment
The chemotherapy consisted of P (100 mg/m2 i.v. on
Day 1, with hydration and mannitol forced diuresis)
and E (100 mg/m2 i.v. on Days 1, 3, and 5 in Arm A and
on Days 4, 6, and 8 in Arm B) every 3 weeks.
Treatment was postponed by 1 week if a patient’s
white blood cell (WBC) count was ,4000/mm3 and/or
the platelet (PLT) count was ,100,000/mm3. Subsequently, the dose was reduced by 25% if the WBC was
3900–3000 or the PLT was 99,000–75,000 and by 50% if
the WBC was 2900–2000 or the PLT was 74,000 –50,000;
if the WBC was ,2000 or the PLT was ,50,000, treatment was postponed by 1 more week. Nephrotoxicity
was monitored by repeating creatinine clearance on Day
18 of each course. If clearance creatinine decreased
.25%, the treatment was postponed until recovery to
normal levels. If hematologic or/and renal toxicities did
not resolve after 4 weeks, the treatment was definitively
stopped. Eighty-one of 107 patients (76%) initially received dexamethasone at a variable dose and continued
it during the initial chemotherapy. The protocol did not
define the standard dose and the timing of desamethasone treatment; therefore, they changed on the basis of
clinical decisions, according to the extent of the edema
and the severity and duration of the symptoms over
time. In the absence of disease progression, death, or
serious toxicity, chemotherapy was continued for six
cycles and thereafter no systemic treatment was given
until disease progression in the brain or elsewhere. At
the end of the protocol chemotherapy, sequential radiation therapy was allowed.
Response Evaluation
During the protocol chemotherapy, patients underwent
clinical examination before each cycle of chemotherapy,
or earlier if needed. Chemotherapy was stopped if any
serious toxicity occurred. The response of the tumor and
the extent of edema were evaluated by CT scan using
contrast enhancement every two cycles or at the time of
clinical progression. Based on the CT scan findings, the
Chemotherapy in Brain Metastases from Solid Tumors/Franciosi et al.
TABLE 1
Demography of the 116 Randomized Patients
1601
TABLE 2
Characteristics of the 56 Patients with Brain Metastases from
Breast Carcinoma
Patient category
No. of patients
Total registered
Not eligible
Creatinine over 1.5
Absence of brain metastases
Double primary, breast and thyroid gland
Clinical diagnosis of brain metastases without
histologic confirmation of the primary
Colon carcinoma
Small cell lung carcinoma
No information available after randomization
Evaluated for responsea
Evaluated for survival
116
6
1
1
1
1
1
1
3
107
107
a
Patients who had insufficient treatment or did not have their objective responses evaluated were
considered nonresponders and included in the denominator of response evaluation.
response in the brain was classified according to World
Health Organization criteria16 and defined as follows:
complete response (CR): complete disappearence of tumor and edema; partial response (PR): more than 50%
reduction in the product of the largest perpendicular
diameters on the CT slices with the largest metastatic
lesions (regression of the edema was not considered, per
se, to be a sign of tumor response); no change (NC): less
than 50% reduction or less than 25% progression; progressive disease (PD): increase of more than 25% in the sites of
the metastatic lesions or the occurrence of new lesions.
Assessment of response at other metastatic sites, if any, was
performed at the same time as BM evaluation.
Statistical Analysis
The aim of randomization was not to compare two
slightly different schedules of chemotherapy (the
change was clinically insignificant), but to force the
investigators to report to the centralized randomization center all the patients being seen on an intentto-treat basis before the treatment started. The aim of
this procedure (which is utilized by our group for most
Phase II studies and is called “technical randomization”) is only to eliminate the possibility of selection
bias in reporting the results of the most favorable
patients, or to eliminate the reporting of “nonevaluable” cases. Due to the design of the study, the sample
size was not based on any expected statistical difference between the two treatment arms. It was initially
estimated that 100 evaluable patients had enrolled in
the study. As said, the difference between the two
treatment schedules (for Arm A and Arm B) was not
expected to be clinically meaningful, and for this reason the results of treatment were assessed irrespectively of the chemotherapy schedule.
Characteristic
No. of patients
%
Total no.
Median age, yrs (range)
Menopausal status
PrePostExtracranial disease
Absent
Present
Type of brain metastasis
Solitary
Two
More than two
Prior systemic treatment
None
Chemotherapy
Endocrine therapy
Both
Performance status (ECOG)
0
1
2
3
4
Neurologic function
1
2
3
4
Unknown
56
56 (41–75)
100%
8
48
14%
86%
11
45
20%
80%
20
14
22
36%
25%
39%
20
15
8
13
36%
27%
14%
23%
9
22
17
4
4
16%
39%
31%
7%
7%
21
15
15
1
4
37%
27%
27%
2%
7%
ECOG: Eastern Cooperative Oncology Group.
Time to progression (TTP), time to failure (TTF),
duration of response (DR), and overall survival (OS)
were measured from the date of randomization to one
of the following dates: 1) the date of progression or
death due to disease (TTP); 2) the date of progression,
death, or suspension of treatment for any reason (protocol violation, toxicity, refusal, loss to follow-up, etc.)
(TTF); 3) the date of progression or death due to
disease but only for patients achieving CR or PR (DR);
or 4) the date of death from any cause (OS).
The minimum number of cycles requested for
evaluation of response was two, unless clinical progression occurred was evident at least 1 month after
the beginning of chemotherapy.
RESULTS
Patient Characteristics
From December 1986 to July 1993, 116 patients were
registered from the medical oncology units of Parma,
Terni, Vicenza, Perugia, Roma, Reggio Emilia, Piacenza,
and Lucca. Six patients were not eligible and three pa-
1602
CANCER April 1, 1999 / Volume 85 / Number 7
TABLE 3
Characteristics of 43 Patients with Brain Metastases from NSCLC
TABLE 4
Characteristics of the 8 Patients with Brain Metastases from
Malignant Melanoma
Characteristic
No. of patients
%
Total no.
Median age, yrs (range)
Gender
Male
Female
Histologic subtype
Adenocarcinoma
Squamous cell
Large cell
Brochioloalveolar
Extracranial disease
Absent
Present
Type of brain metastases
Solitary
Two
More than two
Performance status (ECOG)
0
1
2
3
Neurologic function
1
2
3
4
Unknown
43
59 (28–75)
100%
32
11
74%
26%
21
16
5
1
49%
37%
12%
2%
7
36
16%
84%
19
7
17
44%
16%
40%
11
13
15
4
26%
30%
35%
9%
21
11
4
4
6
49%
26%
9%
9%
14%
NSCLC: nonsmall cell lung carcinoma; ECOG: Eastern Cooperative Oncology Group.
tients were excluded from the analysis because they
were lost to follow-up shortly after registration.
The demographic characteristics of all patients
are reported in Table 1. Patients who received insufficient treatment or did not have their objective responses evaluated were considered nonresponders
and included in the denominator of response evaluation.
The characteristics of patients with BM from BC,
NSCLC, and MM are reported in Tables 2, 3, and 4,
respectively.
Characteristic
No. of patients
Total no.
Median age, yrs (range)
Gender
Male
Female
Extracranial disease
Absent
Present
Type of brain metastasis
Solitary
Two
More than two
Prior systemic treatment
None
Chemotherapy
Immunotherapy
Performance status (ECOG)
0
1
2
3
Neurologic function
1
2
Unknown
8
51 (26–66)
2
6
1
7
3
2
3
3
4
1
3
2
2
1
3
4
1
ECOG: Eastern Cooperative Oncology Group.
TABLE 5
Types of Response of Brain Metastases in the 107 Patients
Considered for Analysis
Type of response
Breast
carcinoma
Lung
carcinoma
Melanoma
Total no.
No responsea
Progressive disease
No change
Complete response
Partial response
Complete plus partial response
56
8
15
12
7 (13%)
14
21 (38%)
43
8
7
15
3 (7%)
10
13 (30%)
8
2
5
1
—
—
—
a
These patients received insufficient treatment or did not have their objective responses evaluated.
Response Rates
The types of response observed in patients with BC,
NSCLC, and MM are reported in Table 5.
Among the 56 patients with BC, 7 (13%) achieved
CR and a total of 21 (38%) achieved CR or PR. Eight
patients who were not evaluable because their treatment was insufficient or their responses were not evaluated were considered to have experienced treatment
failure and included in this analysis. Patients received
a median of 3 cycles, ranging from 1 to 8.
Among the 43 patients with NSCLC, 3 (7%)
achieved CR and a total of 13 (30%) achieved CR or PR.
Eight patients who were not evaluable because their
treatment was insufficient or their responses were not
evaluated were considered to have experienced treatment failure and included in this analysis. Patients
received a median of 3 cycles, ranging from 1 to 8.
Among the 8 patients with MM, none achieved an
objective response. Two patients received insufficient
Chemotherapy in Brain Metastases from Solid Tumors/Franciosi et al.
TABLE 6
Response in other Metastatic Sites in Patients Showing Objective
Regression in the Brain
Patients showing objective regression in the brain
Extracerebral sites not present
Extracerebral sites present but not evaluable
Extracerebral sites present and evaluable
Progression
No change
Partial response
Complete response
Breast
Lung
21
6
4
11
2
3
3
3
13
2
3
8
—
2
5
1
treatment. Patients received a median of 2 cycles,
ranging from 1 to 6.
Table 6 reports the responses assessed in patients
with metastases at other sites who showed an objective regression in BM. Among the 21 BC patients, 11
(52%) had evaluable extracerebral metastatic disease,
and the types of response were CR in 3 patients, PR in
3, NC in 3, and PD in 2. Among the 13 NSCLC patients,
8 (62%) had evaluable extracerebral metastatic disease, and the types of response were CR in 1, PR in 5,
and NC in 2.
Time Parameters
Table 7 shows the time parameters. The TTP was
about 4 months for both BC and NSCLC. The median
duration of response was about 8 months for both BC
and NSCLC patients. The median survival was approximately 8 months for both BC and NSCLC patients.
Approximately one-third and one-fourth of patients
with BC and NSCLC, respectively, were still alive after
1 year. The TTP and survival of patients with MM were
considerably shorter than those of patients with BC
and NSCLC.
Toxicity
In general, the toxicity from this combination was
similar to that observed in our previous studies of BC13
and NSCLC.17 In the current series, there were six
important toxic events. Three patients (3%) died, 1 of
gastric bleeding, 1 of gastric perforation and peritonitis, and 1 of neutropenic fever and diarrhea. Three
patients had to suspend chemotherapy treatment because of atrial fibrillation in one case, severe tubular
kidney damage in one case, and febrile neutropenia
with pneumonitis in one case.
DISCUSSION
To our knowledge, this is the largest study and one
of the largest trials in which chemotherapy was administered as a front-line treatment for patients
1603
with BM from solid tumors. Until now, two barriers
have prevented a rigorous assessment of the activity
of chemotherapy in this setting. The first is the
concept that the BBB would not allow the watersoluble drugs to reach the tumor target. The second
is the practically exclusive administration of lipid
soluble drugs, mostly nitrosureas, which are known
to be completely inactive in most solid tumors, such
as breast carcinoma.
In evaluating the activity of chemotherapy against
BM, another problem centers around methodologic difficulties in assessing response. Indeed, the response
evaluation might be influenced somewhat by the concomitant widespread administration of corticosteroids.
However, it is unethical to negate the administration of
corticosteroids that are known to provide symptomatic
improvement by reducing cerebral edema. For this reason, it is difficult to distinguish the independent effect of
corticosteroids from that of chemotherapy. In any case,
the regression of the edema, which is the earliest and
most dramatic effect of corticosteroid treatment, was not
considered per se to certify a tumor response. Moreover,
the proportion of patients treated with corticosteroids
(76% overall) was similar between the responders and
nonresponders. Therefore, the possibility currently remains that part of the reduction in tumor mass may be
due to corticosteroid administration.
In BM from BC, this chemotherapy induced CR in
13% of the patients and CR or PR in a total of 38%.
These figures are lower than those reported in our
previous trial13 of the same therapy, probably because
the previous study was practically carried out as a
single-institution study. On the other hand, the response rate achieved in this trial of BM was intermediate, between 58% for the untreated patients14 and
17% for the heavily pretreated patients reported by
our group when this chemotherapy was administered
to patients with extracranial disease.18 Indeed, even in
this study a large proportion of patients had been
pretreated with different chemotherapies. Therefore,
it appears that this chemotherapy manifests the same
range of activity in the brain and in other extracerebral
disease sites. Moreover, these results confirm that the
BBB is probably largely disrupted in brain metastases,
which are supplied by their tumoral neoangiogenesis.
A limited number of studies confirm the activity of
other chemotherapies against brain metastases from
BC. Rosner et al. reported 50% neurologic responses
(CR in 10%) of 100 patients treated with different types
of conventional chemotherapy (cyclophosphamide,
5-fluorouracil, and prednisone; cyclophosphamide,
5-fluorouracil, prednisone, methotrexate, and vincristine; or methotrexate, vincristine, and prednisone),
but only a few patients were evaluated with CT scan.12
1604
CANCER April 1, 1999 / Volume 85 / Number 7
TABLE 7
Time Parameters
Breast
Time to progression
Duration of response
Survival
% of patients still alive
After 3 mos
After 6 mos
After 9 mos
After 1 yr
After 2 yrs
After 3 yrs
Lung
Melanoma
No.
Median (range)
No.
Median (range)
No.
Median (range)
56
21
56
17 (0–2871)
33 (8–93)
31 (0–287)
43
13
43
17 (0–3921)
31 (9–3921)
32 (0–392)
8
—
8
11 (2–39)
—
17 (2–48)
73%
56%
37%
32%
9%
3%
Kolaric et al. reported 4 CR and 3 PR among 8 patients
treated with P as a single agent who were evaluated
only by neurologic examination and brain scintigraphy.11 More recently, Boogerd et al. confirmed that
conventional chemotherapies (cyclophosphamide,
methotrexate, and 5-fluorouracil or 5-fluorouracil,
doxorubicin, and cyclophosphamide) induced a 54%
response rate in 22 patients evaluated by CT scan.19
The median survival of approximately 8 months and
the 32% 1-year survival of BC patients in this study
compare favorably with a median survival of only 3–4
months and 1-year survival of 15% reported for patients
treated with radiation and corticosteroids only.6
In patients with BM from NSCLC, this chemotherapy induced CR in 7% and CR or PR in at total of 30%.
Even in this type of primary tumor, the response rate
achieved in BM is similar to the response rate (23%)
reported by our group in a randomized trial in which
the PE combination was administered to 115 patients
with advanced extracranial NSCLC.17
In the literature, there are only a few small studies
assessing the effects of other front-line chemotherapies for patients with brain metastases from NSCLC.
Malacarne et al., who administered carboplatin and
etoposide to a small series of 18 patients, reported a
17% PR rate.20
The median survival of about 7 months and the
25% 1-year survival of the current study for patients
with NSCLC compare favorably with the 3.3-month
median survival reported administering radiation
therapy and corticosteroids.21
The results of this chemotherapy for the few patients with BM from MM are discouraging. This may
be due, in general, to the poor sensitivity of MM to
chemotherapy and particularly to this combination.
The protocol did not include specific recommendations of further therapies after protocol treatment,
73%
56%
45%
25%
10%
7%
50%
25%
13%
—
—
and the individual decisions regarding further therapy
were left to each investigator. However, sequential
radiation therapy to the brain at the end of 6 cycles
was mentioned as being allowed in the protocol. Unfortunately, no specific information was requested regarding this matter. In contrast, systemic therapies
(mostly chemotherapy, but for the breast possibly endocrine therapy or both) were not allowed before the
assessment of tumor progression in any disease site,
according to the protocol.
The possibility that these salvage treatments influenced the duration of overall survival cannot be
ruled out, but they were clinically unavoidable in
treating a certain proportion of the patients with BM,
mostly because of the preterminal phase of the natural
history of the disease.
Regarding toxicity and side effects, a formal evaluation of the quality of life for patients was unfortunately not conducted in this study, as it was in most
other studies performed in the 1980s. Apparently chemotherapy with this combination could be worse than
about 4 weeks of radiation, although a direct comparison is not available. In any case, the toxicity from this
combination was similar to that observed in our previous studies of breast carcinoma and NSCLC,13,17,18
and it is therefore feasible and generally tolerable.
However, we observed a few cases of fatal gastric
bleeding and intestinal perforation, which were probably due to the combined use of corticosteroids. This
suggests that corticosteroid treatment combined with
chemotherapy should be cautiously associated with
gastroprotective agents and strictly monitored.
Our study demonstrates that the most important
determinant of responsiveness of BM from solid tumors is the intrinsic sensitivity of the neoplastic cells
to the chemotherapeutic agents. Only in BM not yet
vascularized, as in the adjuvant setting, would the
Chemotherapy in Brain Metastases from Solid Tumors/Franciosi et al.
water-soluble drugs be unable to overcome the stillintact BBB to reach high concentrations in the brain
and to exert cytotoxic activity against metastatic tumor cells. In fact, the concentration of chemotherapeutic agents is usually very low or absent in cerebrospinal fluid or in normal brain tissue,22 and in
adjacent areas of the normal brain it is inversely related to the distance from the tumor.23
On the other hand, when the BM are clinically
detected, the BBB is often at least partially disrupted,
and the water-soluble drugs can reach cytotoxic concentrations in the tumor tissue. Several reports have
shown that the concentration of some chemotherapy
agents is similar in intracerebral and extracerebral
tumors.22 Platinum has been shown to reach potentially cytotoxic concentrations in intracerebral tumors
similar to those in extracerebral tumors.23 Etoposide
has been found in intracerebral tumors in variable and
sometimes very high concentrations.24
The activity of the PE combination against BM from
BC and NSCLC is of the same order as that achieved in
extracerebral sites. We do not know whether this effect
reflects a general sensitivity of BM to any potentially
active chemotherapy or has to be considered a specific
result of this combination. Indeed, there are too few
studies in the literature in which other chemotherapies
were administered to allow a general conclusions regarding a “normal” sensitivity of BM to any type of
potentially active chemotherapy.
A final consideration regards the relative role of chemotherapy and radiation therapy as treatment modalities in brain metastases from BC and NSCLC. Radiation
therapy is a potentially effective treatment. However, the
survival results achieved in this study, which compare
favorably with those reported for radiation therapy only,
suggest that further randomized studies are warranted to
compare radiation therapy with chemotherapy or to
compare radiation therapy with chemotherapy that is
combined with or followed by radiation therapy.
6.
REFERENCES
20.
1.
2.
3.
4.
5.
Batzdorf U, Block KL, Selch MT. Neoplasms of the nervous
system. In: Haskell CM. Cancer treatment. 3rd edition. Philadelphia, W. B. Saunders Company, 1990:436 –74.
Di Stefano A, Yap HY, Hortobagy GN, Blumenshein GR. The
natural history of breast cancer patients with brain metastases. Cancer 1979;44:1913– 8.
Posner JB. Management of central nervous system metastases. Semin Oncol 1977;4:81–91.
Rizzi A, Tandini M, Rocco G, Rossi G, Robustelli M, Radaelli
F, et al. Lung cancer with a simple brain metastasis: therapeutic options. Tumori 1990;76:579 – 81.
Balch CM, Milton GW. Diagnosis of metastatic melanoma at
distant sites. In: Balch CM, Milton GW, editors. Cutaneous
melanoma: clinical management and treatment results
wordwide. Philadelphia: J. B. Lippincott, 1985:221.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
21.
22.
23.
24.
1605
Gelber R, Larson M, Borgelt B, Kramer S. Equivalence of
radiation schedules for the palliative treatment of brain
metastases in patients with favorable prognosis. Cancer
1981;48:1749 –53.
Greig NH. Brain tumors and the blood tumor barrier. In:
Neuwelt EA, editor. Implications of the blood brain barrier
and its manipulation. Volume 2. New York: Plenum, 1989:
77–106.
Greig NH. Chemotherapy of brain metastases: current status. Cancer Treat Rev 1984;11:157– 86.
Shapiro W. Chemotherapy of metastatic central nervous
system carcinoma. In: Weiss L, Gilbert H, Posner J, editors.
Brain metastases. The Hague: Martinus Nijhoff, 1980.
Wilson C. Single agent chemotherapy of brain tumors: a
five-year review. Arch Neurol 1976;33:739 – 44.
Kolaric K, Roth A, Jelicic I. Phase II clinical trial of cisdichlorodiammine platinum (cis-DDP) for antitumorigenic
activity in metastatic brain tumor. J Cancer Res Clin Oncol
1982;104:287–93.
Rosner D, Nemoto T, Warren WL. Chemotherapy-induced
regression of brain metastases in breast carcinoma. Cancer
1986;58:832–9.
Cocconi G, Lottici R, Bisagni GC, Bacchi M, Tonato M,
Passalacqua R, et al. Combination therapy with platinum
and etoposide of brain metastases from breast carcinoma.
Cancer Invest 1990;8:327–34.
Cocconi G, Bisagni GC, Bacchi M, Boni C, Bartolucci R, Ceci
G, et al. Cisplatin and etoposide as first line chemothrapy for
metastatic breast carcinoma: a prospective randomized trial
of the Italian Oncology Group for Clinical Research. J Clin
Oncol 1991;9:664 –9.
Durand RF, Goldie JH. Interaction of etoposide and cisplatin
in an in vitro tumor model. Cancer Treat Rep 1987;71:673–9.
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting
results of cancer treatment. Cancer 1981;47:207–14.
Crinò L, Clerici M, Figoli F, Carlini P, Ceci G, Cortesi E, et al.
Chemotherapy of advanced non-small-cell lung cancer: a
comparison of three active regimens. A randomized trial of
the Italian Oncology Group for Clinical Research (GOIRC).
Ann Oncol 1995;6:347–53.
Ceci G, Bisagni GC, Cocconi G, Rodinò C, Belsanti V,
Bertusi M, et al. Cisplatin and VP16 in metastatic breast
carcinoma as a third line chemotherapy: a randomized
study comparing low vs. high doses of cisplatin. Tumori
1995;81:241– 4.
Boogerd W, Dalesio O, Bais EM, Van der Sande JJ. Response
of brain metastases from breast cancer to systemic chemotherapy. Cancer 1992;69:972– 80.
Malacarne P, Santini A, Maestri A. Response of brain metastases from lung cancer to systemic chemotherapy with
carboplatin and etoposide. Oncology 1996;53:210 –3.
Ryan GF, Ball DL, Smith JG. Treatment of brain metastases
from primary lung cancer. Int J Radiat Oncol Biol Phys
1995;31:273– 8.
Stewart DJ, Leavens M, Friedman J. Penetration of N-(phosphonacetyl)-L-aspartate into human central nervous system
and intracerebral tumor. Cancer Res 1980;40:3163– 6.
Stewart DJ, Leavens M, Maor M. Human central nervous
system distribution of cis-diamminedichloroplatinum and
use as a radiosensitizer in malignant brain tumors. Cancer
Res 1982;42:2474 –9.
Stewart DJ, Richard MT, Hugenholtz H. Penetration of
VP-16 (etoposide) into human intracerebral and extracerebral tumors. J Neurooncol 1984;2:133–9.
Документ
Категория
Без категории
Просмотров
2
Размер файла
74 Кб
Теги
149
1/--страниц
Пожаловаться на содержимое документа