Although the incidence of gastric cancer has gradually decreased in many Western Countries,
it remains one of the leading causes of cancer-related deaths worldwide, and it now
ranks second only to lung cancer with about 755 000 new cases per year (Karpeh et
al, 2001). Since screening for early detection is not performed in Western Countries,
in approximately 50% of newly diagnosed cases, the tumour is beyond its local–regional
margins (Kelsen, 1996; Karpeh et al, 2001). Surgery remains the mainstay of any curative
treatment, but only when a radical resection is feasible (removal of all gross cancer
cells at the resection margins as determined by histopathological examination). Those
patients who are considered not amenable of curative resection generally receive chemotherapy
in order to obtain palliation of symptoms and improved survival. Since there is no
evidence that a more aggressive treatment could result in a better survival, most
of the patients receive a combination of 5-fluorouracil (5-FU), mitomycin C or cisplatin
(Karpeh et al, 2001). Only a few studies have focused on the role of preoperative
chemotherapy in unresectable gastric cancer. Comprehensively, these trials suggested
that chemotherapy could allow radical surgery in approximately 40% of all cases not
amenable of curative resection at presentation, but at the cost of severe toxicity
(Kelsen, 1996). In a pilot trial, we observed that a preoperative chemotherapy with
weekly cisplatin (CDDP), epidoxorubicin (epi-ADR), 5-FU, 6S-leucovorin, glutathione
and bone marrow support (filgastrim) could allow a radical resection in 13 out of
32 (41%) patients previously considered unresectable (Cascinu et al, 1998). These
encouraging findings followed our demonstration of activity (62% overall response
rate in 105 patients) of this chemotherapy regimen in patients with advanced gastric
cancer. In this latter trial, five of 11 (45%) patients with exclusively locally advanced
unresectable disease could undergo a curative resection after chemotherapy (Cascinu
et al, 1997). In order to test whether the hypothesis of a more aggressive and expensive
approach in this subset of gastric cancer patients could be justifiable, we prospectively
analysed the effects of this intensive weekly treatment in a larger group of gastric
cancer patients not amenable of curative resection.
MATERIALS AND METHODS
Patients’ selection
Patients with previously untreated, histologically confirmed, locally confined, gastric
adenocarcinoma were eligible for the study, only after the primary tumour was considered
not amenable of surgical resection. Unresectable disease was defined jointly by a
medical oncologist, a gastroenterologist and an abdominal surgeon on the basis of
the laparotomy findings and/or CT scan images (tumour size >7 cm, invasion of adjacent
structures, such as pancreas, omentum, aorta, oesophagus, liver), endoscopy and endoscopic
ultrasonography (EUS). Patients with distant, liver and peritoneal metastases were
excluded. The American Joint Committee on Cancer staging system (6th edition) was
applied. Patients were also required to have an Eastern Oncology Cooperative Group
(ECOG) performance status ⩽2, an adequate hepatic (serum bilirubin <1.5 mg dl−1),
renal (serum creatinine <1.5 mg dl−1) and bone marrow function (white blood cell (WBC)
>4000 cells μl−1 with an absolute granulocyte count >1500 cells μl−1, platelet count
>100 000 cells μl−1) and aged between 18 and 70 years. As a potential cardiotoxic
drug (epi-ADR) was included in the chemotherapy regimen, patients with a New York
Heart Association class >2 were excluded from the study. Pretreatment assessment included
complete blood cell count with WBC differential and platelet count, biochemical screening
profile, serum creatinine and/or creatinine clearance, CT scan or radiograph of the
chest, CT scan of the abdomen, endoscopy and a bone scan. Gated pool scan was not
routinely performed unless the patient had a history of cardiac disease, in which
case it was mandatory and the patient was ineligible for the study if the left ventricular
ejection fraction was <45%. The protocol was approved by the institutional review
board, and all patients gave informed consent, which indicated that they were fully
aware of the investigational nature of the study itself.
Chemotherapy
All patients underwent chemotherapy according to the weekly PELF regimen, which consisted
of a once a week administration of CDDP 40 mg m−2 as a 30 min infusion in 250 ml of
normal saline, 5-FU 500 mg m−2 as a 15 min infusion in 100 ml of normal saline and
epi-ADR 35 mg m−2 by intravenous bolus injection. A dose of 250 mg m−2 of 6S-stereoisomer
of leucovorin as a 4 h infusion in 250 ml of normal saline was administered concurrently
with hydration and glutathione 1.5 g m−2 in 100 ml of normal saline over 15 min, which
was infused before each cisplatin administration in order to prevent CDDP-related
neurotoxicity (Figure 1
Figure 1
Diagram showing the treatment given in the first 2 weeks of therapy. The same treatment
schedule was administered for 8 consecutive weeks.
). Antiemetic treatment with dexamethasone 20 mg and ondansetron 8 mg both given intravenously
was administered, respectively, 45 and 15 min before CDDP infusion. At 2 h before
CDDP administration, patients received intravenous hydration with 1500 ml of normal
saline plus 20 mEq of potassium chloride and 15 mEq of magnesium sulphate. Intravenous
fluids administration proceeded for 2 h after CDDP with 1000 ml of normal saline.
All patients received filgastrim 5 μg kg−1 by subcutaneous injection from the day
after to the day before each chemotherapy administration. One cycle of chemotherapy
consisted of 8 weekly chemotherapy administrations. Patients only received 8 weeks
of treatment (one cycle). In the event of toxicity, chemotherapy administration was
delayed by a week or until full recover in case of WBC count <4000 cells μl−1, platelet
count <100 000 cells μl−1 or if grade 2 and 3 mucositis and diarrhoea occurred. The
criteria for patient withdrawal from study were patient's refusal, tumour progression
and any grade 4 toxicities. Chemotherapy was administered as an outpatient procedure
in all cases. The planned delay between the last week of treatment and surgery was
6–8 weeks.
Evaluation of response and toxicity
Objective response to chemotherapy was assessed after 8 weeks of therapy, combining
findings from both CT scan of the abdomen and endoscopy, including a new biopsy of
the tumour, if still visible, or a biopsy of the area originally involved by the tumour.
Endoscopy and endoscopic ultrasonography was performed when clinically indicated.
Partial response (PR) was defined as having both CT scan evidence of PR, according
to the World Health Organisation (WHO) criteria, and endoscopy showing a >50% reduction
of the visible tumour, or complete disappearance of the tumour, but positive histology
on biopsy of the previously involved area. Complete response (CR) was defined as a
complete disappearance of the tumour as seen by CT scan of the abdomen and a complete
resolution of the endoscopic findings without histological evidence of neoplastic
cells on biopsy of the original site of the tumour. Toxicity was evaluated weekly
according to the National Cancer Institute Common Toxicity Criteria (NCICTC). The
decision to perform a laparotomy with the aim of a radical excision was evaluated
each time a complete removal of the tumour was jointly judged feasible by a medical
oncologist, a gastroenterologist and an abdominal surgeon.
RESULTS
In all, 82 patients were enrolled onto this study by coinvestigators from seven Italian
centres. The median age at diagnosis was 57 years (range 29–68 years); 57 (69.5%)
patients were male and 25 (30.5%) were female, most of the patients enrolled were
in good general condition as PS (ECOG) was 0–1 in 72 (88%) patients and two in the
remaining 10 (12%) patients. The primary tumour was located in the body of the stomach
in 40 (49%) cases, in the gastro-oesophageal junction in 18 (22%) cases, in the distal
stomach in 18 (22%) cases and in the proximal stomach in six (7%) cases. In all, 52
(63%) patients underwent laparotomy, as a part of a failed attempt at radical primary
surgery, before study entry, in these cases laparotomy confirmed the presence of locally
advanced, unresectable disease, whereas in the remaining 30 (37%) patients the diagnosis
of locally advanced disease was confirmed by CT scan of the abdomen (23 patients)
and EUS (seven patients). All patients received eight weekly treatments (one cycle
of chemotherapy). Patient characteristics are summarised in Table 1
Table 1
Patient characteristics
No of patients
82
Age (years)
Median
57
Range
29–68
Sex
Male/female
57/25
PS (ECOG)
0
39
1
33
2
10
Sites of primary tumor
Gastro-oesophageal junction
18
Proximal stomach
6
Body
40
Distal stomach
18
Initial stages
T4 N0 M0
13
T4 N1-2 M0
51
T3 N1-2 M0
18
Laparotomy
Yes
52
No
30
COG=Eastern Oncology Cooperative Group.
.
We observed a response to chemotherapy in 40 of 82 patients (49%), six (7%) patients
had a CR and 34 (41%) had a PR. Of these, 30 (36%) patients showed disease stabilisation,
whereas 12 (15%) patients progressed on chemotherapy. Among the 40 responding patients,
37 (45%) had potentially curative radical surgery and three (4%) were found not resectable
at laparotomy. In four (5%) cases, a complete pathological response was confirmed
(Table 2
Table 2
Stage at surgery (37 patients)
Stage
Patients
pT0N0
4
pT1N0
1
PT2N0
2
PT3N0
12
PT2N1
5
PT3N1
13
). Among the 37 patients who received radical surgery after chemotherapy, 16 (50%)
had a failed initial laparotomy. At a median follow-up from the start of the treatment
of 48 months (range 30–60 months), 25 of the 37 resected patients (68%) were alive
and 24 (65%) were disease free, the 4-year survival rate for the whole group was 31%.
The median survival was 17 months for the whole group and 12 months for inoperable
patients, while it was not reached in resected patients (Figure 2
Figure 2
(A) Kaplan–Meier overall survival (OS) curve for the whole group of 82 patients. (B)
Kaplan–Meier survival curves for patients who underwent curative resection of primary
gastric tumour after chemotherapy (resected, - - - - -), and for not resected patients
(not resected, ———).
). There were no deaths associated with chemotherapy or major surgical complications
in this study and the toxicity profile was globally acceptable. We observed mainly
haematological toxicities of grade 2: leucopenia and thrombocytopenia in five and
six patients, respectively, while grade 3–4 haematological toxicities were rare events
(three cases of grade 3–4 leucopenia and two cases of grade 3–4 thrombocytopenia).
Nonhaematological toxicities were uncommon and moderate (Table 3
Table 3
Treatment toxicity (NCICTC): worst toxicity per patient
Grade I
Grade II
Grade III
Grade IV
Leucopenia
6
5
2
1
Thrombocytopenia
5
6
1
1
Anaemia
5
3
2
—
Mucositis
4
3
—
—
Diarrhoea
—
2
—
—
Nausea/vomiting
6
10
1
—
Neurotoxicity
1
2
—
—
NCICTC=National Cancer Institute common toxicity criteria.
). Dose delays and dose reductions were applied in 25 (30%) and seven (8.5%) patients,
respectively. No unplanned admissions were required at any stage during the course
of chemotherapy. All patients considered suitable for surgery after chemotherapy underwent
laparotomy within 6–8 weeks (median 48 days) from the end of chemotherapy, accordingly
to what was originally planned in the protocol. The median hospital stay for surgery
was 10 days (range 8–20 days), accordingly to what was expected. We did not observe
relevant 30-day medical or surgical complications and no patients required return
to operating Theatre.
DISCUSSION
Advanced gastric cancer patients are a heterogeneous population and at least two different
clinical conditions should be considered if the best treatment approach is to be defined.
Patients with metastatic tumours often present in poor general conditions and with
several disease-induced symptoms. In this subset of patients, a palliative treatment
is a reasonable option and a careful evaluation of the therapy-related toxicity is
of primary relevance in the selection of the appropriate chemotherapy regimen. On
the other hand, many patients present with a locally advanced disease not amenable
of a radical resection, but without metastatic involvement of distant sites. These
patients are reported to have a longer survival and a globally better prognosis (Lowy
et al, 1999; Yano et al, 2002). Furthermore, they are potential candidates for a treatment
with curative intent, as an objective response to chemotherapy may allow a radical
resection of the tumour. In these latter cases, an active chemotherapy regimen should
be preferred even when this implies a greater risk of moderate–severe toxicity.
We investigated the role of an intensive weekly chemotherapy regimen in 82 patients
diagnosed with unresectable gastric cancer. The overall response rate to chemotherapy
in our series was 49% (40 of the 82 patients), which compares well to that achievable
with other active chemotherapy regimens available (Findlay et al, 1994; Louvet et
al, 2002). However, the most interesting data arising from our study is the curative
resectability rate, which we obtained in this particularly difficult setting of patients:
in fact, 45% (37 of the 82 patients) of all cases treated could undergo a radical
resection, a procedure that was excluded at presentation. Moreover, the 4-year survival
rate of the resected group was definitely higher (68%) compared to that achieved by
the whole group (31%). These data seem to confirm that complete resection of all gross
disease with negative margins on pathology examination represents the only potentially
curative therapy for gastric cancer, and that a preoperative, effective, chemotherapy
regimen might probably improve the outcome of patients, who would have been otherwise
excluded from curative resection on the basis of initial findings. The chemotherapy
combination we used also showed a favourable profile of toxicity, which was mild and
quite acceptable. Overall, only two cases of grade 4 haematological toxicity (one
case of leucopenia and one case of thrombocytopenia) were reported and no surgical
complications were observed in those who underwent surgery. Other authors explored
preoperative chemotherapy in locally advanced gastric cancer patients with contrasting
results, basically depending on the patients’ population investigated (resectable
or not resectable at presentation) and the chemotherapy regimen employed. The available
data with the ECF regimen (epi-ADR, cisplatin and 5-FU) in this setting are disappointing.
In a small trial by Melcher et al (1996), only one of 10 patients found to have locally
advanced, unresectable, disease proceeded to radical surgery after ECF chemotherapy,
and in a more recent study other authors substantially confirmed the findings previously
reported by Melcher using the same regimen, as none of the four patients with initially
unresectable disease was rendered resectable; moreover, none of them was alive at
a median follow-up of 30 months (Geh et al, 2000). Even though it is possible that
chemotherapy duration, 12 weeks as opposed to the 24 weeks of the Royal Marsden Hospital's
experience, could have negatively affected results, these data do not seem encouraging
for further studies in this group of patients. Interesting results have been initially
reported with the use of the FAMTX regimen (5-FU, doxorubicin and methotrexate). In
patients with high risk, but potentially curable, gastric tumours, 34 of 56 patients
(61%) received a curative resection, but at the cost of substantial toxicity (mainly
neutropenic fever) with one chemotherapy-related death (Kelsen et al, 1996). Nevertheless,
data from a small randomised trial that compared the use of FAMTX as preoperative
therapy before surgery vs surgery alone in operable gastric cancer could not demonstrate
that the FAMTX regimen was suitable as neoadjuvant chemotherapy, and the authors concluded
that more active regimens should be tested in further randomised studies (Songun et
al, 1999). It should be noticed that in preoperatively unresectable patients, a combination
chemotherapy containing methotrexate and 5-FU was reported by Plukker et al (1991)
to allow 40% of curative resections. In a further trial, 34 patients with unresectable
gastric cancer were treated with either of the two neoadjuvant chemotherapies: FEMTXP
(5-FU, epirubicin, methotrexate, cisplatin) or THP-FLPM (pirarubicin, 5-FU, leucovorin,
cisplatin, mitomycin C). Of 33 evaluable patients, only eight (24%) curative resections
could be performed; interestingly, at multivariate analysis salvage surgery was found
to be the only independent prognostic factor in this series (Yano et al, 2002). The
EAP regimen (etoposide, doxorubicin and cisplatin) obtained more than 70% of curative
resections in patients with high-risk, locally advanced gastric cancer. Nevertheless,
toxicity was considerable and all cases were theoretically resectable at presentation
(Schuhmacher et al, 2001). Results with the same regimen in not resectable cases are
clearly less appealing and approached a 44% of resectability rate (Wilke et al, 1990).
A major matter of debate in this area is also accurately defining preoperative staging
procedures. Although a correct diagnosis of the extent of disease is of paramount
importance in locally advanced gastric cancer, standard techniques are still to be
defined. Direct vision by surgical exploration might represent the best initial assessment
available, but would significantly contribute to increase treatment morbidity and
might cause the patients to undergo an unnecessary laparotomy. Laparoscopy, EUS or
a combination of these two techniques could complement traditional staging methods
and provide clinical data not otherwise obtainable (Ajani et al, 1999). Demonstration
exists that these procedures can improve staging of the primary tumour and detect
unsuspected metastatic disease with interesting sensitivity and specificity, thus
allowing a better patient selection and confrontation between different series. Particularly
promising seemed data with regard to the use of EUS in preoperative staging of stomach
tumours (Lightdale et al, 1989; Botet et al, 1991). Endoscopy and endoscopic ultrasonography
showed an accuracy of 75–85% in predicting tumour stage before surgery, but its use
in the evaluation of response to treatment in patients, who received preoperative
chemotherapy, was disappointing and unreliable probably due to chemotherapy-induced
changes in the physical pattern of the tumour (Kelsen et al, 1996; Ajani et al, 1999).
Nevertheless, before a more widely diffusion of these methods occur, traditional procedures
are to be applied in order to define surgical resectability. CT scan proved to possess
an accuracy of 80–90% in defining local diffusion in gastric cancers. Clear CT scan
signs of tumour extension to pancreas, aorta, omentum, oesophagus and liver, and the
presence of bulky tumour (>7 cm) should discourage surgery, as initial treatment in
these patients, as the probability to obtain a radical resection is very low (Sussman
et al, 1988; Rougier et al, 1994). In our trial more than a half of the patients were
considered not resectable by direct surgical exploration: in fact, 52 (63%) patients
underwent laparotomy, as a part of a failed attempt at radical primary surgery, before
study entry. In the remaining 30 (27%) patients, the diagnosis of locally advanced
disease was confirmed by CT scan of the abdomen (23 patients) and EUS (seven patients).
These data demonstrate that in our series preoperative tumour upstaging is unlikely
to have occurred, thus making our findings fully interpretable.
Chemotherapy with weekly CDDP, epi-ADR, 5-FU, 6S-leucovorin, glutathione and bone
marrow support (filgastrim) seemed to be highly effective in patients with locally
advanced, unresectable, gastric cancer, as it allowed a potentially curative resection
in 45% of the cases we observed. Moreover, even though the study design could not
allow any definitive conclusion, the median survival and the 4-year survival time
(68%) of the resected group were suggestive of a survival advantage in this subset
of patients determined by the use of preoperative chemotherapy. These findings are
even more interesting when we consider the favourable profile of toxicity and the
short period of treatment requested (8 weeks as opposed to 12–24 weeks of other chemotherapy
regimens). Taken together, the data obtained from the present study suggest that this
intensive weekly regimen could represent a therapeutic option for patients with locally
advanced, unresectable, gastric cancer, with the aim to allow a curative resection,
and hopefully a prognostic improvement, in about half of all cases. According to these
findings, the PELF weekly regimen has now become our standard ‘off-trial’ treatment
for selected cases, showing clinical characteristics similar to those outlined in
our protocol. However, in the daily clinical practice, this chemotherapy regimen should
not always be considered a possible choice, especially for patients in poor general
conditions, thus making this treatment unsuitable for approximately 15–20% of all
cases. Further, well-designed randomised studies are clearly warranted in order to
confirm our findings. We believe that a randomised clinical trial investigating the
PELF weekly regimen against a docetaxel-containing regimen, as proposed by Ajani et
al (2003),would be of particular interest in order to improve the standard of care
in this setting.