Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: results of a randomized trial in patients with advanced colorectal cancer.

PURPOSE: To determine whether high-dose infusional fluorouracil (FU) is effectively modulated by leucovorin (LV), interferon (IFN) alpha-2b, or both when given to patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients (n = 236) with progressive, measurable disease were randomized to three groups and received FU 2,600 mg/m2 as a 24-hour continuous infusion (CI) weekly for 6 weeks with 2 weeks rest (FU24h) and LV 500 mg/m2 as a 2-hour infusion before FU or IFN 3 x 10(6) U subcutaneously 3 times weekly or both. Treatment continued until progressive disease or unacceptable toxicity was observed. Pairs of treatment arms were analyzed sequentially to detect equivalence or a 25% difference in response rates. RESULTS: The rate of objective remission in patients who received FU24h/LV (44%; 40 of 91) was significantly higher than in patients who received FU24h/IFN (18%; 16 of 90; P < .05). The response rates of patients who received FU24h/LV versus FU24h/LV/IFN (27%; 13 of 49) were statistically equivalent. Significant differences were observed for time to tumor progression (TTP) (FU24h/LV, 7.1 months; FU24h/IFN, 3.9 months; FU24h/LV/IFN, 6.3 months; global P value < .009) and survival (16.6 months, 12.7 months, 19.6 months, respectively; global P value < .04). Unpredictable and life-threatening toxicity in the FU24h/LV/IFN arm required dose reduction of FU to 2,000 mg/m2/day and early stoppage of this arm. Toxicity was manageable in patients who received both FU24h/LV (grade 3 to 4 diarrhea, 21%) and FU24h/IFN (grade 3 to 4 diarrhea, 15%). CONCLUSION: Response rate, TTP, and overall survival were superior for LV-containing regimens compared with IFN modulation alone. The addition of IFN to high-dose infusional FU plus LV offers no advantage and may increase toxicity. The regimen of high-dose infusional FU24h/LV warrants further evaluation in patients with metastatic colorectal cancer.

Phase II evaluation of 5-fluourouracil plus folinic acid and alpha 2b-interferon in metastatic colorectal cancer.

Biochemical modulation of 5-fluorouracil (5-FU) by folinic acid (FA) increases the response rate in patients with metastatic colorectal cancer compared to 5-FU alone. Phase II trials also demonstrated increased efficacy when interferon was added to 5-FU. In two consecutive trials, 76 patients were treated on days 1-5 with FA 200 mg/m2 plus interferon 5 x 10(6) U/m2 and 5-FU 350 mg/m2 as intravenous bolus injection (n = 33, regimen A) or 5-FU 500 mg/m2 as 2-hour infusion (n = 43, regimen B), repeated every 3 weeks with individual 5-FU dose escalation in steps of 50 (regimen A) or 100 mg/m2 (regimen B). In regimen A 5-FU dose reduction to 300 mg/m2 due to toxicity was necessary in 49% of the patients; in regimen B a 5-FU dose of 600 mg/m2 or above was tolerated by 70% of the patients. Dose-limiting toxicity was severe mucositis and/or diarrhea. Objective responses were observed in 5 of 33 patients (15%) in regimen A (3-28%, 95% confidence interval) and 7 of 41 patients (17%) in regimen B (5-29%, 95% confidence interval). Median time to progression was 4.7 and 4.8 months, and median survival 9.9 and 11.4 months for regimens A and B, respectively. Prolonged 5-FU administration over 2 h allows the administration of a higher 5-FU dose compared to bolus injection with no apparent improvement in antineoplastic efficacy. The addition of interferon to the combination of 5-FU plus FA in this dose and schedule does not seem to improve the response rate but appears to increase treatment toxicity.

Interferon-alpha does not improve the antineoplastic efficacy of high-dose infusional 5-fluorouracil plus folinic acid in advanced colorectal cancer. First results of a randomized multicenter study by the Association of Medical Oncology of the German Cancer Society (AIO).

BACKGROUND: High-dose 5-FU given weekly as a 24-h infusion in combination with folinic acid (FA) has been associated with low toxicity and a high response rate. Interferon-alpha (IFN) either alone or in combination with FA has also improved treatment results by modulating 5-FU activity. We therefore initiated a randomized multicenter trial comparing the ability of FA or IFN to modulate infusional 5-FU. The statistical design using a sequential analysis allows us to report on the comparison of 5-FU/FA vs. 5-FU/FA/IFN while randomization of patients into 5-FU/FA vs. 5 FU/IFN continues. METHODS: Chemotherapy-naive patients with advanced progressive colorectal cancer and measurable metastatic lesions were randomized to receive 5-FU 2600 mg/m2 i.v. as a 24-h infusion, combined with either FA 500 mg/m2 as a 2-h infusion (A), or IFN 3 x 10(6) U s.c. 3 x/week (B), or the combination of FA plus IFN as in arms A and B (C). Treatment arms were repeated weekly for 6 weeks followed by a 2-week rest period. These 8-week cycles were administered until tumor progression. Because of the occurrence of 2 toxic deaths among the first 17 patients treated in arm C, 5-FU was reduced to 2000 mg/m2 for all patients in arm C. Sequential analysis according to Whitehead for objective response was planned with alpha = 0.05/3 and a power of 80% (beta = 0.2) to detect a difference of > or = 25% (delta = 0.25) or equivalence of response rates. For pairwise comparison of treatment arms a minimum of 30 patients per arm and a maximum of 90 patients per arm were expected in case of equivalence or difference. RESULTS: An interim analysis was performed after the first 93 of 149 randomized patients were evaluable for response and toxicity (A 31 pts, B 33 pts, C 29 pts). Despite the 5-FU dose reduction in arm C, 28% of patients experienced grade 3/4 toxicity (CTC) including diarrhea, mucositis and handfoot syndrome compared to 16% in arm A and 12% in arm B (not significant). No treatment related toxic death occurred in arms A or B, but 3 patients (10%) in arm C died of diarrhea and septicemia. Among patients treated with 5-FU/FA objective tumor response occurred in 12/31 patients (39%) (21%-56%, 95% confidence interval) (3 CR, 9 PR), no change in 13/31 (42%) and PD in 6/31 (19%) patients. Eleven of 29 patients (38%) (20%-56%, 95% confidence interval) receiving 5-FU/FA/IFN achieved complete (3 patients) or partial (8 patients) remissions, 10/29 patients (34%) had stable disease and 8/29 patients (28%) tumor progression. According to the sequential analysis the rates of objective responses observed in patients treated with 5-FU/FA or 5-FU/FA/IFN were equivalent. CONCLUSION: This interim analysis allows the conclusion that infusional 5-FU plus FA/IFN is no more active than infusional 5-FU plus FA alone. However, 5-FU/FA/IFN despite 5-FU dose reduction was associated with unacceptably high toxicity, including 10% deaths. Therefore, further investigation of this regimen is not justified. The study is continued with the comparison of 5-FU/FA vs. 5-FU/IFN.

[Thrombosed popliteal aneurysm--a cause of acute lower leg ischemia]. / Das thrombosierte Popliteaaneurysma--eine Ursache der akuten Unterschenkelischämie.

Popliteal artery aneurysms (PAA) frequently remain asymptomatic up to the event of acute thromboembolic occlusion. Acute occlusions in the femoro-popliteal level without cardial source of embolism, a pulsating tumor in the knee pit or preexisting abdominal-or groin aneurysms are suspicious for the disease. Between 01/87 and 07/93 we saw 21 popliteal aneurysms in 14 patients. In 50% of the cases the aneurysms were found bilaterally. Arteriosclerosis was the most frequent cause, in 30% as a generalised dilative angiopathy. 18 aneurysms were operated upon, 11 in the stage of acute ischemia among a total of 190 acute vascular occlusions in the same period. Treatment consisted in total resection and anatomical reconstruction by means of saphenous vein interposition. The patency rate in our patients operated in the stage of acute ischemia was 73% during this observation period; one major amputation was carried out. The postoperative course of all 7 electively operated aneurysms was without complications. PAA is readily diagnosed by ultrasound. Because of the catastrophic consequences of an acute ischemia resulting from thrombosis we also tend to operate asymptomatic cases. For that reason the contra lateral knee of the healthy appearing leg should be included in the examination as well as higher located possible locations of dilatative angiopathy. A thrombotic treatment, PTA, stent implantation or embolectomy cannot be recommended because of remaining wall adhesive thrombi with danger of embolisation.

[May recurrent goiter be resected bilaterally? Value and results of intraoperative laryngoscopy]. / Darf die Rezidivstruma doppelseitig operiert werden? Stellenwert und Ergebnisse der intraoperativen Laryngoskopie.

Operations for recurrent goiter are considered to range among the most difficult procedures in thyroid surgery and are marked by unusually high subsequent damages of the recurrent nerve. Results from 89 patients with recurrent goiter operated over the last six years and our own experiences with intraoperative laryngoscopy are presented. This procedure is applicable in 60% of all cases with true bilateral thyroid recurrency and accounts for a realistic help in deciding whether to continue the operation with simultaneous resection of the contralateral side.

[Need for thyroidectomy in differentiated thyroid cancers]. / Zur Notwendigkeit der Thyreoidektomie bei differenzierten Schilddrüsenkarzinomen.

In a retrospective case series study we compared data collected from 142 unselected patients with cancer of the thyroid gland treated in 1985-1994 with results from corresponding studies with reference to the necessity for radical thyroidectomy in cases of differentiated thyroid carcinoma. We standardly treated our patients by either primary or subsequent complete total thyroidectomy within 48 h after initial surgery followed by 131I ablation, achieving an overall R0 tumor clearance in 94.1% of cases. Recurrent laryngeal nerve palsy was diagnosed postoperatively in 7.7% of cases. Local tumor recurrence or nodal or distant spread occurred in 16.9% of patients with papillary, 9.1% of patients with follicular and 10% of patients with medullary carcinoma. Only one patient with papillary thyroid carcinoma died after 5 years at the age of 82, whereas 83% of anaplastic cancer patients died within 3 years. We conclude from our data that radical surgery ought to be performed for both differentiated thyroid cancer and undifferentiated cancer to reduce the rate of recurrence. When surgical management is careful radical thyroidectomy as standard treatment is associated with a reasonable rate of perioperative morbidity.

[Surgical therapy of the acne tetrad]. / Operative Therapie der Aknetetrade.

On the basis of a 3 years experience with surgical treatment of acne tetrad (acne conglobata, apocrine acne) in 22 patients, we can draw the following conclusions: 1. Radical surgical excision yields better long-term results than local incision. Recurrences are mostly the result of non-radical surgery. 2. In cases of limited acne--especially if it is localized either in the axilla or the groin--primary wound closure may be successfully attained. 3. Gentamycin chains may support the primary wound healing in defect closures of infected areas. 4. In the axilla, we suggest wound closure by myocutaneous island flaps as the best procedure after extensive excision. 5. Specific antibiotic protection, perioperatively, according to previous culture and sensitivity testing can guarantee a postoperative course free from infection. 6. Open wound therapy with secondary healing of the soft tissue defects proved to be the treatment of choice in perineal procedures. 7. In view of the poor prognosis of conservative methods in chronic acne, and because of the risk of subsequent manifestation of chronic septicemia, early surgical excision is desirable.

[Acute appendicitis]. / Akute Appendicitis.

The appendectomy rate in the Federal Republic of Germany has decreased considerably over the past 20 years; in Hannover it has declined by 50%. The number of patients not undergoing operations after hospitalization has increased from 20% to about 65%. Mortality has decreased by 80%, now reaching 0.7 for 100,000 of the population. More than 80% of the deceased are over 65 years old. The main cause of death is advanced appendicitis including perforation. In the North German Patient Appeal Office 10% of all complaints in general surgery concern appendicitis, mostly because of delayed diagnosis. A considerable number of appendectomies is carried out simultaneously in gynecological operations.

[Principles in stenosing surgical disease: multiple-staged surgery (author's transl)]. / Taktik beim stenosierenden Colon-Prozess: Mehrzeitiges Vorgehen.

Colonic surgery today is usually performed in a one-stage procedure. Multiple resection is indicated only for bowel obstruction or severe inflammation. There is some discussion about the necessity of colostomy in left colon resection, mainly in cases of anterior resection. We strongly suggest a double loop transverse colostomy, since anastomotic leaks are frequent even with subtile techniques, and increasingly old high-risk patients have to be operated upon. Also, the fact that younger residents operate is no justification for forsaking this safety measure. According to the literature, most surgeons feel this way.

[Diagnosis and therapy of liver echinococcus (author's transl)]. / Diagnostik und Chirurgie der Leberechinococcen

From 1970 to April 1975 42 patients were treated for Echinococcus of the liver at the Bonn University Dept. of Surgery. There were 33 cases of E. cysticus and 9 cases of E. alveolaris. These two types of Echinococcus, different in parasitology and epidemiology present different clinical manifestation of disease with different course and prognosis. Angiography with celiaco- and superselective hepaticography are decisive for diagnosis. Therapy can only be surgical with total removal of the parasites. In E. cysticus this is almost always possible by enucleation-resection or pericystectomie following evacuation of the cyst and instillation of 20% sodium-chloride or formaldehyde. Such radicality is the exception in E. alveolaris. Here partial resections, biliodigestive and hepatodigestive anastomoses as palliative measures are carried out predominantly to ensure bile passage.

[Catheter embolisation of the splenic artery as treatment for acute bleeding from varices (author's transl)]. / Katheterembolisation der Milzarterien zum Stopp der akuten Varizenblutung

Embolisation of the splenic artery with fibrin foam, in order to stop acute bleeding from varices, was carried out in two patients. This was performed immediately after diagnostic arterial indirect demonstration of the portal vein; by this method it is possible to achieve at least a temporary cessation of bleeding from oesophageal or gastric varices. The procedure is indicated in desparate situations, if intubation has been unsuccessful or has had to be discontinued, when endoscopic sclerosis is contra-indicated or when an emergency shunt cannot be carried out because of poor liver function or the general condition of the patient. Permanent results cannot be expected and recurrence of bleeding cannot be avoided. The use of splenic embolisation depends on stopping the acute bleeding in order to obtain an interval during which liver function can be improved so that a decompressing shunt operation becomes possible subsequently.