Original Article
Death Related to Pleural and Pericardial Effusions Following
Chemoradiotherapy in a Patient with
Advanced Cancers of the Esophagus and Stomach
Naoyuki Shigematsu,1 Naoto Kitamura,1 Yoshirou Saikawa,2 Eiji Ikeda,3Jun-ichi Fukada,1 Etsuo Kunieda,1 Yuko Kitagawa,2 Keiichi Fukuda4 Yasunori Okada,3 Atsushi Kubo1

Department of Radiology, Keio University, School of Medicine
2
Department of Surgery, Keio University, School of Medicine
3
Department of Pathology , Keio University, School of Medicine
4
Department of Internal Medicine, Keio University, School of Medicine
1(Received for publication on June 4, 2007)(Revised for publication on August 30, 2007)(Accepted for publication on September 20, 2007)

Abstract. Chemoradiotherapy improves therapeutic outcome in many different types ofcancer. However, there is concern about the occurrence of delayed complications, as patients are surviving longer. Because patients with esophageal cancer receive a wide rangeof irradiation field to the mediastinum and the heart, they may have delayed complicationsof heart and lung functions as previously reported in Hodgkin’s disease. We presented a caseof death related to uncontrollable pleural and pericardial effusions in a patient with advanced cancers of the esophagus and stomach who achieved a complete remission following
chemoradiotherapy and salvage gastric resection, focusing on detailed pathophysiologicalconditions related to concurrent chemoradiotherapy. (Keio J Med 56 (4) : 124－129, December
2007)
Key words: esophageal cancer, chemoradiation, pleural effusion, pericardial effusion.

Introduction
Chemoradiotherapy improves therapeutic outcome inmany different types of cancer, including cancer of thehead and neck, esophagus, lung and uterine cervix, andbiological basis for chemoradiotherapy has been reported.1 More recently, patients with gastric cancer havebeen reported to achieve a complete remission following
chemoradiotherapy,2, 3 although irradiation has scarcely
been used in gastric cancer so far. Chemoradiotherapy,
which has been conventionally performed mainly for inoperable esophageal cancer, is currently used in the treatment even for early esophageal cancer and there is a report stating that it is comparable to surgery in terms oftherapeutic outcome.4 Nevertheless, patients treated withchemoradiotherapy are considered to be at an increased
risk for potentially concurrent adverse effects of irradiation and chemotherapy. There is concern about the occur-

rence of delayed complications, as patients are surviving
longer owing to the improvement of therapeutic outcomeof chemoradiotherapy. Because patients with esophageal
cancer receive a wide range of irradiation to the mediastinum and the heart, they may have complications, including pleural effusions due to mediastinal fibrosis, as
previously reported in post-irradiation complications in
Hodgkin’s disease.5-1 0 We encountered a patient withadvanced synchronous cancers of the esophagus andstomach who achieved a complete remission withchemoradiotherapy, followed by salvage resection ofgastric cancer, but died of uncontrollable massive pleuraland pericardial effusions. Pathological findings frompostmortem examination were available. We report herein a case of death related to pleural and pericardial effusions following chemoradiotherapy, focusing on detailed
pathophysiological conditions related to concurrent
chemoradiotherapy.

Corresponding Author: Naoyuki Shigematsu M.D. Tel 03-3353-1211 Fax 03-3359-7425 Department of Radiology, Keio University School of Medicine, 35
Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. shige@rad. med. keio. ac. jp124Keio J Med 2007; 56 (4): 124－129

Case Presentation
A 71-year-old male developed difficulty swallowing inJanuary 2003. Detailed examinations conducted in February led to the diagnosis of advanced cancers of theesophagus (Squamous cell carcinoma, LtMt- , Type2,
T3N3M0, stage III) and the stomach (Well differentiateda d e n o c a r c i n o m a ( t u b 1 ) , G r o u p V, U L e s s - A n t
cType2T3(SE)N2M0, T3N2M0, stage IIIB). Fig. 1
shows endoscopic photos and pathological findings ofspecimens. External irradiation was given at a total doseof 60 Gy in 30 fractions of 2 Gy each during a period
from March through April, while reducing the irradiation
field to the primary esophageal and gastric cancer lesions(Fig. 2). Simultaneously, CDDP was administered bydrip infusion at a dose of 6 mg/m2 and 120 mg of TS-1
was orally administered on the day of radiotherapy. Endoscopic and pathological assessment of response to
chemoradiotherapy, conducted in May, revealed a complete response for esophageal cancer and a partial response for gastric cancer (Fig. 3). Subsequently, the control of the esophageal lesion was persistent, but the gastric lesion gradually increased in size. Thus, chemotherapy, consisting of drip infusion of CDDP at a dose 10 mg/
week and oral TS-1 at a dose of 120 mg/day, was started
in December 2003 and continued for one month. However, because no favorable outcome was attained, the patient underwent total gastrectomy with D1+ β dissection
and Roux-en-Y gastric bypass in February 2004. Although histopathological diagnosis of the stomach was amoderately differentiated tubular adnocarcinoma withInf β, int, ss, ly1, v1, pPM (-), pDM (-), and n2 (+), postoperative pathological examination judged lymph node
involvement as (-) (Fig. 4). The patient was followed on
an outpatient basis. A follow-up CT scan obtained in October revealed a small amount of pericardial effusions, aswell as pleural effusions on the left side (Fig. 5). In November, the patient was readmitted to our hospital because of he had developed dyspnea and edema of thelower extremities. On admission, his body temperature
was 36.7℃, blood pressure 114/83mmHg. Blood gas
analysis values on room were pH7.501, PaCO 2
31.3mmHg, PaO2 66.4mmHg, HCO3 24.2mmol/l, BE
1.3mmol/l, and SaO2 93.5%. Blood chemistry revieled
mild liver dysfunction, with WBC7000/μl, Hb 14.7g/dl,
Plt 11.1x104/μl, TP 7.0g/dl, Alb 3.2g/dl, TB 2.4mg/dl(DB 1.0mg/dl), BUN 34.4mg/dl, Cr 1.0mg/dl, AST
57IU/L, ALT 34IU/L, LDH 389IU/L, ALP 494IU/L,
AMY30IU/l, and CRP 0.16mg/dl. These elevated parameters had declined on the second day and normalized
within a few days. Tumor markers were within normal
limits; CEA 2.0ng/ml, CA19-9 18.0ng/ml, and SCC
0.2ng/ml. Chest CT scan showed a large bilateral pleuraland pericardial effusions without thickening of either thevisceral or the parietal pleura and no pulmonary masses

125

were detected (Fig. 6). There was no remarkable mediastinal lymphadenopathy. CT scan and ultrasonography of
the abdomen revealed edema of the mesenterium andmild ascites, but no remarkable hepatic findings, such as
dilated bile ducts, liver-enlargement, or splenomegaly.
There was no detectable lymph node swelling, nor was
there any evidence of deep venous thrombosis.
A consulting cardiologist assessed the patient’s cardiac
function using echocardiography and recommended diuretics and steroids. A 20 mg dose of furosemide and 16
mg of dexamethasone were infused continuously, and for
3 days 20 g/day of albumin were given followed by a
100 mg bolus shot of potassium canrenoate. A repeat ofchest X-ray showed no significant changes in the pleural
effusion. The cardiologist re-assessed the cardiac function, and judged pericardiocentesis to be unnecessary.
Bilateral-thoracentesis and drainage were then performed. The drained fluid was clear and yellowish. Repeated pleural effusion cultures were all negative. In addition to surgical drainage, the aforementioned medications were continued. Dexamethasone was tapered to
8mg on the 6th day and continued for additional 6 days.
The furosemide was raised to 40mg/day. And administration of 20g of albumin per day was continued until death.
Difficulty breathing was transiently alleviated, but jaundice and generalized edema progressed rapidly, ultimately leading to the patient death in December. The cardiologist evaluated our patient’s cardiac function several
times and consistently confirmed that pericardiocentesis
was not necessary, even as late as the day before death.
Five cytological examinations of pleural effusion fluids
were conducted during the clinical course. Two consecutive results were class II. The third result was class III,
showing atypical large cells, but the pathologist suggested that these findings might be attributable to inflammatory reaction. The last two cytological examinations wereboth consistent with class I. An autopsy was performed
after obtaining the family’s consent. Pathological postmortem examination revealed no evidence of recurrent
cancer of the esophagus or stomach, including the lymph
node area. There was a finding of fibrinous pericarditis
in the heart (Fig. 7), causing cardiac tamponade associated with pericardial effusions of 1000 ml (thin bloody).
This may in turn have resulted in marked findings, suchas congestive edema of the bilateral lungs (left: 520 g,right: 780g) (Fig. 8 A, B), pleural effusions (left: 2000
ml, right: 1000 ml), and severe hepatic congestion (970g) (Fig. 8 C, D). Furthermore, abdominal ascites (680ml) and generalized edema were noted, as well as fibrinous pleuritis in the lungs (Fig. 9). Secondary finding associated with irradiation in the lower part of the thoracic
spine area was markedly hypocellular marrow, composedlargely of fat cells.

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Shigematsu N, et al: Effusions by Radiotherapy for Esophagus

Fig. 1 Esophageal lesion is endoscopically shown as LtMt 1/3Circ. Type 2 (A) and pathologically as moderately differentiatedsquamous cell carcinoma (B); gastric lesion is endoscopically shown as U Less-Ant eType2 (C) and pathologically as moderately
differentiated tubular adenocarcinoma (D).

Fig. 2 A wide-range of irradiation of 30 Gy was delivered through two antero-posterior opposed fields to the lower part of theesophagus and the stomach, including the surrounding lymph node area, followed by irradiation of 30 Gy limited to the esophageal andgastric lesions. Last 14 Gy of a total dose of 60 Gy was given through two oblique fields, excluding the spinal cord from the irradiation
field.

Fig. 3 Both endoscopic and pathologic findings of the esophageal
lesion show CR (A, B); for the gastric lesion an endoscopic
finding show PR, although a markedly reduced tumor can be seen(C), but pathologically residual cancer cells can be seen, although
they were few (D).

Fig. 4 Specimen collected after total gastrectomy reveals
macroscopically residual cancer (A) and microscopicallyregrowth of cancer cells (B). Residual cancer cells can behistopathologically seen as moderately differentiated tubular
adenocarcinoma with Inf β, int, ss, ly1, v1, pPM (-) and pDM (-),
but lymph node metastasis is negative (C).

Keio J Med 2007; 56 (4): 124－129

Discussion
Pulmonary complications of irradiation for chest lesions, especially radiation pneumonitis, have been so far
frequently reported.11-15 However, data concerning postirradiation pleural effusions are limited to case reports of
Hodgkin’s disease.5, 6, 10 There are also only a few reportson pericarditis and myocardial infarction associated with
irradiation.7-9 Conventional radiotherapy for esophageal
cancer is usually indicated for advanced cancer. In view ofthe fact that the rate of curable advanced cancer is low,
no report is available concerning delayed complicationsof radiotherapy. Recently, the number of curable advanced esophageal cancer has also increased as a resultof chemoradiotherapy.4 Ishikura et al. reported complications following definitive chemoradiotherapy for esophageal cancer. In their report, complete remission was attained in 78 of 139 patients treated with chemoradiotherapy, and ten of these 78 patients had pleural and pericardial effusions and five died of intercurrent disease.1 6 In
the case of this study, the patient had synchronous advanced cancers of the esophagus and stomach. In addition, because the patient was elderly, radical surgery or
treatment with curative intent was unlikely. However, thepatient remarkably responded to chemoradiotherapy.
Complete response of esophageal cancer to chemoradiotherapy was achieved, and subsequently the patient underwent salvage surgery for gastric cancer, leading tocomplete remission of double cancer. However, massive
pleural and pericardial effusions thereafter occurred andwere uncontrollable. Ultimately, the patient died of theseeffusions. An autopsy was performed and detailed findings were available concerning pathophysiologic conditions of pleural and pericardial effusions related tochemoradiation.
There was no pathological evidence of recurrence ofesophageal or gastric cancer. Cancerous lesions had completely resolved. In this patient, fibrinous pericarditis
was the most outstanding feature that may have beencaused by irradiation. Such pericarditis was associatedwith pericardial effusions, thereby resulting in cardiac
tamponade. Possible causes of death in this patient werecardiac tamponade-associated congestive edema andpleural effusions of the bilateral lungs and hepatic congestion. Pleuritis was also noted outside the irradiation
field, as well as within it, which appeared to be a secondary finding due to thoracocentesis and an indwellingdrainage catheter.
Life prolongation might have been expected by pericardiocentesis. However, pericardiocentesis was not performed in this patient. According to echocardiography,
the ejection fraction was sufficiently high (80%), and the
cardiologist concluded that there was no evidence of cardiac tamponade. Moreover, with laboratory results yielding no evidence of recurrence, the pericardial effusions

127

were highly likely to have been associated with cancer
recurrence.
When pleural and pericardial effusions have occurred
after chemoradiotherapy for esophageal cancer, it may bedifficult to determine whether such effusions occur associated with treatment or cancer recurrence, leading todifficulty in the selection of appropriate treatment. Pericardiocentesis may be helpful in prolonging patient’s life
if pleural and pericardial effusions are related to treatment, like in this patient. With this in mind, accurate diagnosis and careful assessment of such pleural and pericardial effusion are required. The patient received 46 Gyof conventional two antero-posterior opposed fields irradiation to the slightly left side of the mediastinum and 14
Gy of two opposed fields irradiation upward to the rightand downward to the left. Thus, high-dose irradiation
was given to the mediastinum, heart, and inner side ofthe left lung field. Therefore, it is highly likely that thepatient may have first had pericardial effusions and pleural effusions on the left side, followed by cardiac tamponade occurring in association with an increased
amount of pericardial effusions. This may in turn have
led to hepatic congestion and generalized edema. It
seems essential to avoid unnecessary irradiation to themediastinum and heart in planning radiotherapy foresophageal cancer, by employing three-dimensional radiotherapy planning, including multi-portal irradiationand intensity modulated radiation therapy,1 7-1 9 that has
already been used in radiotherapy for other types of cancer.
Conclusions
We presented a case of death related to uncontrollable
pleural and pericardial effusions in a patient with advanced cancers of the esophagus and stomach whoachieved a complete remission following chemoradiotherapy and salvage gastric resection. When pleural andpericardial effusions have occurred following chemoradiotherapy for esophageal cancer, physicians must consider the possibility of treatment-related complications.
Three-dimensional treatment planning will also be needed in irradiation for esophageal cancer.
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Shigematsu N, et al: Effusions by Radiotherapy for Esophagus

Fig. 6 A large amount of pleural effusions on the bilateral sides
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Fig. 7 The serosal surface of heart is macroscopically coated withthe exudate (A), and microscopically the exudate comprises fibrin
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