Burak Sakar

Long-term survival after curative resection for pancreatic ductal adenocarcinoma

4227 Background: The aim of the study was to determine prognostic factors of long-term survival after curative surgical treatment for pancreatic cancer. METHODS Between 1994 and 2000, resection with curative intent was performed on 75 patients with pancreatic ductal adenocarcinoma admitted to Department of Surgery, Medical Faculty of Istanbul. Clinical and demographic features, postoperative adjuvant treatment (5-fluorouracil continuous infusion and external beam irradiation concomitantly), and pathologic variables were analyzed. RESULTS A total of 75 patients was included in the final analysis. The median survival after surgery for all 75 patients was 11.6 months (95% CI: 10,00-13,34). Overall survival was influenced by postoperative adjuvant therapy (p=0.001), T stage of the disease (p=0.001), postoperative high level of CA19-9 (p=0.006) and nodal status (p=0.02). Location of the tumor was not prognostic for survival, although it was close to statistical significance (p=0.058). Multivariate analysis showed that T stage of the disease (p=0.001) and presence of adjuvant therapy (p=0.001) independently correlated with overall survival. CONCLUSIONS Based on the analysis carried out, the authors conclude that the main prognostic factors for long-term survival after pancreatic cancer surgery are related to the tumor itself and adjuvant chemoradiation therapy which significantly improves survival after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas. No significant financial relationships to disclose.

Anemia in oncology practice: relation to diseases and their therapies.

Anemia is common in patients with cancer and is a frequent complication of myelosuppressive chemotherapy. In this study, we investigated the incidence and severity of chemotherapy-induced anemia caused by the most common chemotherapy regimens, including the new generation of chemotherapeutic agents, used in the treatment of the major nonmyeloid malignancies in adults. Five hundred fifty-two patients with histologically proven carcinoma originating from breast (n = 165), lung (n = 128), colon (n = 75), ovary (n = 84), and malignant lymphoma (n = 100) were included in this study. Hemoglobin levels for each patient were measured with an automatic counter during both pretreatment and before each chemotherapy cycle during therapy. To document the incidence of anemia, the National Cancer Institute grading system was used. Before chemotherapy, 44% of patients with breast carcinoma had anemia. There was a 16% increase in the incidence of anemia after chemotherapy. Severe anemia was observed in less than 1% of patients. No difference was found in the incidence of anemia between the fluorouracil, doxorubicin, cyclophosphamide (FAC) and cyclophosphamide, methotrexate, fluorouracil (CMF) regimens used in the adjuvant setting. However, single-agent chemotherapy with newer generation caused more anemia when compared with the FAC regimen (p < 0.005). Chemotherapy resulted in a significant decrease in hemoglobin levels when compared with pretreatment values in patients with lung cancer (p < 0.001). During treatment, the increase in the incidence of grade II anemia was associated with a parallel decrease in the incidence of grade I anemia. The incidence of severe anemia did not exceed 15%. The incidence of anemia was equivalent in both patients with small-cell lung cancer and those with non–small-cell lung cancer treated with the etoposide and cisplatin (EP) combination. Seventy-one percent of patients with colon cancer had anemia before initiation of chemotherapy. No difference was observed in posttreatment hemoglobin values compared with pretreatment values. Patients treated with irinotecan and fluorouracil and leucovorin (FUFA) combination showed similar rates of anemia. Incidence of anemia in patients with ovarian cancer at admission was 68%. Chemotherapy resulted in a prominent increase in incidence of anemia, which increased to 91.5%. There was an increase in grade II anemia, which corresponded to the decrease in grade I anemia. Less than 10% of patients developed severe anemia. No difference in the incidence of anemia was observed in patients with ovarian cancer treated with either cisplatin and cyclophosphamide or cisplatin combination. Showing a high incidence of anemia (82%) at presentation, hemoglobin levels in patients with malignant lymphoma were unaltered with chemotherapy. Severe anemia occurred in less than 3% of patients. There was a higher incidence of anemia in patients with non-Hodgkin’s lymphoma receiving the cyclophosphamide, epirubicin, vincristine, prednisone (CEOP) regimen in contrast to patients with Hodgkin’s lymphoma treated with the doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) combination. There was a prominent decline in the hemoglobin levels with cisplatin-based combinations in contrast to combinations including noncisplatin agents (p < 0.001). In this study, we have observed equivalent rates of treatment-related anemia when compared with previous data in patients with specific tumor types. The incidence of pretreatment anemia was high in various malignancies. The mechanisms underlying the propensity for a higher risk of pretreatment anemia in patients with malignant disorders and its influence on the outcome has to be elucidated by further population-based and molecular studies.

The prevalence and determinants of the use of complementary and alternative medicine in adult Turkish cancer patients.

A study was undertaken to analyze the extent of using complementary alternative medicine (CAM) and to compare sociodemographic and medical characteristics of users and non-users of CAM in Turkish oncology patients. A total of 615 patients with cancer who attended ambulatory patient care units answered the questionnaires. Medical information was reviewed from chart data. Some 291 patients (47.3%) had used at least one type of CAM since the time of initial diagnosis. CAMs almost always consisted of herbal agents (95%). Nettle (Urticae herba) used in conjunction with (88%) or without (56%) various herbal agents were the most popular and prominent CAMs used by patients. Univariate and multivariate comparisons of users and non-users of CAM were performed. In multivariate analysis, female sex (p=0.0006), high income (p=0.0008), advanced stage at diagnosis (p=0.02), and usage of multiple chemotherapy applications (p=0.03) were determined as independent factors for CAM use.

Timing of Death From Tumor Recurrence After Curative Gastrectomy for Gastric Cancer

In Western literature, there are few studies investigating the predictors of early versus late recurrence after curative gastrectomy for gastric cancer. The current study analyzed (1) patients who died of recurrent gastric cancer and (2) prognostic factors, which can be applied to timing of death from tumor recurrence. Of 492 patients who underwent curative resection (R0) for gastric cancer in the Department of Surgery, Medical Faculty of Istanbul between 1994 and 2000, 142 patients who died of recurrence were included into study. None of the patients had received postoperative adjuvant treatment. The patients were divided into 2 groups: an early recurrence group that included 102 patients who recurred and died within 2 years after surgery, and a late recurrence group, which included 40 patients who died of recurrence more than 2 years after surgery. Clinicopathologic findings were compared between the early and late recurrence groups. Multivariate analysis was performed to investigate the independent factors, which are predictive for early versus late recurrence, and prognostic factors independently associated with the survival period. In multivariate analysis, the early recurrence group, when compared with the late recurrence group, was characterized by lymph node metastasis (N1-3 versus N0; P = 0.002). Overall survival was influenced by nodal status (N1-3 versus N0; P = 0.003), type of operation performed (radical total versus radical subtotal gastrectomy; P = 0.003), Eastern Cooperative Oncology Group performance status (PS 3–4 versus PS 1–2; P = 0.004), and tumor localization (cardia versus corpus and antrum; P = 0.046). In contrast, T stage of the disease was not prognostic for survival, although it was close to statistical significance (P = 0.066). Multivariate analysis showed that poorer performance status at initial presentation (P = 0.001) and lymph node metastasis (P = 0.032) independently correlated with overall survival (P = 0.002). Lymph node status was the most important factor predictive for early versus late recurrence and patients with lymph node metastases were at more risk of death within 2 years after curative operation for gastric cancer. Postoperative chemoradiotherapy should be especially recommended for patients at high risk of recurrence of adenocarcinoma of the stomach or who have undergone curative resection.

Prognostic features and survival of inoperable hepatocellular carcinoma in Turkish patients with cirrhosis

Background:Primary hepatocellular carcinoma (HCC) is common in Turkey and its prognosis is poor. In the current study the authors analyzed the prognostic factors and survival in Turkish patients with inoperable HCC with cirrhosis. Methods:Clinical and demographic data of 91 patients consecutively admitted to the authors’ institute from 1988 to 2000 were reviewed. A univariate analysis was performed using the Kaplan–Meier method to identify predictors of survival and were compared using the Mantel log-rank test. Independent factors correlated with survival were determined using the Cox regression analysis. Results:Cirrhosis was diagnosed in all patients. Coinfections with HCV and HBV were not observed. Overall median survival was 16.9 months. On univariate analysis, poor performance status (Eastern Cooperative Group); high α-fetoprotein (AFP); low albumin; high bilirubin; high alkaline phosphatase; high lactic dehydrogenase; high alanine and aspartate aminotransferase; high γ-glutamyl transpeptidase; high platelet count; low prothrombin activity; hepatitis B surface antigen positivity; the presence of ascites, encephalopathy, and portal vein thrombosis; poor differentiation and diffuse type of tumor; and no treatment were associated with shorter survival. Multivariate analysis showed that only independent risk factors were related to performance status (Eastern Cooperative Group) at initial presentation and with pathologic characteristic of the tumor: abnormal AFP level. Conclusion:HCC occurred only in patients with liver cirrhosis. Survival time can be predicted from information collected by the physician at the initial assessment.

Fourth versus eighth week surgery after neoadjuvant radiochemotherapy in T3-4/N0+ rectal cancer: Istanbul R-01 study

BACKGROUND AND PURPOSE The optimum duration between neoadjuvant radiochemotherapy and transmesorectal excision in locally advanced rectal cancer has not been defined yet. This randomized study was designed to compare the efficacy of four-week versus eight-week delay before surgery. METHODS One-hundred and fifty-three patients with locally advanced low- or mid-rectum rectal adenocarcinoma were included in this single center prospective randomized trial. Patients were assigned to receive surgical treatment after either four weeks or eight weeks of delay after chemoradiotherapy. Patients were followed for local recurrence and survival, and surgical specimens were examined for pathological staging and circumferential margin positivity. RESULTS 4-week and 8-week groups did not differ with regard to lateral surgical margin positivity (9.2% vs. 5.1%, P=0.33, respectively), pathological tumor regression rate (P=0.90), overall survival (5-year, 76.5% vs. 74.2%, P=0.60) and local recurrence rate (11.8% vs. 10.3%, 0.77). Overall survival was better in patients with negative surgical margins (78.8% vs. 53.0%, P=0.04). Local recurrence rate was significantly higher among patients with positive surgical margin (28.5% vs. 9.3%, P=0.02). CONCLUSIONS Intentional prolongation of the chemoradiotherapy-surgery interval does not seem to improve clinical outcomes of patients with locally advanced rectal cancer. Surgical margin positivity seems to be more important with this regard.

Adjuvant intraperitoneal chemotherapy with cisplatinum, mitoxantrone, 5-fluorouracil, and calcium folinate in patients with gastric cancer: a phase II study.

Gastric carcinoma remains one of the leading causes of cancer-related death in the world. Clinical studies have revealed that approximately two thirds of the patients seek treatment for early recurrence within the abdominal cavity. The aim of this phase II study was to evaluate the toxicity, feasibility, and efficacy of adjuvant intraperitoneal chemotherapy (IPCT) with cisplatin, mitoxantrone, 5-fluorouracil (5-FU), and folinic acid in patients with stage II-III gastric cancer. Patients with stage II and III gastric cancer aged between 15 and 70 years, after curative resection, with adequate liver, renal, and cardiac function were included in the study. The chemotherapy regimen consisted of cisplatin 60 mg/m2, mitoxantrone 12 mg/m2, 5-FU 600 mg/m2, and folinic acid 60 mg/m2, delivered intraperitoneally, diluted in 2 l normal saline. Intraperitoneal fluid was not drained. Each course of IPCT was repeated every 4 weeks for a total 6 cycles. Thirty-nine patients were enrolled in the study. Twenty-eight of the 39 patients (71.8%) completed six courses of the planned schedule. One patient (2.6%) died after a fourth cycle of IPCT from an undetermined reason. The major nonhematologic toxicity from IPCT was grade I-III nausea and/or vomiting experienced by 27 patients (69.2%). Twenty-four (61.5%) patients reported abdominal discomfort. Median follow-up was 23 (range: 3–105) months. Twenty-five patients (64.1%) were dead. Median disease-free survival and overall survival were 12 (CI 95%; 8.3–15.7 months) and 19 months (CI 95%; 10.5–27.5 months), respectively. The cumulative 5-year disease-free survival and overall survival were 24.7% and 30.7%, respectively. The regimen was generally associated with acceptable toxicity. However, adjuvant IPCT has similar survival rates in comparison to no adjuvant treatment; thus, it cannot be currently recommended outside the context of a clinical trial.

A Phase II Study of Cisplatin, Ifosfamide and Epirubicin Combination Chemotherapy in Adults with Nonmetastatic and Extremity Osteosarcomas

Background: Osteosarcoma is a rare malignancy, and patients with this disease benefit from adjuvant chemotherapy. While cisplatin, anthracyclines and ifosfamide are the most commonly used agents in the treatment of osteosarcoma, a search for the best combination with higher efficacy and minimal toxicity continues. We planned to evaluate the efficacy of epirubicin combined with cisplatin and ifosfamide in patients with localized primary osteosarcoma. Methods: Patients with nonmetastatic extremity osteosarcoma who were older than 15 years were included in the study. The preoperative chemotherapy regimen consisted of epirubicin 90 mg/m2, cisplatin 100 mg/m2 on day 1 and ifosfamide 2.0 g/m2/day with an equivalent dose of mesna on days 2–4, repeated every 21 days. Six cycles of this combination regimen were administered (3 cycles prior to surgery and 3 cycles postoperatively). Results: Forty-five patients with localized osteosarcoma entered this phase II trial. Median follow-up was 64 months. Thirty-two patients (84%) received the assigned 6 cycles of chemotherapy. Complete and good histological response to neoadjuvant chemotherapy was 26 and 37%, respectively. The 5-year disease-free and overall survival rates were 41.9% (95% CI 33.6–50.2) and 48.2% (95% CI 39.6–56.8). The most prominent grade 4 toxicity was neutropenia occurring in 32% of patients. The lungs were the most frequent site of relapse (32%). Conclusions: The combination of cisplatin, ifosfamide and epirubicin is an active, reasonably well-tolerated regimen without grade 3 or 4 cardiac toxicity in patients with nonmetastatic extremity osteosarcoma and deserves further investigation in the context of prospective phase III trials.

Colon cancer with isolated metastasis to the kidney at the time of initial diagnosis

Blood-borne metastases to the kidneys from solid tumors have received little attention in the medical literature because they usually occur in a setting of advanced systemic disease, and renal involvement is a elatively minor cause of symptoms. Although the frequency of metastases to the kidney in cancer patients is 7–13% in large autopsy series, incidental discovery of a renal metastasis as the first manifestation of a primary tumor is a very rare event. The most common primary malignancy to involve the kidney is bronchogenic carcinoma, followed by breast and gastrointestinal cancers. In this article, we report a patient with left colon cancer and isolated metastasis to the right kidney at the time of initial diagnosis. Left hemicolectomy and right nephrectomy were performed. Adjuvant systemic chemotherapy consisting of 5-fluorouracil (5-FU) and folinic acid (FA) was given. 5-FU and FA were stopped after four cycles because metastases to the lung and liver occurred about 3 mo after the surgery during adjuvant chemotherapy. Capecitabine was started. The patient died 9 mo after the discovery of the isolated renal metastasis. Nephrectomy is more for diagnostic clarification in the setting of synchronous primary because it has no effect on survival and its effect on quality of life is minimal; as seen in our case, the other organ metastases rapidly occur and the survival is limited. Nephrectomy may also compromise the choice of chemotherapy agents that require renal clearance, thus a careful evaluation of renal functions is necessary if a nephrectomy is performed. In the matter of a decreased renal clearance, the doses of these drugs should be decreased or the choice should be reevaluated.

Tamoxifen and Gallstone Formation in Postmenopausal Breast Cancer Patients: Retrospective Cohort Study

Tamoxifen is being used successfully in breast cancer patients as adjuvant hormonal therapy. The aim of this retrospective cohort study is to evaluate the impact of tamoxifen on gallstone formation in postmenopausal breast cancer patients. A total of 3165 patients who were treated for invasive breast cancer between 1990 and 1997 were reviewed. The data were collected from four university hospitals in a population-based registry. Among these patients, 2462 were excluded from the study owing to improper follow-up and other reasons. Premenopausal patients were also excluded. Of the 703 patients included in the study, 457 had received adjuvant therapy including tamoxifen, and the other 246 had not. Gallstone formation was assessed by annual abdominal ultrasonography. The mean follow-up period was 4.6 years (range 1–7 years). There were no significant differences between the groups of breast cancer patients treated with or without tamoxifen regarding the age of the patients at the time of breast cancer diagnosis, the age at menopause, the duration between the onset of menopause and the time the breast cancer was diagnosed, the presence of diabetes, and the body mass index. At the end of 5 years the incidence of gallstone formation in tamoxifen-treated patients was 37.4%, whereas it was 2.0% in patients who did not receive tamoxifen (p < 0.0001). The incidences of gallstones being detected in 171 tamoxifen-treated patients were 0.4%, 3.7%, 24.4%, 33.1%, and 37.4% cumulatively during the first, second, third, fourth, and fifth years, respectively. Hence adjuvant tamoxifen therapy leads to gallstone formation in postmenopausal breast cancer patients and is most apparent after 3 years of treatment.