Download Concurrent Proton Beam Radiotherapy and Systemic Chemotherapy

Jpn J Clin Oncol 2005;35(1)40–44
doi:10.1093/jjco/hyi001
Concurrent Proton Beam Radiotherapy and Systemic
Chemotherapy for the Metastatic Liver Tumor of
Gastric Carcinoma: a Case Report
Takeshi Gohongi1, Koichi Tokuuye2, Hiroyuki Iida1, Reiko Nakai1, Naoto Gunji1,
Yasuyuki Akine2 and Kazuo Orii1
1
Department of Surgery, Tsukuba-Gakuen Hospital, Tsukuba, Ibaraki and 2Department of
Radiation Oncology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan
Received June 12, 2004; accepted August 30, 2004
We report a case of a woman with a metastatic liver tumor from gastric carcinoma, who has been
successfully treated with concurrent proton beam therapy and systemic chemotherapy. A 76-yearold woman underwent distal gastrectomy with regional lymph node dissection for advanced
gastric carcinoma on January 17, 2002. She received five courses of sequential chemotherapy
with methotrexate–5-fluorouracil after the surgical resection. A metastatic liver tumor was
detected in the caudate lobe of the liver by computed tomography at 6 months after the surgical
resection. We employed concurrent proton beam therapy and systemic chemotherapy which
consisted of 5-fluorouracil (250 mg/body per day, as a 24-h intravenous injection for 4 weeks)
and low dose cisplatin (10 mg/body on days 1–5 every week for 4 weeks). Proton beam therapy
targeting the metastatic liver tumor was performed in a daily fraction of 3 Gy, 5 days per week, with a
total dose of 66 Gy over 30 days. The tumor disappeared 3 months after the treatment and
no recurrence has been observed for 2 years after termination of the treatment. Throughout
the entire course of treatment, the patient received injections of granulocyte stimulating factor
subcutaneously for grade 3 leukopenia. She never complained of abdominal symptoms, such as
epigastralgia, nausea or diarrhea. Liver failure related to proton irradiation has not been observed.
This concurrent proton beam radiotherapy with systemic chemotherapy could be an effective
treatment modality for metastatic liver tumor from gastric carcinoma.
Key words: chemoradiotherapy – 5-fluorouracil – gastric carcinoma – metastatic liver tumor – proton
INTRODUCTION
Gastric carcinoma is one of the most common gastrointestinal
malignancies in Japan for which the primary curative treatment
is surgical resection including systematic dissection of lymphatic tissues. The prognosis of patients with advanced gastric
carcinoma is still poor because of its high relapse rate even
after curative resection. Systemic adjuvant chemotherapy has
been studied extensively in past decades. However, an effective chemotherapeutic regimen in a post-operative setting has
yet to be identified. Patients die from the development of
symptomatic metastatic disease arising from unresected microscopic metastases. Liver metastasis is one of the common
failure patterns of gastric carcinoma after surgery along
with peritoneal dissemination and extensive lymph node metastases. We report a case of a woman with a metastatic liver
For reprints and all correspondence: Takeshi Gohongi, Department of Surgery,
Tsukuba-Gakuen Hospital, Tsukuba, Ibaraki 305-0857, Japan.
E-mail: [email protected]
tumor from gastric carcinoma successfully treated with
concurrent proton beam therapy and systemic chemotherapy.
CASE REPORT
A 76-year-old woman was referred to our hospital for appetite
loss and nausea in December 2001. On physical examination,
her conjunctiva was slightly anemic and laboratory tests
showed her hemoglobin level to be 8.2 g/dl. Gastric endoscopic
examination revealed a type 3 lesion on the lesser curvature of
the antrum. Pathological examination of biopsy specimens
showed moderately differentiated adenocarcinoma. Barium
gastrography showed almost complete obstruction at the pyloric
ring and barium flow was not observed in the duodenum
(Fig. 1a). Computed tomography (CT) and magnetic resonance
imaging (MRI) demonstrated no metastases in the lung, liver or
brain, but multiple swollen lymph nodes along the common
hepatic artery, whose sizes were 20 mm in maximum diameter (Fig. 1b). She previously underwent an appendectomy
for acute appendicitis at age 45 and cholecystectomy for
# 2005 Foundation for Promotion of Cancer Research
Jpn J Clin Oncol 2005;35(1)
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(a)
Figure 2. CT at 6 months after operation. A metastatic liver tumor in the
caudate lobe appears 4 cm in diameter and adjacent to the inferior vena
cava. The main trunk of the portal vein and inferior vena cava are involved
by the tumor.
(b)
Figure 1. Barium gastrography (a) and computed tomography (CT) (b) before
operation demonstrate pyloric stenosis due to gastric carcinoma and lymph
nodes swelling along common hepatic artery.
gallbladder stones at 50. At laparotomy on January 17, 2002,
the tumor was located in the antrum and there was extensive
lymph node swelling along the common hepatic artery but no
peritoneal dissemination. She underwent distal gastrectomy and
systematic dissection of regional lymph nodes encompassing
the common hepatic artery, left gastric artery and celiac artery.
Pathological examination of the resected specimen revealed
that moderately differentiated adenocarcinoma of the stomach
invaded the depth of the serosa membrane. Metastases in
regional lymph nodes were detected in the infrapyloric, greater
curvature and anterior superior group of the common hepatic
artery nodes. Conclusive stage grouping according to the
Japanese Research Society for Gastric Carcinoma proved to
be stage IIIb (t3, n2, P0, H0). As adjuvant chemotherapy we
applied methotrexate (MTX)/5-fluorouracil (5-FU) sequential
chemotherapy (MTX; 150 mg/body, 5-FU; 900 mg/body,
every 2 weeks). After five courses of the systemic chemotherapy, a metastatic liver tumor was detected by abdominal
CT, whose size was 40 mm in diameter (Fig. 2). The tumor was
located in the caudate lobe and appeared to involve the main
trunk of the portal vein and inferior vena cava. There were no
other metastases in the lung or brain, and no lymph node
swelling or peritoneal dissemination. ECOG (Eastern Cooperative Oncology Group) performance status of the patient was
grade 2 at the time of diagnosis because of shortness of breath
after daily exercise and general fatigue, although respiratory
function and laboratory tests showed no abnormality. After we
informed her of the disease status, we opted for non-surgical
therapy in consideration of her poor performance status. We
chose concurrent proton beam therapy and systemic chemotherapy for the metastatic liver tumor from gastric carcinoma
after the patient gave her informed consent for this treatment.
Chemotherapy consisted of systemic infusion of 5-FU at a
daily dose of 250 mg/body continuously for 4 weeks and
cisplatin at a daily dose of 10 mg/body on days 1–5, 8–12,
15–19 and 22–26 (Fig. 3).
In the treatment of proton beam therapy, a clinical target
volume was firstly contoured in the radiographically
demonstrated gross tumor with 5 mm adjacent normal tissue
on each CT image of the treatment planning CT and on the
cranio-caudal dimension. Six treatment ports [anterior, posterior, right anterior oblique (330 , 300 ), right posterior oblique
(210 )], a 10 mm treatment margin for uncertainty of the
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Concurrent proton beam radiotherapy and systemic chemotherapy
Figure 3. The treatment schedule performed in this case. The proton beam was
delivered concurrently with chemotherapy in a daily fraction of 3 Gy, 5 days a
week, with a total dose of 66 Gy for 30 days.
Figure 5. CT at 3 months after the proton irradiation and chemotherapy. The
tumor was replaced by fibrous tissue.
Figure 4. Dose distribution of the proton beam to the metastatic liver tumor.
The tumor was satisfactory covered within the 100% dose level and the dose of
the surrounding liver tissue was acceptably low.
positioning and a 5 mm respiratory-gaiting margin to caudal
direction for uncertainty of respiratory gaiting were determined. Optimal parameters were calculated for the beam
delivery system including a length of the spread-out Bragg
peak, range of proton beams, and shapes of compensating
bolus and a collimator size. Dose distribution obtained
using a pencil-beam algorithm showed that the tumor was
satisfactorily covered within the 100% dose level and the
dose of the surrounding liver tissue was acceptably low
(Fig. 4). Patient positioning was adjusted by fluoroscopy at
each treatment session and respiratory-gated irradiation was
used to minimize irradiation of normal liver tissue. The proton
beam was delivered concurrently with chemotherapy in a daily
fraction of 3 Gy, 5 days a week, with a total dose of 66 Gy over
30 days (Fig. 3). During the course of the therapy, leukopenia
of grade 3 was observed through days 10–21 according to the
National Cancer Institute-Common Toxicity Criteria (version
2.0) and she received subcutaneous injections of granulocyte
stimulating factor (GCSF) of 75 mg [50 mg/m2 · body surface
area (1.5 m2)] every day from day 10 to 13 and day 21 to 23.
After the injections of GCSF, her white blood cell count
(WBC) recovered to >3000/mm3. Although she experienced
general fatigue throughout the therapy, she never complained
of abdominal symptoms, such as epigastralgia, nausea or diarrhea during or after the treatment. Serum levels of aspartate
aminotransferase (AST), alanine aminotransferase (ALT),
lactate dehydrogenase (LDH), alkaline phosphatase (ALP)
and g-glutamyl transferase (g-GTP) were within the normal
range. Gastritis or gastric ulcer in the residual stomach was not
observed by gastric endoscopy after the therapy. Three months
after the treatment, the metastatic tumor in the caudate lobe
had completely disappeared and volume reduction of noncancerous liver was not observed on abdominal CT or MRI
(Fig. 5). Oral administration of 300 mg of tegafur has been
continued in the outpatient clinic and she has been free of
recurrence on both blood and radiological examination for
2 years after termination of the therapy (Fig. 6).
DISCUSSION
Despite recent advances in the treatment of metastatic liver
tumors, the prognosis of patients with metastatic liver tumor
from gastric carcinoma is still dismal (1). Curative resection of
a metastatic liver tumor from gastric carcinoma could be
achieved when non-curative factors such as peritoneal dissemination and extensive lymph node metastases do not exist (2).
However, metastatic liver tumors are frequently accompanied
by peritoneal dissemination and multiple metastases in both
lobes of the liver (3), resulting in a curative resection rate of
only 10–15% among all hepatic resections of metastatic liver
tumors from gastric carcinoma (4). In addition, surgical
resection is often difficult because of risk factors related to
the general status of patients. Although the tumor was solitary
and there was no other recurrence in this case, we had to plot
strategies other than surgical resection because of the poor
general condition of the patient.
Jpn J Clin Oncol 2005;35(1)
Figure 6. CT at 2 years after the proton irradiation and chemotherapy. There is
no metastasis and recurrence in the whole abdomen, brain or either lung (images
not shown).
Chemotherapy via the systemic route or arterial infusion
through a catheter in the hepatic artery has been widely studied
in past decades. Patients with metastatic liver tumors from
gastric carcinoma who have survived more than 5 years
with systemic chemotherapy or a combination of hepatic resection, systemic chemotherapy and hepatic arterial infusion have
been reported (5,6). However, we considered that the recurrent
tumor in this case might be less sensitive to chemotherapeutic
drugs, because MTX–5-FU sequential chemotherapy had
already been applied as a post-operative adjuvant therapy.
Therefore, we chose proton beam radiotherapy along with
chemotherapy as the treatment for the metastatic liver tumor
in the caudate lobe. Proton beams have relatively similar biological effectiveness both on the tumor and on the surrounding
normal tissue to X-rays, while dose distribution is completely
different from conventional X-ray radiotherapy (7). Proton
beam therapy has an advantage over conventional X-ray radiotherapy for treating deep-seated tumors, since its dose distribution is more localized to tumors while delivering a lesser
dose to the dose-limiting normal tissues (8). It enables the
delivery of higher doses of radiation to target tumors with
reduced normal tissue complications. Clinically it is widely
used to treat various malignancies such as ocular melanoma,
skull base tumor, lung cancer, esophageal cancer, hepatocellular carcinoma and prostate cancer (9). However, there is no
report so far of proton beam therapy to metastatic liver tumors
from gastric carcinoma. It would be difficult to achieve
curative treatment to the tumor in the caudate lobe with
conventional X-ray radiotherapy because it is located adjacent
to the residual stomach and the tolerance dose of the liver is
limited. Use of proton beam therapy makes it possible to avoid
side effects related to the irradiation of the normal gastric body
while delivering a high dose to the target tumor with curative
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intent. In this case, the metastatic liver tumor has been completely regressed and no recurrence has been detected for
2 years after the therapy. The patient has been free of epigastralgia or upper abdominal discomfort, which may be related to
gastritis or gastric ulcer of the residual stomach. Radiationinduced hepatic injury and volume reduction of the irradiated
liver have not been observed either by CT, MRI or laboratory
tests. The superiority of proton beams may have contributed to
achieving local control of the metastatic liver tumor from
gastric carcinoma and have been beneficial for survival.
Regarding chemotherapy, we chose a concomitant low
dose of 5-FU/cisplatin (FP therapy) to enhance the radiation
effects on the local tumor as well as to control distant micrometastases. FP therapy is a well-established regimen for the
recurrence of various gastrointestinal malignancies (10,11),
including gastric carcinoma (12,13), and has a mechanism
of biochemical modulation of 5-FU anti-tumor effect different
from MTX–5-FU sequential chemotherapy (14). Also, both
drugs have been reported to be radiosensitizers, which enhance
the anti-tumor effects of irradiation (15), in addition to its
direct effect on microscopic nests of cancer cells in the
whole body. Although the dose of 5-FU and cisplatin was
chosen to be low in this case, mainly in order to seek radiosensitizing effects and to reduce severe hematological and
gastrointestinal toxicities (16), the patient experienced hematologic toxicity of grade III during the therapy and received
GCSF injections with success. Total WBC count and number
of granulocytes must be carefully monitored during the therapy
to avoid life-threatening complications due to severe bone
marrow suppression.
In conclusion, concurrent proton beam therapy with systemic chemotherapy using 5-FU and low-dose cisplatin
appeared effective and feasible for the metastatic liver
tumor from gastric carcinoma after surgical resection.
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