Ludger Staib

Values and limitations of 18F-fluorodeoxyglucose-positron-emission tomography with preoperative evaluation of patients with pancreatic masses.

The aim of this study was to determine the value and limitations of 18F-fluorodeoxyglucose (FDG)–position-emission tomography (PET) for differentiating benign and malignant pancreatic disease and for staging malignant disease. One hundred fifty-nine patients with 89 malignant and 70 benign pancreatic lesions all received PET, computed tomography (CT), and endoscopic retrograde cholangiopancreatography (ERCP) before pancreatic surgery. The original reports were compared for all patients (group I; N = 159), for a subgroup that neither had fasting plasma glucose levels ≥130 mg/dL or known elevated levels of C-reactive protein ([CRP], group II; n = 123), and for the remaining patients (group III; n = 36). For group I, accuracy values (areas under receiver operating characteristic [ROC] curves) for differentiation of benign/malignant masses were 0.86 (PET), 0.93 (ERCP), 0.82 (CT), and 0.95 for ERCP + PET (N = 159). For group II, ROC areas increased to 0.92 (PET), 0.94 (p < 0.05; n = 123) (ERCP), 0.82 (CT), 0.97 (p < 0.05; n = 123) (ERCP + PET). The results for group III were 0.71 (PET), 0.81 (CT), and 0.93 (ERCP); (n = 36). With 54 patients of group II that either had contradictory or indeterminate/technically unsuccessful CT/ERCP, PET was correct in 43 patients (84%). Sensitivity/specificity for lymph node staging was 49%/63%, respectively. For patients with hepatic metastasis, PET was 70% sensitive and 95% specific, missing some metastasis that were <1 cm. PET detected peritoneal metastasis in 25% of patients, missing poorly localized microscopic spread. For selected patients who have indeterminate pancreatic masses but no hyperglycemia or serologic evidence of active inflammation, FDG-PET is an independent functional assay that significantly adds to the diagnostic accuracy of ERCP and CT in the differentiation of benign and malignant pancreatic disease. PET can reliably detect hepatic, peritoneal, and other distant metastases that are ≥1 cm.

Is 18F-fluorodeoxyglucose positron emission tomography in recurrent colorectal cancer a contribution to surgical decision making?

Abstract Background: Accuracy of 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) and contribution to surgical decision making in recurrent or metastatic colorectal cancer were evaluated. Methods: One hundred whole-body PET tests in colorectal cancer patients (1994 to 1998) were compared with computed tomography (CT), liver ultrasonography, and carcinoembryonic antigen (CEA) test. Mean follow-up was 12 months. Results: Sensitivity, specificity, and accuracy of FDG-PET for malignant findings were, respectively, 98%, 90% and 95%; for 87 CT scans, 91%, 72%, and 82%; for 98 CEA tests, 76%, 90%, and 82%; for detection of liver metastases with PET, 100%, 99%, and 99%; and for 68 ultrasound tests, 87%, 96%, and 93%. PET accuracy for local recurrence was 96%. Additional information was provided by PET in 86% of cases (abdomen, thorax, liver). PET influenced surgical decisions in 61% of cases. Conclusion: FDG-PET adds relevant accuracy to the conventional staging of patients with colorectal cancer and may cost-effectively help to select the appropriate treatment.

Surgery of colorectal cancer: Surgical morbidity and five- and ten-year results in 2400 patients: Monoinstitutional experience

The objective of this study was to determine surgical morbidity and long-term outcome of colorectal cancer surgery for quality control reasons and as the basis for new treatment modalities. Surgically treated colorectal cancer patients (mean age 65 years) were followed prospectively in a university center (110 months mean follow-up, 1978-1999). Overall survival (OAS), radicality, extent of resection, recurrence, and morbidity were analyzed (log-rank test of survival, multivariate analysis). Altogether, 2452 colorectal cancers localized in the colon (CC, 44.6%), rectum (RC, 44.8%) or multicentric (CRC, 10.6%) were of UICC stages I (19%), II (30%), III (21%), IV (20%), or undetermined (10%). Radicality and stage but not tumor localization influenced the OAS (p <0.0001). The 5-year/10-year OASs were 50%/42% (all), 78%/66% (R0), 46%/36% (R1), 4%/0% (R2), 0% (unresected) and 86%/79% (I), 70%/58% (II), 42%/33% (III), 3%/0% (IV) or 21%/12% (undetermined), respectively (p <0.0001). Multivisceral resections (17%) resulted in morbidity and survival rates equal to those for standard resection. The overall tumor recurrence rate was 27%, mainly with both local and distant relapse (15%). Surgery-related complications occurred in 18% (all), 14% (CC), 21% (RC), or 20% (CRC). The perineal infection rate (RC) was 4%, overall anastomotic leakage 1%, and mortality rate 0.8%. A prospective, uniform follow-up used over two decades warrants quality control in colorectal cancer surgery, which was curative for half of the patients. The morbidity and mortality were low and were not increased by multivisceral resections.

In vitro concentration response studies and in vitro phase II tests as the experimental basis for regional chemotherapeutic protocols.

The theoretical pharmacologic benefit of regional vs. systemic chemotherapy is defined and the concentration response behavior of cytostatic drugs and their optimal exposure times are described with human cancer cell lines (HT29, NMG64/84) and fresh human tumor cell suspensions in the human tumor colony assay (HTCA). The theoretical pharmacological advantages are 5.8 to 6 for adriamycin (ADM), 8 for cisplatinum (CDDP), 6.3 for epidoxorubicin (EPI), 22 to 58 for 5-fluorouracil (5FU), 4.6 for mitomycin C (MMC), and 6.3 for mitoxantrone (NOV). The drugs differed in their cytotoxic potency in vitro and thus also potential efficacy for regional chemotherapy; however, all but 5-fluorodeoxyuridine (5FUDR) exerted cytotoxicity dependent on exposure time and concentration. On average, elevation of the test concentrations by 1 lg doubled responses in fresh human tumor cell suspensions. From these results and clinical considerations, optimal times were defined for the regional chemotherapy strategies of hepatic artery infusion, intraperitoneal instillation, and chemoembolisation as performed at our institution.

Ampullectomy for adenoma of the papilla and ampulla of Vater.

Introduction: The frequency of malignant adenomas of the papilla figures between 15 and 30%. Villous adenoma is considered to be a premalignant lesion. Treatment: Resection of the papilla is indicated in large tubular and small tubulovillous adenoma. Ampullectomy, however, is mandatory in villous adenoma with severe dysplasia and large villous or tubulovillous adenoma. If villous adenoma with a low-risk pT1 N0 M0 G1/2-cancer is treated by ampullectomy, local lymph dissection should also be performed. Ampullectomy includes extirpation of the ampulla of Vater and reinsertion of the common bile duct and the pancreatic main duct into the duodenal wall. Results: Hospital mortality after ampullectomy is less than 0.4%, and surgical morbidity, e.g., cholangitis, below 10%.

Increase of Survival Benefit in Advanced Resectable Colon Cancer by Extent of Adjuvant Treatment: Results of a Randomized Trial Comparing Modulation of 5-FU + Levamisole With Folinic Acid or With Interferon-α

Background:The benefit of adjuvant therapy in curatively resected lymph node-positive colon cancer was established using 5-fluorouracil (5-FU) and levamisole (LEV) for 12 months. 5-FU cytotoxicity can be modulated by folinic acid (FA) or interferon-α (INF-α). The aim of this study was to investigate the efficacy of modulating 5-FU+ LEV by either FA or IFN-α in the adjuvant treatment of high-risk colon cancer. Methods:Patients with curatively resected colon cancer (stages UICC IIb and III) were stratified according to T, N, and participating center and randomized to receive a 12-month treatment using 5-FU + LEV alone or in combination with FA or IFN-α. Results:A total of 855 of 904 entered patients (94.6%) were eligible. The median follow-up of all eligible patients was 4.6 years. Addition of FA to 5-FU + LEV improved recurrence-free and overall survival in comparison with 5-FU + LEV alone (P = 0.007 and P = 0.004, respectively, 1-sided). The 5-year overall survival rates were 60.5% (95% confidence interval, 54.3–66.7) and 72.0% (95% confidence interval, 66.5–77.5) for 5-FU + LEV and 5-FU + LEV + FA, respectively. Addition of INF-α showed a tendency to improve recurrence-free survival, however, without altering overall survival. Toxicities (WHO III + IV) were generally tolerable except one toxic death in the control arm and were observed in 9.9% of the patients receiving 5-FU + LEV alone and in 13.3% and in 30.7% of patients receiving additional FA and IFN-α, respectively. Conclusions:Addition of IFN-α was associated with increased toxicity without markedly influencing the outcome and should therefore not be recommended for adjuvant treatment. Addition of FA increased the 5-year recurrence-free and overall survival rate by 9.3 and 11.5 percentage points, respectively. 5-FU + LEV + FA for 12 months may be an effective adjuvant treatment option for locally advanced high-risk colon cancer.

Prognostic factors influencing the survival of patients with colon cancer receiving adjuvant 5-FU treatment

AIM Adjuvant chemotherapy is recommended for stage III colon cancer. The aim of this study was to identify important prognostic factors among patients with colon cancer receiving adjuvant 5-FU-based treatment. METHODS Data sets of 855 colon cancer patients treated between 1992 and 1999 within a multicenter adjuvant trial comparing 5-FU modulation with folinic acid or interfereron-alpha were examined. Backward elimination in a proportional hazards model was used to identify prognostically relevant clinical and pathological factors. RESULTS Tumor recurrence (p<0.001), duration of adjuvant treatment (p<0.001), tumor substage (p=0.004), age (p=0.005), grading (p=0.016), treatment-related toxicity (p=0.021), and treatment (p=0.031) were identified in descending order of importance as prognostic factors for overall survival. CONCLUSIONS Adjuvant 5-FU-based treatment should be performed for at least 6months with a stepwise adjustment of 5-FU doses until toxicity >WHO II. Substages should be reported separately and used for stratification in future trials due to their broad variation in outcome. In the future, this may result in adjuvant treatment of stage III colon cancer adjusted for the risk of substages.

Regional chemotherapy of nonresectable colorectal liver metastases with mitoxantrone, 5‐fluorouracil, folinic acid, and mitomycin C may prolong survival

Regional chemotherapy of isolated, nonresectable colorectal liver metastases (CRLMs) by hepatic artery infusion (HAI) has the advantages of high response rates and the possibility of downstaging and resection of CRLMs. 5‐Fluorodeoxyuridine (5‐FUDR) has been the drug studied in most Phase II and III trials. The meta‐analysis of the Phase III trials comparing HAI with systemic or supportive therapy confirmed an advantage for response and even survival for HAI. Hepatic artery infusion with 5‐FUDR, however, is hepatotoxic, inducing sclerosing cholangitis (SC). The authors have introduced 5‐fluorouracil (5‐FU) with folinic acid for HAI and found equal effectivity but no SC when compared with HAI with 5‐FUDR. Now, they report a new combination chemotherapy protocol based on HAI with 5‐FU with FA and on in vitro Phase II studies suggesting mitoxantrone and mitomycin C as active drugs for HAI in CRLM.

Intraperitoneal chemotherapy with mitoxantrone in malignant ascites

A retrospective analysis of intraperitoneal mitoxantrone instillation therapy for malignant ascites in advanced breast and gynecologic pelvic cancers was performed to confirm the efficacy and safety of this therapy. Several smaller phase II trials had suggested good palliative effects. In 143 patients (37 breast cancer and 106 gynecologic cancers), 257 instillations were registered. Response in breast cancer was induced in 49% and in 63% with gynecologic cancer. Severe or life-threatening clinical or laboratory side effects related to intraperitoneal mitoxantrone occurred in 2.7% (clinical) or 1.9% (laboratory) of the 257 instillations. Induction of adverse side effect was dose dependent. Intraperitoneal chemotherapy with mitoxantrone for treatment of malignant ascites in breast cancer and gynecologic malignancy is effective and well tolerated. For this treatment 30 mg mitoxantrone in > or = 1000 mL carrier solution (e.g., saline) is recommended. A minimal concentration of at least 10 micrograms/mL should be achieved.

Colon cancer: survival after curative surgery

Several new aspects have evolved during the past years concerning factors that influence survival in surgically and medically treated colon cancer patients that are relevant to the treating team for the treatment strategy and patient’s choice. The 5-year-survival rates dependent on UICC stages/substages (I: 68%–100%, II: 58%–90%, III: 33%–76%, IV: <5%–9%) show remarkable variations between published reports, surgical hospital units, individual surgeons, and continents (USA vs Europe). Those variations may be due to surgical techniques, training status, hospital and individual case volume, and, also, referral patterns and statistical evaluation methods. Survival times and cure rates are significantly improved by adjuvant chemotherapy in UICC III and in substages of UICC II (e.g. UICC II B) by 5%–12%, when compared with surgical controls. In three recently published trials standard adjuvant chemotherapy was further improved by increased survival rates, e.g. from 59% to 71% in stage III and IIB patients. Molecular and genetic factors, such as thymidylate synthase (TS), microsatellite instability (MSI) or loss of chromosome 18q/“DCC” might have an independent impact on prognosis in the spontaneous course, and TS could help to better select patients for adjuvant chemotherapy.