Esophageal cancer

Potential of FDG-PET on decision of treatment for esophageal cancer

Author(s)：: Masanobu Nakajima, Yasushi Domeki, Hitoshi Satomura, Masakazu Takahashi, Hiroto Muroi, Satoru Yamaguchi, Kinro Sasaki, Hiroyuki Kato
Affiliation(s)：: Department of Surgery I, Dokkyo Medical University

(Background) The evaluation of FDG-PET as a tool on decision for treatment of malignancies is now controversial. The efficacy of FDG-PET on decision for therapeutic modality was examined on esophageal cancer patients.
(Patients) 272 esophageal cancer patients were treated in our institute. Among them, 166 patients who underwent FDG-PET examination were analyzed.
(Methods)1. Maximum standardized uptake value (SUV Max) of 125 patients who underwent endoscopic or surgical resection was evaluated in every stage, and analyzed if we could decide treatments according to SUV Max. 2. SUV Max before and after neoadjuvant chemotherapy (NAC) were measured on 34 patients. Thereafter, the usability of those values on evaluation of the therapeutic effect was analyzed. 3. SUV Max before and after concurrent chemoradiotherapy (CRT) were measured on 41 patients, and the effectiveness on evaluation of the therapeutic effect was analyzed.
(Results)1. The mean SUV Max of pT1a tumors (n=19) was 1.53, pT1b (n=33) was 4.07, pT2 (n=10) was10.24, pT3 (n=53) is 11.02, and pT4(n=10) was 14.20 (p＜0.05). The cases of pT1a-EP and pT1a-LPM were 11 cases. Among them, 10 cases were not detected by FDG-PET. A case in which FDG was uptaken was superficial carcinoma with circumferential growth. There was no significant difference between pT3 and pT4, therefore, decision whether invasive tumor is resectable or not was thought to be difficult. 2. Among the cases underwent NAC, mean SUV Max before NAC was 16.51 while those after NAC was 8.22, the decrease rate was 50.3%. Histological response after NAC was Grade 0; 3 cases, Grade 1a; 23, Grade 1b; 5, Grade 2; 0, and Grade 3 was 3 cases. When the relationship between the decrease rate of SUV Max and histological effect was analyzed, the all cases who acquired the decrease rate more than 50% were histologically more than Grade 1b. Mean SUV Max after NAC in Grade 3 cases was 1.43. This value was significantly lower than mean SUV Max 7.08 of other histological effect cases (poorer than Grade 1b) (p＜0.05). In the comparison about the superiority as a predictor of histological effect of NAC, the absolute SUV Max after NAC is superior to the decrease rate of SUV Max. 3. Among the cases underwent concurrent CRT, mean SUV Max before CRT was 11.21, meanwhile those after CRT was 2.72. With regard to clinical therapeutic effect, PD is 3 cases, SD is 4, PR is 12, and CR was acquired in 22 cases. CR rate was 53.6%. The mean decrease rate of SUV Max after CRT was 78.1% in CR cases, on the other hand, it was 48% among PD, PR and SD cases. It was statistically significant (p＜0.05). The mean SUV Max after CRT in CR cases was 1.65. It was significantly lower than that of other clinical effect groups (4.37) (p＜0.05). As a predictor of therapeutic effect after CRT, the absolute SUV Max after CRT was thought to be more sensitive than the decrease rate of SUV Max. (Conclusions) SUV Max can become an indicator to decide whether the endoscopic resection is suitable or not. SUV Max after NAC may be a promising factor to predict the histological effect of NAC, and it is possible to lead to the individualized treatment for responders. And also, SUV Max after CRT is useful for predicting clinical effect, and it is possible to become an important indicator to discuss the necessity of additional therapy such as salvage surgery.

Impact of sarcopenia and body weight loss during neoadjuvant chemotherapy the risk of postoperative infectious complications in patients with esophageal cancer

Author(s)：: Tsutomu Hayashi, Soji Ozawa, Kenichi Kamachi, Akihito Kazuno,
Eisuke Ito, Hirohito Miyako, Osamu Chino, Toshio Nagori, Sotaro Sadahiro,
and Seiei Yasuda
Affiliation(s)：: Department of Gastrointestinal Surgery, Tokai University School of Medicine

Background
Malnutrition is common among patients receiving neoadjuvant chemotherapy (NAC) for the treatment of esophageal cancer because of inadequate oral intake resulting from stenosis of the esophagus and gastrointestinal toxicities associated with chemotherapy. Furthermore, recent studies have suggested that sarcopenia occurs in patients with malignancies associated with protein metabolic disorder. Malnutrition and sarcopenia might be risk factors for postoperative complications after an esophagectomy in patients who have received NAC. However, the impact of sarcopenia on postoperative complications has not been previously evaluated. The aim of the present study was to investigate whether sarcopenia occurring in patients who received NAC for esophageal cancer is associated with the risk of postoperative infectious complications. Here, sarcopenia was evaluated by estimating the cross-sectional area of the psoas muscle (CSA) on computed tomography (CT) images.
Methods
Sixty-six patients who underwent an esophagectomy after receiving NAC containing cisplatin/5-fluorouracil (CF) or docetaxel/cisplatin/5-fluorouracil (DCF) at Tokai University Hospital between January 2010 and April 2013 were included in this study. The clinical data and neoadjuvant treatment details (including adverse effects) were collected from the hospital's clinical database. The CSA of the psoas muscle was measured at the level of the L4/L5 intervertebral disk. Measurements were performed semi-automatically by manually outlining the borders of the psoas muscles and calculating the CSA using image processing software (SDS Viewer;, Techmatrix, Tokyo, Japan). The rate of decrease in the body weight (%BW) and the cross-sectional area of the psoas muscle (%CSA) were calculated as follows: 100 x ([pre-NAC BW or CSA value] – [post-NAC BW or CSA value])/pre-NAC BW or CSA value. The cut-off values for %BW and %CSA were defined as 5%. Univariate and multivariate analyses were conducted to explore the risk of postoperative complications in relation to clinical and demographical data (age, BMI, serum albumin [alb], dysphagia and gastrointestinal toxicities), %BW, and %CSA.
Results
The median patient age was 66 years, and the median BMI and serum alb levels were 4.00 mg/dL and 21 kg/m2, respectively. Dysphagia and gastrointestinal toxicities were observed in 17 patients (26%) and 38 patients (56%), respectively. The median %BW and %CSA values were 2.0% and 3.0%. Infectious complications occurred in 30 patients (45%). The number of patients with a %BW and %CSA of more than 5% were 20 (30%) and 27 (41%), respectively. In univariate analyses, age (≥70 years old: odds ratio [OR], 1.737; P = 0.412), BMI (≤18.5 kg/m2: OR, 0.455; P = 0.619), serum alb (≤3.5 mg/dL: OR, 0.269; P = 0.166), dysphagia (OR, 1.500; P = 0.575), and gastrointestinal toxicities (OR, 0.727; P = 0.619) were not associated with infectious complications, whereas %BW (≤5%: OR, 4.375; P = 0.015) and %CSA (≤5%: OR, 6.045; P = 0.001) were associated with infectious complications. In a multivariate analysis, %BW (OR, 3.387; P = 0.049) and %CSA (OR, 5.100; P = 0.004) were independent risk factor for infectious complications.
Conclusions
Sarcopenia and body weight loss occurring during NAC contribute to the risk of infectious complications after an esophagectomy. Especially, sarcopenia has a strong impact on the risk of infectious complications.

Tumor-suppressive effects and mechanism of efatutazone, a novel PPARγ agonist in esophageal squamous cell carcinoma

Author(s)：: Hiroshi Sawayama¹, Takatsugu Ishimoto¹, Masayuki Watanabe¹, Naoya Yoshida¹, Yoshifumi Baba¹, Masaaki Iwatsuki¹, Hidetaka Sugihara¹, Daisuke Izumi¹, Naomi Yokoyama¹, Hiroshi Onuma², Yoshinobu Shiose² and Hideo Baba¹
Affiliation(s)：: ¹Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University. ²Research and development division, Daiichi Sankyo Co.,LTD.

Background & Objective: The peroxisome proliferator-activated receptor gamma (PPARγ) plays various roles in lipid metabolism and inflammatory response, cellular differentiation and apoptosis. The effect of PPARγ is tissue- and cancer-specific, and further investigation into the potential use of PPARγ agonists as anticancer agents is a significant area of anti-cancer research. Efatutazone, a novel and third-generation thiazolidinedione PPARγ agonist, selectively activates PPARγ mediated transcription without little affecting on other PPAR subtypes, and has been demonstrated to have anti-proliferative effects for diverse malignancies. However, the significance of PPARγ expression in esophageal squamous cell carcinoma (ESCC) and the anti-proliferative effects and mechanism of PPARγ agonists remain unclear.
Methods: Immunohistochemical staining was performed using paraffin sections of tissues obtained from the 145 resectable ESCC patients with radical surgery. The anti-tumor effects and mechanism of efatutazone were investigated with ESCC cell lines in vitro and in vivo. Furthermore, we evaluated the optimal combination therapy of efatutazone with molecular targeted agents. The expression levels of mRNA were determined by real-time RT-PCR using TaqMan probes. The total protein levels were evaluated by a Western blotting analysis, and the localization of protein was examined by confocal microscopy. All the procedures involving animals and their care were approved by the Animal Care and Use Committee of Kumamoto University. Informed consent was obtained from the human subjects.
Results: We demonstrated that PPARγ expression, which was detected in the normal esophageal squamous epithelium, was heterogeneous in the tumors of ESCC patients, and exhibited an inverse relationship with the expression of Ki-67, as determined by immunohistochemistry. PPARγ expression is associated with a good prognosis regarding the disease-free survival and esophageal cancer-specific survival in both univariate and multivariate Cox hazard analysis. PPARγ expression was examined of nine human ESCC cell lines, and various levels of PPARγ expression were observed. However, efatutazone demonstrated anti-proliferative effects in all nine ESCC cell lines in vitro. We evaluated the anti-proliferative effect of efatutazone in vivo and a 50.4±13.6% (average ± SD) reduction in tumor volume was observed with treatment using efatutazone compared with the control. Efatutazone appeared to act by upregulating p21Cip1 protein in the nucleus via inactivation of the Akt pathway and dephosphorylation of p21 at Thr145, without affecting the transcriptional activity of p21Cip1. Furthermore, we demonstrated that treatment with efatutazone led to phosphorylation of epidermal growth factor receptor (EGFR) and activation of the mitogen-activated protein kinase (MAPK) pathway. Hence, we tried to use molecular targeted agents in combination with efatutazone to suppress the MAPK or EGFR signaling. We first used MEK inhibitor (U0126) in combination with efatutazone. Inactivation of ERK1/2 was detected after the treatment with efatutazone combined with U0126, however EGFR/AKT signaling was activated by combination treatment compared with the treatment with efatutazone alone, and additive effect was not adequately observed. We then evaluated combination of efatutazone with anti-EGFR antibody (cetuximab) and this combination therapy provided a synergetic effect by negatively regulating both the PI3K-AKT and MAPK pathways in vitro and in vivo.
Conclusions: Our findings are that PPARγ functions as a tumor suppressor in ESCC, and that efatutazone inhibited the proliferation of ESCC cells via inactivation of the AKT pathway. Furthermore, we revealed favorable effects using efatutazone with cetuximab based on a signaling analysis. These results suggest that efatutazone, both alone and in combination with cetuximab, has therapeutic potential for the treatment of ESCC.

A phase II trial of DCF-R in advanced esophageal cancer (KDOG 0501-P2)

Author(s)：: Katsuhiko Higuchi¹, Shouko Komori², Satoshi Tanabe¹, Chikatoshi Katada³, Mizutomo Azuma¹, Hiromichi Ishiyama², Tohru Sasaki¹, Kenji Ishido¹, Natsuya Katada⁴,Kazushige Hayakawa², Wasaburo Koizumi¹
Affiliation(s)：: ¹Department of Gastroenterology, Kitasato University East Hospital, Japan, ²Department of Radiology and Radiation Oncology, Kitasato University School of Medicine, Japan, ³Department of Gastroenterology, Kitasato University School of Medicine, Japan,⁴Department of Surgery, Kitasato University School of Medicine, Japan

Background: In our previous phase I study (Radiother Oncol 2008,87:398), definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) was tolerable and active in patients with advanced esophageal cancer (AEC) and the recommended dose for the phase II study was determined. This phase II study was conducted to confirm the efficacy and toxicity of DCF-R in AEC.
Patients and Methods: Patients with previously untreated carcinoma of the thoracic esophagus who had T4 tumors, M1 lymph-node metastasis, or both received an infusion of docetaxel (35 mg/m2) and an infusion of cisplatin (40 mg/m2) on day 1 and a continuous infusion of 5-fluorouracil (400mg/m2/day) on days 1-5, every 2 weeks, plus concurrent radiation (RT). The total RT dose was initially 61.2, but was lowered to multiple-field irradiation with 50.4 Gy to decrease esophagitis and late toxicity. Consequently, the number of cycles of DCF administered during RT was modified from 4 to 3. After DCF-R, patients received at least 2 cycles of DCF (docetaxel 40 mg/m2 on day 1, cisplatin 60 mg/m2 on day 1, and 5-fluorouracil 600 mg/m2on days 1-5, every 4 weeks). The primary endpoint was the clinical complete response rate (cCRR). Secondary endpoints were tumor response, progression free survival (PFS), overall survival, and safety.
Results: 42 patients (36 men, 6 women) were enrolled. The median age was 62 years (range: 46-75). PS 0/1/2 was 14/25/3. TNM classification T4M0/non-T4M1LYM/T4M1LYM was 20/12/10. The total scheduled dose of RT 61.2Gy /50.4Gy was 12/30 patients. The cCRR was 52.4% (95% CI:37.3-67.5%). According to scheduled dose of radiation, the cCR rates were 33.3% (95% CI: 6.7-60.0%) in the 61.2 Gy group and 52.4% (95% CI: 42.5-77.5%) in the 50.4 Gy group. Grade 3 or higher major toxicities comprised leukopenia (71.4%), neutropenia (57.2%), anemia (16.7%), febrile neutropenia (38.1%), anorexia (31.0%), and esophagitis (28.6%). There was one treatment-related death caused by aspiration pneumonia. Grade 3 or higher late toxicities comprised one pericardial effusion (Grade 4), three cases of esophagitis (Grade 3), and one case of thoracic aortic aneurysm (Grade 3). As of January 2013, the median PFS was 11.1 months (95% CI:6.9-15.3 months) and the median survival time was 23.1 months (95% CI:5.6-40.6 months).
Conclusions: DCF-R frequently caused myelosuppression and febrile neutropenia, but was highly active and suggested be a promising regimen in AEC. The irradiation dose of 50.4 Gy for further studies of DCF-R is recommended.

Detection of circulating tumor cells in patients with un-resectable esophageal
squamous cell carcinoma

Author(s)：: Daisuke Matsushita,　Yoshikazu Uenosono, 　Takaaki Arigami, 　Takahiko Hagihara,
Naoto Haraguchi,　Shigehiro Yanagita, Yasuto Uchikado, 　Hiroshi Okumura,
Shoji Natsugoe
Affiliation(s)：: Department of Surgical Oncology and Digestive Surgery, Kagoshima University, Japan

Background: Esophageal squamous cell carcinoma (ESCC) is a poor prognostic disease among gastrointestinal tract cancers. Furthermore, patients with ESCC have not a few recurrence after curative surgical treatments. In fact, it is clinically difficult to assess the therapeutic curability after surgery and chemo (-radiation) therapy . To date, the presence or absence of circulating tumor cells (CTC) has been reported to be one of recurrent factors in molecular biological studies. Recently, Cellsearch system (CSS) has been developed as a simple blood assay for CTC detection. In the present study, we analyzed CTC using CSS and the relationship between the presence or absence of CTC and the therapeutic efficacy in patients with ESCC.
Methods: CTC was determined by CSS (Veridex; LLC, Raritan, NJ). Initially, cell spiking study using three ESCC cell lines (KYSE50, KYSE220, and KYSE270) was done to assess the sensitivity and specificity of CSS. Next, we examined CTC in 81 patients with ESCC who were received chemo (-radiatio) therapy as the first treatment. All patients had no other malignant disease. In this study, all blood samples (n=81) were collected before treatment. Furthermore, 59 blood samples after chemo (-radiation) therapy were used.
Results: Cell spiking study demonstrated the linear relationship between the expected CTC numbers and the number of CTC determined by CSS in each serial dilution. Before started treatment, CTC positive rate in all patients was 28.4% (23/81). There was significant different of CTC positivity in distant metastasis status. In spite of short term observation, there were significant differences in overall survival time between the presence and absence of CTC (Log-rank test p=0.007). In 59 patients assessed CTC before and after chemo (-radiation) therapy, partial responder (PR) and stable disease (SD), progressive disease(PD) were identified in 28, 12 and 19 patients, respectively. In PR and SD groups, there was only three cases (7.5%) with increase CTC counts. On the other hand, only 4cases (21.1%) were showed decrease CTC counts in PD group. The accuracy rate of CTC for the therapeutic efficacy was 88.1% (52/59), respectively.
The numbers of CTC was not correlated with serum CEA/ SCC level in this patient.
Conclusinos:CTC assay using CSS may have a clinical utility for predicting tumor progression and monitoring the therapeutic efficacy in patients with ESCC.

Preliminary results of proton therapy combined with concurrent chemotherapy for squamous cell carcinoma of the esophagus

Author(s)：: Hitoshi Ishikawa¹, Takayuki Hashimoto¹, Toshiki Ohno1, Masashi Mizumoto¹,Kayoko Ohnishi¹, Teruto Aihara¹, Toshikazu Moriwaki², Katsuji Hisakura³, Hideto Terashima³, Toshiyuki Okumura¹, Hideyuki Sakurai¹
Affiliation(s)：: Department of Radiation Oncology¹, Gastroenterology², and Gastroenterological and Hepatobiliary Surgery³, University of Tsukuba, Faculty of Medicine,

Purpose/Objective(s): Proton beam therapy (PBT), which can deliver a large dose to the tumor and allow the sparing of surrounding normal tissues, is a promising modality for the management of esophageal cancer. The aim of the present study is to evaluate preliminary treatment outcomes of concurrent chemoradiotherpy using proton beams for patients with squamous cell carcinoma of the esophagus.
Materials/Methods: Definitive PBT was performed for 44 esophageal cancer patients between November 2008 and December 2011. Among them, chemotherapy (cisplatin, 70mg/m2 day 1, and and 5-fluorouracil (5FU), 700 mg/m2/24 h on days 1-4, every 28 days, 2-4 cycles) was concurrently combined with PBT for a total of 28 consecutive patients with esophageal squamous cell carcinoma. The subjects in the present study consisted of 26 men and 2 women and their median age was 69 years, ranging from 52 to 79 years. Fifteen subjects (53%) were regarded as inoperable due to deep tumor invasion to adjacent organs and their intercurrent diseases in 3 and 12, respectively, whereas the remaining 13 subjects (47%) refused to receive surgical resection. The tumors were located at cervical, the upper thoracic, middle thoracic, and lower thoracic esophagus in 2, 9, 13, and 4 subjects, respectively. The median primary tumor length was 53 mm, ranging from 10 mm to 120 mm. According to 2009 Union for International Cancer Control TNM staging system, the subjects were stratified into T1 in 11, T2 in 7, T3 in7, and T4 in 3, respectively and stage I in 12, stage II in 8, and stage III in 8, respectively. Before start of PBT, the metallic markers were inserted at the edges of the tumor under endoscopy. A total dose of 60 gray equivalent (GyE) with a conventional fractional dose of 2 GyE was delivered with conformal PBT, and an additional boost of 6 to 10 GyE was given when residual tumors were suspected based on the endoscopic examination and/or esophagography at 50 GyE. Maximum dose to the spinal cord was restricted to 45 GyE. The median follow-up time for survivors was 24 months (range, 7-54 months).
Results: PBT was successfully completed for all subjects, and 2 or more cycles of chemotherapy were also administered for all but one subject. All tumors except one showed definite reduction in the overall sizes; 21 (75%) regressed completely and the remaining 6 tumors (21%) showed partial response at 1-2 month after PBT based on endoscopy, esophagography, and chest CT. Tumor recurrences were observed in 10 (36%) subjects; 5 at the esophagus alone, 1 at mediastinal lymph node alone, 1 at both of the esophagus and mediastinal lymph node, and 3 at the distant organs (lung in 2 and liver in 1). The 2-years disease-specific survival rates of subjects with Stage I-II and Stage III were 100% and 17%, respectively. With regard to treatment-related morbidity, Grade 3 esophagitis and leucopenia were observed in 7 (25%) and in 7 (25%), respectively, as acute toxicities. Regarding late toxicity, esophageal ulcer and stenosis developed in each subject, but there was neither grade 2 nor severe late cardio-pulmonary toxicity in the present study at the current.
Conclusions: Although the number of study subjects was small and the data was immature because of short follow-up time in the present study, almost all treatments were successfully completed and no severe cardio-pulmonary dysfunction was observed. Taking these results into consideration, definitive high-dose PBT concurrently combined with chemotherapy consisted of the standard dose of cisplatin and 5FU seems to be effective and feasible for patients with esophageal squamous cell carcinoma.

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