Prognostic value of desmoplastic reaction characterisation in stage II colon cancer: prospective validation in a Phase 3 study (SACURA Trial).

BACKGROUND: The characterisation of desmoplastic reaction (DR) has emerged as a new, independent prognostic determinant in colorectal cancer. Herein, we report the validation of its prognostic value in a randomised controlled study (SACURA trial). METHODS: The study included 991 stage II colon cancer patients. DR was classified by the central review as Mature, Intermediate or Immature based on the presence of hyalinised collagen bundles and myxoid stroma at the desmoplastic front. All clinical and pathological data, including DR characterisations, were prospectively recorded and analysed 5 years after the completion of the registration. RESULTS: The five-year relapse-free survival (RFS) rate was the highest in the Mature group (N = 638), followed by the Intermediate (N = 294) and Immature groups (N = 59). Multivariate analysis revealed that DR classification was an independent prognostic factor, and based on Harrell's C-index, the Cox model for predicting RFS was significantly improved by including DR. In the conditional inference tree analysis, DR categorisation was the first split factor for predicting RFS, followed by T-stage, microsatellite instability status and budding. CONCLUSIONS: Histological categorisation of DR provides important prognostic information that could contribute to the efficient selection of stage II colon cancer patients who would benefit from postoperative adjuvant therapy.

Our experience of repeat laparoscopic liver resection in patients with recurrent hepatocellular carcinoma.

BACKGROUND: Repeat liver resection is an effective treatment approach for patients with recurrent hepatocellular cell carcinoma (HCC). However, the surgical feasibility and oncological significance of repeat laparoscopic liver resection (r-LLR) remain unproven. This study evaluates and compares the clinical outcomes of non-anatomic r-LLR applied towards recurrent HCC, with those of primary LLR (p-LLR) for primary HCC. METHODS: This retrospective study reports 104 patients with HCC, treated with LLR between 2014 and 2018. Twenty eight of these patients underwent r-LLR for recurrent HCC. The clinical and surgical variables were reviewed for all cases. RESULTS: The analysis was limited to non-anatomic resection across both groups (r-LLR: 89% (25/28) vs. p-LLR: 80% (61/76)). There were no statistically significant differences about patient background between the two groups, with the exception of Child-Pugh classification. r-LLR surgical techniques included single-site laparoscopic adhesiolysis (32%, 8/25), Pringle maneuver (8%, 2/25), and crush-clamp method using BiClamp for hepatic parenchymal transection (72%, 18/25). No severe postoperative complications were observed in the r-LLR group. Postoperative hospital stays and procedure-related postoperative survival were similar for both groups. CONCLUSIONS: Non-anatomical r-LLR renders comparable surgical and oncological outcomes. Our data suggest that non-anatomical r-LLR is a safe and feasible therapeutic approach to recurrent HCC.

Phase II study of 5-fluorouracil-leucovorin plus bevacizumab for chemotherapy-naïve older or frail patients with metastatic colorectal cancer (OGSG 0802).

BACKGROUND: Older or frail patients are often underrepresented in clinical trials for metastatic colorectal cancer (mCRC). We here assessed the efficacy and safety of 5-fluorouracil (5-FU)-leucovorin plus bevacizumab in such patients. METHODS: The study (OGSG 0802) was designed as a single-arm, open-label, multicenter phase II trial. Eligible patients had mCRC and at least one of the following: an age of ≥ 65 years, an Eastern Cooperative Oncology Group performance status of 1 or 2, a serum albumin level of ≤ 3.5 g/dL, incompatibility with oxaliplatin or irinotecan, and a history of abdominal or pelvic radiotherapy. Patients received 5-FU (600 mg/m2) and l-leucovorin (200 mg/m2) on days 1, 8, and 15 together with bevacizumab (5 mg/kg) on days 1 and 15 every 4 weeks. The primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-one patients were enrolled and eligible. Median age was 76 years (range 56-90 years), and 51% of patients had a performance status of 0. The ORR was 36.6% [95% confidence interval (CI) 22.1-53.1%], median PFS was 9.4 months (95% CI 7.4-17.7 months), and median OS was 24.0 months (95% CI 19.9 months-not reached). The most common treatment-related adverse events of grade ≥ 3 were neutropenia (24%), anorexia (10%), leukopenia (7%), and mucositis/stomatitis (7%). There were no treatment-related deaths. CONCLUSION: Weekly 5-FU-leucovorin with biweekly bevacizumab may be a tolerable and effective treatment option for older or frail patients with mCRC.

Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG).

PURPOSE: Oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) is not inferior to standard weekly fluorouracil and folinate for stage II/III colon cancer. However, protein-bound polysaccharide K (PSK) has been evaluated as postoperative adjuvant therapy for colorectal cancer. This report is the first of MCSGO-CCTG, which compared UFT/LV to UFT/PSK as adjuvant chemotherapy for stage IIB or III colorectal cancer in patients who had undergone Japanese D2/D3 lymph node dissection. METHODS: The primary endpoint was the 3-year disease-free survival (DFS). A randomized non-inferiority study compared UFT/LV to UFT/PSK. The overall survival, adverse events, compliance, and quality of life were also investigated as the secondary endpoints. RESULTS: Between March 2006 and December 2010, 357 patients were randomized to UFT/PSK (n = 178) or UFT/LV (n = 179) (median age 65 years, colon/rectum 67.4/32.6%, stage IIB/IIIA/IIIB/IIIC 11.1/15.7/55.0/18.2%). The 3-year DFS rate was 82.3% in those receiving UFT/LV and 72.1% in those receiving UFT/PSK. The non-inferiority of UFT/PSK adjuvant therapy to UFT/LV therapy was not verified (-9.06%, 90% confidence interval -17.06 to -1.06%). The 3-year overall survival rate was 95.4% in those receiving UFT/LV and 90.7% in those receiving UFT/PSK. CONCLUSIONS: As adjuvant chemotherapy for stage IIB and III colorectal cancer patients, UFT/PSK adjuvant therapy was not non-inferior to UFT/LV therapy with respect to the DFS.

[Improvement of Pain Control after Dealing with Chemical Coping-A Case of Local Recurrence of Rectal Cancer].

A 57-year-old female underwent abdominoperineal resection for rectal cancer. Although she received postoperative adjuvant chemotherapy, she had presacral recurrence with pain 26 months postoperatively. We provided palliative care in parallel with systemic chemotherapy, but she had difficulty controlling pain despite using high-dose opioids at 43 months after surgery. Multimodal therapy contributed to a reduction in opioid use for a brief time. Nevertheless, she required high-dose opioid therapy again at 50 months after the procedure. Since she used a rescue dose for relieving anticipatory anxiety for pain, we estimated that she developed chemical coping. After we tried analgesic adjuvant therapy and psychotherapy, her opioid use was reduced. For 10 months afterward, her disease worsened with time, but her pain was well-controlled. In cases where it is difficult to control pain, protection against exacerbation or opioid dose escalation should be considered. Furthermore, psychological contexts, including chemical coping, should also be considered. It may lead to the use of a proper dose of opioids and improve quality of life for patients.

Clinical outcomes and prognostic factors for gastric cancer patients with bone metastasis.

BACKGROUND: Bone metastasis due to gastric cancer is rare, and the clinical features have not been fully evaluated. We investigated the clinical features, treatment outcomes, and prognostic factors in gastric cancer patients with bone metastasis. METHODS: We retrospectively collected data on 34 consecutive patients who were diagnosed radiologically with bone metastasis due to gastric cancer. We estimated the overall survival after the diagnosis of bone metastasis using the Kaplan-Meier product-limit method and evaluated which clinicopathological factors were associated with prognostic factors for survival using univariate and multivariate Cox proportional hazards regression models. RESULTS: The treatment for the primary tumor was surgery in 16 patients (47.1%) and chemotherapy in 18 patients (52.9%). The median serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels at the time of bone metastasis were 375.5 and 249 IU/L, respectively. Ten patients (29.4%) were diagnosed with bone metastasis and gastric cancer at the same time. The 6-month survival rate after the diagnosis of bone metastasis was 63.8%, and the median survival time was 227.5 days. Multivariate analysis revealed that metachronous metastasis (p = 0.035) and extraosseous metastasis (p = 0.028) were significant risk factors for poor survival. CONCLUSIONS: The prognosis of gastric cancer with bone metastasis was poor, and metachronous metastasis and extraosseous metastasis were shown to be poor prognostic factors. Serum ALP, LDH, and tumor markers are not always high, so aggressive diagnosis using appropriate modalities such as bone scan, MRI, or PET-CT may be necessary in routine practice even in asymptomatic patients.

[A Case of Self-Expandable Metallic Stent Placement to Treat Colon Obstruction Due to Metastatic Gastric Cancer].

A66 -year-old woman presented with abdominal pain and nausea. She was diagnosed with wall thickening of the gastric antrum and bowel obstruction caused by tumors of the splenic flexure on computed tomography. Aself -expandable metallic stent(SEMS)was placed in the splenic flexure of the colon 4 days after transanal ileus tube replacement. No complication was observed, and she could ingest a normal diet, permitting her discharge from the hospital 12 days after SEMS placement. She was diagnosed with gastric cancer(Type 4, cT4a[SE], N2, H0, P1, M1[LYM], cStage IV )on upper gastrointestinal endoscopy and computed tomography, and administration of S-1 plus oxaliplatin(SOX)was started. Nab-paclitaxel as the second-line chemotherapy was administered after 8 courses of SOX therapy because of an increase in the amount of ascites. No late complication associated with stent placement was recognized. SEMS placement was suggested to be effective for treating colon obstruction due to metastatic gastric cancer.

[A Case of Laparoscopic Resection of Sigmoid Colon Cancer Complicated by an Iliopsoas Abscess Preceded by Abscess Drainage].

For colon cancer complicated by iliopsoas abscess, it is unclear whether surgery should be performed prior to abscess drainage. We were able to perform laparoscopic sigmoid resection safely after first draining the abscess. We believed it would be beneficial to avoid surgery in the presence of abscess and inflammation, and the minimally invasive operation was performed after improvements of the patient's general status and inflammation.

[Examination of Patients with Malignant Obstruction Treated with Chemotherapy after Ileo/Coleostomy].

Management for obstructive cancer of the colon diverges into many ways. The aim of this study was to evaluate the treatment course of patients with malignant obstruction after ileo/coleostomy. Thirty-six patients with malignant obstruction who underwent ileo/coleostomy in our hospital from May 2012 to January 2016were enrolled in the study. Clinical outcomes were the period before treatment initiation, chemotherapy, radiotherapy, primary lesion resection, and death, and these were retrospectively analyzed. Although 9 stomal complications occurred, no case experienced a delayed treatment start. However, patients with perioperative complications, sepsis due to the tumor, pneumonia, cerebral infractions, and ileus needed a long recovery period before treatment initiation. Patients who need ileo/coleostomy must be considered for performance status and ways to decrease perioperative complications to prevent stomal complications from chemo/radiotherapy.

[Three Cases of Bleeding from Advanced Gastric Cancer during Chemotherapy Treated with Transcatheter Arterial Embolization(TAE)].

Case 1: An 71-year-old man underwent chemotherapy with S-1 plus trastuzumab to treat type 3 gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4b[Panc], N3, H0, CY1, P0, M1). For anemia and active bleeding from the tumor, transcatheter arterial embolization(TAE)was performed with metallic coils on the splenic artery. Infarction of the spleen and left pleural effusion were observed. Second-line paclitaxel(PTX)chemotherapy was administered 4 weeks after TAE. Case 2: An 76-year-old man underwent chemotherapy with S-1 plus cisplatin to treat type 3 gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4a, N3, H0, P1, M1). For anemia and active bleeding from the tumor, TAE with gelatin sponge(Serescure®)was performed on the left and right gastric artery. Radiotherapy(31 Gy)with S-1 was performed because TAE was not effective for bleeding. After chemoradiotherapy, nab-PTX was administered. Case 3: An 74- year-old man underwent second-line chemotherapy with nab-PTX to treat type 4 advanced gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4a, N3, H1, P0, M1). For progression of anemia due to tumor bleeding, TAE with gelatin sponge(Serescure®)was performed on the left gastric artery. TAE was effective, and he was discharged from the hospital. In 2 of 3 cases, hemostasis was achieved by TAE. Therefore, TAE is effective to decrease bleeding from gastric cancer during chemotherapy.

[A Case of an Elderly Patient with Unresectable Gastric Cancer Treated by Paclitaxel and Ramucirumab].

An 80-year-old man was admitted to our hospital with appetite loss in December 2014. Gastroduodenal scope, abdominal computed tomography(CT), and laparoscopy revealed type 4 advanced gastric cancer(poorly differentiated adenocarcinoma) with multiple lymph node(LN)involvement and multiple peritoneal metastasis. S-1(80mg/body)was administrated between January 2015 and September 2015 in the outpatient clinic. A partial response was obtained, but a gastric tumor, ascites, and LN re-growth were observed. Since October 2015, paclitaxel(PTX)(70mg/m2; day 1, 8, and 15)and ramucir- umab(RAM)(8mg/kg; day 1 and 15)have been administered. After 2 courses, bi-weekly PTX plus RAM were continued for grade 3 neutropenia and grade 2 anorexia. The tumor and LNs partially responded, and the ascites disappeared. With this dosage and administration schedule, the partial response(PR)was maintained for approximately 8 months without any severe adverse reactions. This successful case might indicate that it is important for elderly patients with gastric cancer that progressed with prior chemotherapy regimens to consider appropriate reduction of the PTX dosage, schedule, and continuation of RAM.

[Clinical Experience of Ramucirumab for Treating Advanced Gastric Cancer].

BACKGROUND: The REGARD and RAINBOW trials showed that ramucirumab(RAM)alone and RAM plus paclitaxel(PTX) were effective therapies for advanced gastric cancer patients previously treated with chemotherapy. In this retrospective study, we evaluated the safety and efficacy of RAM alone and PTX plus RAM in such patients. METHODS: Patients who were received RAM at 8mg/kg or RAM plus PTX at 80mg/m2(on days 1, 8, and 15 of a 28-day cycle)between June 2015 and March 2016 were enrolled in this study. We compared the clinical outcome of RAM alone(RAM group, n=10)with that of RAM plus PTX(PTX+RAM group, n=13). RESULTS: The RAM group contained many more patients with poor performance status or prior chemotherapy of 2 or more regimens than the PTX+RAM group. All patients in both groups received chemotherapy on an outpatient basis. One case of grade 3 or 4 hematological adverse events was found in the RAM group and 6 cases were found in the PTX+RAM group. The overall response rate was 10% in the RAM group and 30% in the PTX+RAM group. Progression-free survival was 54 days in the RAM group and 187 days in the PTX+RAM group(p=0.0374). Overall survival was 158 days in the RAM group and was not reached in the PTX+RAM group(p=0.1091). CONCLUSIONS: RAM alone and RAM plus PTX can be administered safely on an outpatient basis and are beneficial for advanced gastric cancer patients previously treated with chemotherapy.

Phase II Study of Oral Tegafur/Uracil and Leucovorin plus Bevacizumab as a First-Line Therapy for Elderly Patients with Advanced or Metastatic Colorectal Cancer.

BACKGROUND/OBJECTIVE: Oral tegafur/uracil and leucovorin (UFT/LV) therapy is effective and safe for elderly patients with advanced or metastatic colorectal cancer (CRC). However, there are few studies on the combination of bevacizumab with UFT/LV. This clinical study evaluated the efficacy and safety of UFT/LV plus bevacizumab as a first-line therapy for elderly patients with advanced or metastatic CRC. METHODS: Forty patients with advanced or metastatic CRC aged ≥ 75 years were enrolled in this multicenter, open-label, single-arm phase II study. All patients received oral UFT (300-600 mg) and LV (50 mg) twice daily on days 1-21 and intravenous bevacizumab (5 mg/kg) on days 1 and 15 of a 4-week cycle (University Hospital Medical Information Network No. UMIN000003447). RESULTS: The median follow-up period was 14.7 months. The response rate was 20.0% [95% confidence interval (CI): 9.1-35.6], median progression-free survival was 8.9 months (95% CI: 5.3-11), and median overall survival was 21.7 months (95% CI: 13.7-23.4). The only grade 3 hematological toxicity was neutropenia (3.0%), and the incidence rates of grade 3 nonhematological toxicity were low at ≤ 10%. CONCLUSION: UFT/LV plus bevacizumab is a promising first-line regimen for elderly patients with advanced or metastatic CRC. The combination is well tolerated and efficacious.

[Efficacy and Safety of Pertuzumab for HER2-Positive Metastatic Breast Cancer].

The CLEOPATRA trial showed a significant improvement in the progression-free survival (PFS) and overall survival of patients with HER2-positive first-line metastatic breast cancer (MBC) who were treated with pertuzumab (PER), trastuzumab (TRA), and docetaxel (DTX), compared to those treated with placebo, TRA, and DTX. PER was approved in 2013 for treating HER2-positive MBC in Japan. Herein, we present the retrospective review of data from 10 HER2-positive MBC patients who received PER in our hospital between September 2013 and August 2014.T he median age was 52 years (range, 45-66 years), and 7 patients were positive for ER.Six patients had not received any previous chemotherapy for their metastatic disease, while the others had received comparatively heavy pretreatment doses of chemotherapy.Our patients received the PER, TRA, and DTX regimen, although 2 patients were treated without DTX. Four patients experienced a partial response, 6 patients experienced stable disease (SD), and 3 patients experienced SD for ≥6 months. The response rate was 40%, and the clinical benefit rate was 70%.The median PFS was 7.3 months (range, 2.5-11.5 months). Grade 3 neutropenia and allergic reactions were observed in 1 and 2 patients, respectively; no Grade 4 adverse events were observed, and thus, the regimen was well tolerated. Further clinical research seems to be warranted for developing new treatment strategies involving PER for HER2-positive MBC.

[Three Cases of Bleeding from Advanced Gastric Cancer Treated by Transcatheter Arterial Embolization(TAE)and Continued Chemotherapy].

Case 1: A man in his 70s was underwent transcatheter arterial embolization (TAE) because of progressive anemia, and the gastroduodenal artery and left gastric artery were embolized. Two weeks later, he started chemotherapy (S-1, Tmab). Case 2: A man in his 60s was underwent TAE because of anemia. The left gastric artery and right gastroepiploic artery were embolized. Bleeding was controlled and he continued chemotherapy. Case 3: A man in his 70s was who vomited blood during the course of chemotherapy underwent TAE, during which contrast dye extravasated from the anterior gastric artery. The splenic artery was embolized. After TAE, abdominal pain and splenic infarction appeared, but could be treated by conservative therapy. Chemotherapy was started 4 weeks later. TAE is an effective method for controlling bleeding from advanced gastric cancer.

[A Case of Disseminated Carcinomatosis of the Bone Marrow with Disseminated Intravascular Coagulation Caused by Cecal Cancer Successfully Treated with mFOLFOX6].

Disseminated carcinomatosis of the bone marrow is often accompanied by disseminated intravascular coagulation syndrome (DIC). This condition is rarely caused by colorectal cancer, and there are no established therapies. OUR CASE: A 66-year-old woman was admitted to our hospital because of DIC. She had been diagnosed with cecal cancer and multiple metastases of the lymph nodes, liver, and bone. She was diagnosed with disseminated carcinomatosis of the bone marrow and treated with systemic chemotherapy by modified FOLFOX6 (mFOLFOX6). Subsequently, the DIC rapidly resolved, and she was discharged from the hospital.

[Examination of the Usefulness of Palliative Self-Expanding Metallic Stents in Patients with Malignant Colorectal Obstruction].

Self-expanding metallic stents (SEMS) are a useful palliative option in malignant colorectal obstruction. The aim of this study was to evaluate the clinical outcomes of SEMS used for palliation. Patients with malignant colorectal obstruction who underwent SEMS insertion in our hospital from April 2014 to March 2015 were enrolled in the study. Clinical outcomes and complications of palliative SEMS insertion were retrospectively analyzed. Nine patients were enrolled in the palliative SEMS group. The success rate was 100%, while the complication rate was 11%. Successful SEMS insertion may enable oral intake in a few days, but 3 patients required up to several weeks to resume oral intake. Palliative SEMS are effective and beneficial for malignant colorectal obstruction.

[A Case of Bone Metastasis from Early Gastric Cancer after a Five-Year Disease-Free Interval Following Gastrectomy].

A woman in her 50s underwent distal gastrectomy and D1+b dissection in December 2005 for early gastric cancer that was diagnosed as a signet-ring-cell carcinoma, fStage Ⅱ (T1a, N2, H0, P0, CY0, M0) with 12 lymph node metastases in the second field. Multiple bone metastases were diagnosed on the basis of CT and bone scintigraphy findings and serum ALP elevation (2,743 IU/L) I n December 2010. Fourteen courses of S-1 plus CDDP and 4 mg of zoledronate were administered from January to September in 2011. Pancytopenia, D-dimmer elevation, myelocytes, and metamyelocytes were observed in October 2012, indicating she had bone marrow metastasis. She was treated with a transfusion, anti-DIC therapy, and paclitaxel. She died from gastric cancer in December 2012. We report a rare case of recurrence with bone metastasis from early gastric cancer. S-1 plus CDDP chemotherapy and zoledronate therapy is an effective treatments for multiple bone metastases from gastric cancer.

[A Case of Rectal Stenosis For Gastric Cancer Recurrence Effectively Treated with a Colonic Stent].

A man in his 70s underwent distal gastrectomy and D1 dissection with Roux-en-Y reconstruction in March 2009 for advanced gastric cancer with peritoneal metastasis. He was diagnosed with signet-ring cell carcinoma, Stage Ⅳ(T4a, N3a, H0, P1, CY1, M1) and R2. Seventeen cycles of S-1 plus CDDP were administered from April 2009 to December 2010 and 19 cycles of S-1 monotherapy were administered from January 2011 to March 2014. He developed peritoneal recurrence with serum tumor marker elevation in May 2014. Stenosis of the common bile duct, hydronephrosis, and rectal stenosis in Ra-Rs was observed in June 2014. A bile duct stent and a double J catheter was inserted. A colonic stent (NitiTM, 22 mm×6 cm) was also inserted. He could eat after the surgery and was discharged from the hospital. We suggest that a colonic stent is an effective treatment for colon stenosis due to peritoneal metastasis from gastric cancer.

[Two Cases of Bleeding Advanced Gastric Cancer Treated with Palliative Radiation Therapy].

Case 1: A man in his 70's was being treated with chemotherapy for unresectable advanced gastric cancer. Blood transfusion, endoscopic intervention including argon plasma coagulation, and transcatheter arterial embolization (TAE) were all used to treat repeated tumor bleeding causing anemia, but controlling the bleeding was difficult. In order to control the hemorrhage, radiation therapy of 31 Gy/10 Fr to the cancer was administered. After receiving radiation therapy, the anemia stopped. Case 2: A man in his 70's considered an operation for advanced gastric cancer, but his cardiac performance was poor and it was impossible to perform an operation. We conducted radiation therapy of 39 Gy/13 Fr for the purpose of preventing bleeding from gastric cancer. After receiving radiation therapy, the anemia stopped. We believe that radiation therapy is effective to stop bleeding from gastric cancer.