Gastric cancer is among the most common causes of cancer-related death, and palliative
chemotherapy is the ultimate treatment in the majority of patients (Wils, 1998). In
recent years, second-generation combination chemotherapy regimens have produced high
response rates and impressive survival times (Cascinu et al, 1997; Webb et al, 1997;
Hill and Cunningham, 1998). However, the activity of these treatments has been demonstrated
in patients with good performance status and young age and, therefore, they do not
reflect the characteristics of patients in the community with advanced gastric cancer
(Tebbutt et al, 2002). Current epidemiological data show that gastric cancer rarely
occurs before the age of 40 years, its incidence increases thereafter and peaks in
the seventh decade (Greenlee et al, 2000).
Patients older than 65 years have been often excluded from or underrepresented in
the study populations of combination chemotherapy trials (Hutchins et al, 1999). This
demographic selection occurred in the populations of gastric cancer patients treated
with intensive combination chemotherapy regimens like the ECF (Tebbutt et al, 2002)
or the weekly PELF. The weekly PELF (cisplatin, fluorouracil, epi-doxorubicin, leucovorin)
regimen plus filgrastim support yielded a 62% response rate and a median survival
time of 11 months in a large phase II trial (Cascinu et al, 1997). This efficacy was
confirmed in subsequent studies (Cascinu et al, 1998, 2001), but demographic data
suggest that only a minority of patients treated with the weekly PELF regimen were
older than 65 years. In the PELF trials, severe haematology and nonhaematologic toxicities
were uncommon, but more than half of the patients had mild-to-moderate side effects
and even using routine filgrastim support, up to one-third of patients showed grade
II or III neutropenia (Cascinu et al, 1997, 1998, 2001).
To date, the development of active and safe regimens for treating elderly patients
with advanced gastric cancer should be considered a relevant issue in medical oncology.
Age itself is not a contraindication to anticancer medical therapies (Goodwin et al,
1996; Balducci and Beghe, 2000; Balducci and Yates, 2000) and specific tools are available
to identify nonfrail elderly patients who could benefit from chemotherapy (Goodwin
et al, 1996; Balducci and Yates, 2000).
On these bases, we sought to investigate the weekly combination of cisplatin, fluorouracil
and 6S-stereoisomer leucovorin (PLF) as first-line chemotherapy for elderly patients
with advanced gastric cancer. Drugs, doses and pace of chemotherapy administrations
were those of the weekly PELF regimen, but without epirubicin. This choice was made
under the hypothesis that the omission of the anthracycline could have reduced the
incidence of neutropenia with improved tolerability of chemotherapy to elderly patients.
In a pilot clinical trial, the weekly PLF regimen showed a favourable activity/toxicity
ratio and chemotherapy did not require routine filgrastim support (Graziano et al,
2002).
MATERIALS AND METHODS
Patients characteristics
Chemotherapy-naive patients with pathologically confirmed, relapsed, locally advanced
or metastatic gastric cancer were considered eligible for study entry. The study was
addressed to patients older than 65 years; frail elderly patients were excluded according
to the following criteria: age >85 years, dependence in one or more activities of
daily living, presence of three or more comorbid conditions and presence of one or
more geriatric syndromes (Balducci and Yates 2000). The Katz and Lawton scales were
used to assess activities of daily living (Scott et al, 1997); the Katz activities
of daily living (ADL) rates the ability to perform routine activities as bathing,
dressing, feeding oneself or getting into or out of bed, chairs and vehicles. The
Lawton instrumental activities of daily living (IADL) rates more sophisticated functions
as the ability to use the telephone, to shop, to handle money, to prepare food or
to perform other household tasks. Classic geriatric syndromes which had to be excluded
before study inclusion were: dementia, delirium, severe depression, frequent falls,
neglect and/or abuse, and spontaneous fractures (Balducci and Yates, 2000). The procedures
for performing the above-mentioned geriatric assessments were reported in the study
protocol. Each patient was evaluated from the same oncologist at each participating
institution.
Additional inclusion criteria were: presence of measurable disease, Eastern Cooperative
Oncology Group (ECOG) performance status 0–1, granulocytes count >1500 μl, platelet
count >100 000 μl, serum creatinine <1.5 mg dl−1 with creatinine clearance ⩾60 ml min−1
as estimated by using the Cockcroft–Gault formula (Cockcroft and Gault, 1976), bilirubin
level <1.5 mg dl−1 and liver enzymes <1.5 times the institutional upper limit. The
protocol was approved by each local institutional review board and written informed
consent was obtained from all participants.
Study design
Chemotherapy consisted of a 1-day per week administration of intravenous cisplatin
35 mg m−2 with standard hydration and glutathione 1.5 g m−2, followed by fluorouracil
500 mg m−2 and 6S-stereoisomer leucovorin 250 mg m−2 (PLF). All patients received
emesis prophylaxis with 5-HT3 inhibitors. Routine prophylactic support with granulocyte
colony-stimulating factors was not allowed, but filgrastim was introduced after the
first treatment delay for grade II/III neutropenia and maintained thereafter. Erythropoietin
was allowed for the treatment of anaemia, when haemoglobin declined to a level ⩽10 mg dl−1.
Full doses of the anticancer drug were given if granulocyte count was >1500 μl−1 and
platelet count was >100 000 μl−1. In the case of any grade II or more toxicity except
alopecia, chemotherapy was delayed a week and then restarted after full recovery.
Doses of anticancer drugs were not reduced in the case of grade II–III neutropenia,
but these patients started 5-day therapy with filgrastim 5 μg Kg−1 day−1 (days +1–+5)
after the first treatment delay. Similarly, dose of anticancer drugs were not reduced
after an episode of grade II–III anaemia and erythropoietin was allowed when haemoglobin
levels were ⩽10 mg dl−1. Patients with persisting neutropenia or anaemia and who needed
a second treatment delay received a 25% dose reduction of all drugs. Also, this dose
reduction was planned in the case of grade III toxicity, except alopecia. Patients
with unsolved grade II or more toxicity after two consecutive treatment delays, or
experiencing grade IV toxicity except alopecia went off study.
Response and toxicity assessment
Pretreatment evaluation consisted of baseline studies including: medical history,
physical examination, blood chemistries, urinoanalysis and ECG. Also, chest X-rays,
abdominal computed tomography or magnetic resonance, bone scan and any other test
to identify the extent of disease was performed. All patients had physical examination
and blood chemistries before each weekly administration of chemotherapy and toxicity
was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC,
1998). Tumour measurements for response assessment were performed after eight weekly
cycles; patients with responsive or stable disease received six additional weekly
cycles and they underwent a second measurement at the end of the treatment program.
Follow-up controls were performed every 2 months thereafter. The World Health Organization
criteria (WHO, 1979) were used to evaluate responses.
Statistical plan
The primary end point of this study was to determine the response rate and the toxicity
of the weekly PLF regimen in elderly patients with advanced gastric cancer. The secondary
objective was to measure the time to disease progression and the survival time.
The study was conducted using the two-stage Simon (1989) design. The sample size was
calculated to reject a 10% response rate in favour of a target response rate of 30%,
with significance level of 0.05 and a power of 0.90. In the initial stage, a total
of 18 evaluable patients were to be entered and evaluated for response. If there were
⩽2 responses, accrual was to be stopped. If >2 responses were observed in the initial
stage, then 19 additional patients were to be entered in the second stage to achieve
a total of 35 evaluable patients (assuming that two patients might be inevaluable).
If >6 responses were observed in 35 patients, an accrual of at least 55 assessable
patients was planned to ensure a 25% maximum width of the confidence interval with
an expected 30% response rate. The time to disease progression (TTP) was measured
from the date of registration to the date of documented disease progression or death.
The survival time was measured from the time of registration to the date of death
resulting from any cause.
RESULTS
From January 1999 to December 2001, 58 patients entered on this study. Four patients
did not complete eight weekly cycles due to early progression (two patients), refusal
after grade III fatigue (one patient) and persistent grade II nephrotoxicity (one
patient). The side effects reported by these four patients were included in the overall
analysis of toxicity and they were considered as progressions in the intention-to-treat
analysis of response. The baseline clinico-pathologic characteristics of the 58 patients
are reported in Table 1
Table 1
Characteristics of the 58 patients enrolled in the study
Number of patients
58
Sex ratio
Male
31
Female
27
Median age (range)
76 years (67–82)
ECOG performance status
0
31
I
27
Prior gastrectomy
Curative
40
Palliative
12
Not performed
6
Sites of the disease
Liver plus lymphnodes
17
Abdominal relapse plus lympnhodes
13
Liver
11
Lymphnodes
10
Primary tumour plus liver
4
Primary tumour plus lympnhodes
2
Lung plus liver
1
CEA level
<10 ng ml−1
20
>10 ng ml−1
38
.
At the end of the treatment program, the best intention-to-treat overall response
rate in the 58 patients was 43% (95% CIs: 30–56%) with five complete responses, 20
partial responses, 15 stable diseases and 18 progressions. The five complete responders
showed complete disappearance of disease signs after eight weekly administrations
and they confirmed the result at the second re-evaluation. The complete responses
were obtained in liver metastases (two patients), lymphnodal metastases (two patients),
liver plus lymphnodal metastases (one patient). In all, 18 patients achieved partial
response after eight weekly cycles and two additional patients with initial stable
disease showed partial response after 14 cycles. Three patients with stable disease
after eight PLF cycles showed disease progression at the second re-evaluation. In
the whole group, the median time to disease progression was 5.3 months and the median
survival time was 8.6 months.
Toxicity was generally mild and the maximun grade of haematologic and nonhaematologic
toxicities per patient is reported in Table 2
Table 2
Treatment-related toxicity in the 58 enrolled patients
Number of patients (%)
Adverse event
Grade 1
Grade 2
Grade 3
Grade 4
All grades
Neutropenia
10 (17)
20 (35)
10 (17)
0
40 (69)
Thrombocytopenia
8 (14)
2 (3)
0
0
10 (17)
Anaemia
26 (45)
15 (26)
0
0
41 (71)
Nausea
21 (36)
4 (7)
0
0
25 (43)
Vomiting
19 (33)
9 (15)
0
0
28 (48)
Diarrhoea
8 (14)
2 (3)
0
0
10 (17)
Fatigue
18 (31)
22 (38)
1 (2)
0
41 (71)
Anorexia
15 (26)
10 (17)
0
0
25 (43)
Neuropathy
9 (15)
1 (2)
0
0
10 (17)
Nephrotoxicity
4 (7)
1 (2)
0
0
5 (9)
Mucositis
5 (8)
6 (10)
0
0
11 (19)
. According to the treatment protocol, the 30 patients who experienced grade II/III
neutropenia started filgrastim which was maintained until the end of the treatment
program. The 5-day therapy with filgrastim was started after the fourth PLF administration
in 15 patients, after the fifth in nine patients and after the sixth in the remaining
six patients.
Fatigue was the commonest treatment-related toxicity and it resulted grade I in 18
patients, grade II in 22 patients and grade III in one patient. Anaemia was recorded
in 31 patients whose haemoglobin concentrations declined to a level of 10–12 g dl−1
in 26 patients and to 8–9.9 g dl−1 in 15 patients. None of the patients showed episodes
of grade III anaemia and blood transfusions were not necessary in the study population.
Other side effects like stomatitis, peripheral neurotoxicity, nephrotoxicity were
uncommon and generally mild. At least one treatment delay was carried out in 45 patients
and 22 patients had a 25% dose reduction of anticancer drugs. Neither grade IV toxicity
nor toxic death were observed.
DISCUSSION
Gastric carcinoma often occurs in the 60th and 70th decades, but large trials of palliative
chemotherapy in elderly patients are almost lacking. To the best of our knowledge,
six phase II studies have been published in international peer-reviewed journals between
1990 and 2002 (Wilke et al, 1990; Cascinu et al, 1994; Cascinu and Catalano, 1995;
Di Bartolomeo et al, 1995; Hartung et al, 2000; Ikeda et al, 2002). In five of these
trials, chemotherapy consisted of leucovorin-modulated 5-fluorouracil in combination
with cisplatin, epi-doxorubicin, etoposide or mitomycin-C. A phase II study investigated
the toxicity profile and the activity of single-agent doxifluridine (Ikeda et al,
2002). In general, the tumour control rate seemed promising and no toxic death was
observed across all studies. Unfortunately, these trials often enrolled patients with
concomitant illnesses or poor performance status and consequently, the number of elderly
patients did not exceed 30 in each of them. More recently, Tebbutt et al (2002) have
reported the results of a phase III trial investigating protracted venous infusion
5-fluorouracil in oesophago-gastric cancer patients. In this study, there was no age
limitation for patient eligibility and chemotherapy achieved good results of palliation
in a cohort of patients with a median age of 72 years.
In the present investigation, the weekly combination of cisplatin, fluorouracil and
folinic acid showed promising tumour control rate and it was safely delivered to nonfrail
elderly patients with advanced gastric cancer. Patients were treated on outpatient
basis and they showed good compliance to treatment with only one early refusal. A
specific assessment of either quality of life or clinical benefit was not planned
in this study; however, a record of abdominal pain was performed by means of the memorial
pain assessment card and sustained pain relief was observed in 20 out of 28 patients
(71%) who were monitored before, during and after PLF chemotherapy.
A major issue in the field of anticancer chemotherapy for elderly patients is the
identification of prognostic indicators, which can be used to balance benefits and
risks of medical therapies. Many clinical investigations have been addressed to these
issues and to date, several prognostic and predictive tools can be used to identify
frail and non-frail elderly patients (Reuben, 1997). Also, pharmacokinetic studies
have clarified major differences in the metabolism of anticancer drugs in the elderly
with specific cares to be used when treating patients ageing more than 65 years (Balducci
and Beghe, 1999).
There are many different methods to assess the functional status in elderly patients
and the comprehensive geriatric assessment (CGA) is considered as one of the most
complete tool for this purpose (Repetto et al, 2002). The CGA requires a professional
team approach and it may be time consuming and costly (Ingram et al 2002). For these
reasons, alternative scales and less-extensive methods have been implemented in cancer
chemotherapy trials for the evaluation of elderly patients. In particular, the IADL
and the ADL scales are considered as the most sensitive assessments of function in
older individuals (Balducci and Beghe, 2000), and in both elderly men and women, increasing
score on the ADL–IADL scales is predictive of mortality (Scott et al, 1997). In the
present investigation, the CGA was not included in the study plan, however, specific
criteria to exclude frail elderly patients, together with the accurate monitoring
of sideeffects and general measures for minimising toxicity allowed the safe and successful
administration of combination chemotherapy in a population of patients whose median
age was 76 years. Indeed, the eligibility criteria were quite stringent and a proportion
of elderly patients could not be enrolled in this trial. On the other hand, we opted
for a conservative approach since an unfavourable cost/efficacy ratio may occur when
palliative chemotherapy is administered to patients with advanced gastric cancer and
low-performance status or comorbities (Janunger et al, 2001).
The favourable results of the weekly PLF regimen together with its easiness of administration
on outpatient basis and the use of old, low-cost drugs make this treatment worth of
further investigation. At some point during chemotherapy, about half of the patients
received filgrastim and about 20% of them started erythropoietin. These supports increased
treatment-related expenses and, therefore, they may have partially reduced the advantage
of low-cost chemotherapeutic agents. In this perspective, further assessments of the
weekly PLF regimen could consider a short 3-day filgrastim course between cycles and/or
additional treatment delays for neutropenia instead of the immediate use of filgrastim
after the first delay. PLF chemotherapy may represent a valid alternative to more
expensive combinations including CPT-11 or oxaliplatin and it could be compared to
palliative single-agent fluorouracil in a randomised trial for elderly patients with
advanced gastric cancer.