[Peritoneal carcinomatosis of colorectal origin: results of cytoreductive surgery with peritonectomy and hyperthermic intraoperative chemotherapy]. / Peritonealkarzinose kolorektalen Ursprungs : Ergebnisse der zytoreduktiven Chirurgie mit Peritonektomie und hyperthermer intraoperativer Chemotherapie.

Until recently peritoneal carcinomatosis (PC) arising from colorectal cancer (CRC) was considered to be a terminal disease manifestation. Despite palliative systemic chemotherapy (CHT) the majority of patients died within a few months. Nowadays cytoreductive surgery (CRS) of the peritoneal cavity in combination with hyperthermic intraperitoneal CHT and perioperative systemic CHT may offer a chance for long-term survival in selected groups of patients. In this study we report the results obtained with this treatment strategy in 30 consecutive patients. Data were assessed prospectively. After a median follow-up of 16.9 months the median survival time in all 30 patients reached 24.3 months. Favorable prognostic factors are a low extent of intraperitoneal metastases as characterized by a low peritoneal cancer index (median survival PCI ≤ 10: 33.2 months vs. PCI 11-19: 12.1 months) and a complete or nearly complete CRS (median survival CCR 0/1: 33.1 months vs. CCR2/3: 12.1 months). The 2-year overall survival was 89% for patients with a PCI ≤ 10 and 65% for those with surgical CCR 0/1 cytoreduction. As not every patient with CRC and PC may profit from this relatively aggressive therapy an interdisciplinary patient selection (tumor board) and treatment in experienced surgical oncology centers is recommended.

[Multimodal therapy for colon cancer: state of the art]. / Kolonkarzinom: Aktueller Stand der multimodalen Therapie.

In UICC stage I a selected group of patients with T1 tumours and a low risk profile regarding simultaneous lymph node metastases can be treated by endoscopic resection alone, if the tumour is thereby completely removed. In UICC stage II an adjuvant chemotherapy (CT) should not be routinely performed. However, in high risk UICC stage II patients (T4 tumour, less than 12 examined lymph nodes, emergency surgery, intraoperative tumour perforation), an adjuvant CT with infusional 5-FU/FA should be recommended. The state of the art in UICC stage III is an adjuvant CT with FOLFOX. In this tumour stage no beneficial effect of CT involving irinotecan or monoclonal antibodies has been documented. Due to CT-induced side effects an infusional 5-FU/FA protocol or oral capecitabine should be given in patients older than 70 years. In stage UICC IV with resectable liver metastases, surgical resection of the primary tumour and the metastases should be implemented. Since no conclusive data are currently available regarding the beneficial effect of neoadjuvant, perioperative or adjuvant CT in this setting, the therapeutic strategy should be individually discussed between surgeons and oncologists (tumour board). In cases of non-resectable liver metastases a neoadjuvant CT should be performed, preferentially with a FOLFOX protocol in combination with targeted therapies, i.e., the monoclonal antibody cetuximab, aimed at tumour regression with radical metastasectomy as the secondary intent (R0). Patients with UICC stage II colon cancer and microsatellite instability (MSI) apparently experience a better prognosis but do not profit from an adjuvant CT with 5-FU/FA alone. If a CT is under consideration for these patients, the MSI status should be determined on tumour tissue. In cases of a positive result a combination CT, i.e., with FOLFOX, should be given. The relevance of the MSI status in other tumour stages is as yet unknown. Before targeted therapies, i.e., cetuximab or panitumumab, are initiated, the KRAS status needs to be determined, since therapies with antibodies against the epithelial growth factor receptor (EGFR) are only effective in tumours bearing the KRAS wild-type.

Adjuvant chemoradiotherapy of advanced resectable rectal cancer: results of a randomised trial comparing modulation of 5-fluorouracil with folinic acid or with interferon-α.

BACKGROUND: Standard adjuvant chemoradiotherapy of rectal cancer still consists of 5-fluorouracil (5-FU) only. Its cytotoxicity is enhanced by folinic acid (FA) and interferon-α (INFα). In this trial, the effects of FA and IFNα on adjuvant 5-FU chemoradiotherapy in locally advanced rectal cancer were investigated. METHODS: Patients with R(0)-resected rectal cancer (UICC stage II and III) were stratified and randomised to a 12-month adjuvant chemoradiotherapy with 5-FU, 5-FU+FA, or 5-FU+IFNα. All patients received levamisol and local irradiation with 50.4 Gy. RESULTS: Median follow-up was 4.9 years (n=796). Toxicities (WHO III+IV) were observed in 32, 28, and 58% of patients receiving 5-FU, 5-FU+FA, and 5-FU+IFNα, respectively. No differences between the groups were observed for local or distant recurrence. Five-year overall survival (OS) rates were 60.3% (95% confidence interval (CI): 54.3-65.8), 60.4% (54.4-65.8), and 59.9% (53.0-66.1) for 5-FU, 5-FU+FA, and 5-FU+IFNα, respectively. A subgroup analysis in stage II (pT3/4pN0) disease (n=271) revealed that the addition of FA tended to reduce the 5-year local recurrence (LR) rate by 55% and increase recurrence-free survival and OS rates by 12 and 13%, respectively, relative to 5-FU alone. CONCLUSIONS: Interferon-α cannot be recommended for adjuvant chemoradiotherapy of rectal cancer. In UICC stage II disease, the addition of FA tended to lower LR and increased survival. The addition of FA to 5-FU may be an effective option for adjuvant chemoradiotherapy of UICC stage II rectal cancer.

[Quality criteria for treatment of colorectal cancer. From a surgeon's viewpoint]. / Qualitätsanforderungen zur Behandlung des Kolon- und Rektumkarzinoms. Aus chirurgischer Sicht.

The surgeon is the key "prognosis factor" for colorectal cancer. For this reason quality criteria were recently established (including minimum numbers) in order to treat patients who are entitled to the best quality of care and to improve the prognosis. The aim of this study was to critically discuss the existing demands on the surgeon based on the current literature and our own results and to formulate evidence-based quality criteria for surgical clinics. After reviewing the current literature criteria were compiled, discussed and finally presented in a summarized form. These are based on current developments on the diagnostic and therapy of large intestine and colorectal carcinoma. New developments of the German Cancer Society for planning of organ centers are incorporated. The quintessence of our study is that the number of cases alone is not decisive for the success of therapy. Important are the application of the correct surgical-oncology operation procedure, adherence to standards and the training of surgeons. Following the S3 guidelines stage-oriented therapy should additionally be carried out in a structured sequence. This includes an interdisciplinary decision making on the diagnostic and therapy strategy (tumor board). The organization structure of the hospital (teams, tumor board, emergency care with intensive care unit, emergency diagnostic and options for interventional measures) can be more important than the hospital case numbers alone. These demands which have been evaluated from published data and own results are designed to raise the therapy of colorectal cancer to the best possible level of quality and to effect a further improvement in the prognosis.

[Diagnosis and treatment of colorectal liver metastases - workflow]. / Diagnostik und Therapie von Lebermetastasen kolorektaler Karzinome - Workflow.

In this review, standards of diagnosis and treatment of colorectal liver metastases are described on the basis of a workshop discussion. Algorithms of care for patients with synchronous / metachronous colorectal liver metastases or locoregional recurrent tumour are presented. Surgical resection is the procedure of choice in the curative treatment of liver metastases. The decision about the resection of liver metastases should consider the following parameters: 1. General operability of the patient (comorbidity); 2. Achievability of an R 0 situation: i. if necessary, in combination with ablative methods, ii. if necessary, neoadjuvant chemotherapy, iii. the ability to eradicate extrahepatic tumour manifestations; 3. Sufficient volume of the liver remaining after resection ("future liver remnant = FLR): i. if necessary, in combination with portal vein embolisation or two-stage hepatectomy; 4. The feasibility to preserve two contiguous hepatic segments with adequate vascular inflow and outflow as well as biliary drainage; 5. Tumour biological aspects ("prognostic variables"); 6. Experience of the surgeon and centre! Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases provided a complete resection of both intra- and extrahepatic disease is feasible. Even in bilobar colorectal metastases and 5 or more tumours in the liver, a complete tumour resection has been described. The type of resection (hepatic wedge resection or anatomic resection) does not influence the recurrence rate. Preoperative volumetry is indicated when major hepatic resection is planned. The FLR should be 25 % in patients with normal liver, 40 % in patients who have received intensive chemotherapy or in cases of fatty liver, liver fibrosis or diabetes, and 50-60 % in patients with cirrhosis. In patients with initially unresectable colorectal liver metastases, preoperative chemotherapy enables complete resection in 15-30 % of the cases, whereas the value of neoadjuvant chemotherapy in patients with resectable liver metastases has not been sufficiently supported. In situ ablative procedures (radiofrequency ablation = RFA and laser-induced interstitial thermotherapy = LITT) are local therapy options in selected patients who are not candidates for resection (central recurrent liver metastases, bilobar multiple metastases and high-risk resection or restricted patient operability). Patients with tumours larger than 3 cm have a high local recurrence rate after percutaneous RFA and are not optimal candidates for this procedure. The physician's experience influences the results significantly, both after hepatectomy and after in situ ablation. Therefore, patients with colorectal liver metastases should be treated in centres with experience in liver surgery.

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 celiac artery infusion in the adjuvant treatment of pancreatic cancer.

UNLABELLED: We performed adjuvant celiac artery infusion in pancreatic cancer, to find out whether this treatment prolongs survival and changes the biology of the disease after resection, especially by reducing liver metastasis. PATIENTS AND METHODS: Thirty-one patients received cyclic celiac artery infusions (CAI) after resection of their pancreatic cancer (27 ductal, 4 cystadenocarcinoma). The treatment consisted of 6 cycles (1 cycle = 5 days treatment) intra-arterial infusion using Seldingers technique with mitoxantrone A (Novantron) 10 mg/m2 d1, 5-fluorouracil + folinic acid 600 mg/m2 + 170 mg/m2 d2-d4 and cis-platinum 60 mg/m2 d5. Four to 5-week intervals between each cycle of chemotherapy were scheduled. The patients were monitored for toxicity, development of disease progression and survival. RESULTS: The median survival time was 21 months. During an observation period of 19 months, 70% of the patients developed disease progression. In 50% of cases the progression was local, in 40% intraperitoneal while in 15% liver metastases developed. The median survival time of the CAI (celiac artery infusion)-treated patient group compared favorably to the median survival of 9.3 months in a matched historical control group, being significantly longer (p < 0.0003). CONCLUSION: Adjuvant celiac artery infusion seemed to prolong median survival and the occurrence of liver metastases appeared to be delayed or reduced.

[Interferon-alpha in adjuvant treatment of colorectal carcinoma]. / Interferon-alpha in der adjuvanten Behandlung des kolorektalen Karzinoms.

UNLABELLED: Based on preclinical and clinical studies, in this German three-arm adjuvant multicenter trial the FOGT (Forschungsgruppe Onkologie Gastrointestinale Tumoren) studied whether one of the 5-FU modulations with either folinic acid(FA) or Interferon alpha-2a (IFNa) is superior to the recommended standard of adjuvant treatment in R0-resected colon cancer, 5-fluorouracil (5-FU) plus levamisole (LEV) for 12 months, in terms of overall survival rates. PATIENTS/METHODS: From 7/92 to 10/99 813 patients with resected colon cancer stage II (only T4N0M0, 63 pts.) and stage III (750 pts.) were randomized into three treatment groups and stratified according to N-stage and participating centers (64 hospitals). The patients received a postoperative loading course with 5-FU [450 mg/m2 d1-5 (arms A and C)] or 5-FU [450 mg/m2 plus folinic acid (Rescuvolin, medac, Hamburg, Germany), 200 mg/m2 d1-5 (arm B)]. After completion of the first chemotherapy cycle LEV was administered orally at 150 mg/d d1-3, every 2 weeks. After a 4-week chemotherapy-free interval the treatment was continued weekly for up to 52 weeks. The standard group, arm A (279 pts.) was treated with 5-FU i.v. (450 mg/m2 at d 1, q 1 w) plus LEV. 5-FU plus LEV was modulated in arm B (283 pts.) with FA (200 mg/m2 d1, q 1 w), and in arm C (251 pts.) with IFNa at 6 million units 3x/week, q 1 w. Chemotherapy doses were adjusted to toxicity if toxic events > WHO 2 occurred. The patients were followed-up to determine relapse rates and--patterns and survival. Survival rates were calculated according to Kaplan-Meier, and treatment costs and immune effects were analysed. RESULTS: Toxic event(s) > WHO2, mainly leukopenia, diarrhea and nausea, occurred in 113 pts. (14%), in arms A (8%), B (13%) and C (32%). Discontinuance rates were 28% (all), 29% (A), 21% (B), 34% (C), but 80% of patients received > or = 6 months treatment. Overall relapse rates were 27% (all), 30% (A), 24% (B) and 28% (C). Tumors relapsed either locally (2% each) or distant (A: 22%, B: 20%, C: 22%). 4-year overall survival rates in arms A, B and C were 66%, 77%, 66%, respectively. The 4-year survival rate in arm B was significantly superior to arms A and C (p < 0.02, log-rank). There were no signs of a superior immune function in either treatment arm (skin test, proliferation, cytotoxicity, flow cytometry). Treatment costs per patient were 2,500 [symbol: see text](arm A), 3,500 [symbol: see text](arm B) or 10,850 [symbol: see text](arm C), respectively. CONCLUSION: Adjuvant therapy with 5-FU plus FA plus LEV for 12 months is superior to the recommended standard (5-FU + LEV, 12 m). IFNa-modulation of 5-FU (plus LEV) adds toxicity and high treatment costs without therapeutic benefit.

Toxicity and effects of adjuvant therapy in colon cancer: results of the German prospective, controlled randomized multicenter trial FOGT-1.

In this adjuvant three-arm multicenter trial, we studied whether modulating the standard 5-fluorouracil (5-FU) treatment with either folinic acid (FA) or interferon-alpha-2a (IFN-alpha) was superior to the recommended standard of adjuvant treatment in R0 resected colon cancer, 5-FU plus levamisole (LEV) for 12 months, in terms of toxicity and outcome. From July 1992 to October 1999, a total of 813 patients with resected colon cancer in stage II (T4N0M0; n = 63) or stage III (TxN1-3M0; n = 750) were randomized into three treatment groups and stratified according to N stage and participating centers (64 hospitals). The patients received a postoperative loading dose of 5-FU (450 mg/m2 on days 1 to 5 [arms A and C]) or 5-FU (450 mg/m2) plus FA (Rescuvolin, Medac, Hamburg, Germany, 200 mg/m2 on days 1 to 5 [arm B]). After completion of the first chemotherapy cycle, LEV was administered orally at a dosage of 150 mg per day on days 1 to 3, once every 2 weeks. After a 4-week chemotherapy-free interval, the treatment was continued weekly for 52 weeks. Treatment in one arm A ("standard") (n = 279) consisted of 5-FU intravenously (450 mg/m2 on day 1, once a week) plus LEV. 5-FU plus LEV was modulated in arm B (n = 283) with FA (200 mg/m2 on day 1, once a week) and in arm C (n = 251) with IFN-alpha at 6 million units three times a week repeated weekly. Treatment dosages were adjusted if toxic events above WHO grade 2 occurred. Patients were closely followed to determine recurrence and survival; the latter was calculated according to Kaplan-Meier analysis. Toxic events above WHO grade 2, mainly leukopenia, diarrhea, and nausea, occurred in 113 (14%) of 649 patients who had completed treatment in arms A (8.4%), B (13.5%), and C (31.7%). Discontinuance rates were as follows: 28% for all patients, 29% in arm A, 21% in arm B, and 34% in arm C. Overall relapse rates were 27% for all patients, 30% in arm A, 24% in arm B, and 28% in arm C. Relapses were local (8%), distant (78%), or combined (12%). Four-year overall survival rates in arms A, B, and C were 66.1%, 77.5%, and 66.2%, respectively. The 4-year survival rate in arm B was significantly higher compared to arm A (P <0.02, log-rank test) with arm A being equal to arm C. Adjuvant therapy with 5-FU plus FA plus LEV for 12 months is superior to the recommended standard (5-FU + LEV for 12 months). IFN-alpha modulation of 5-FU (plus LEV) adds to the toxicity with no therapeutic benefit.

Adjuvant regional chemotherapy in advanced pancreatic cancer: results of a prospective study.

BACKGROUND/AIMS: In order to improve the dismal prognosis of patients suffering from advanced pancreatic cancer we treated 20 patients with adjuvant regional chemotherapy following resection of the tumor. METHODOLOGY: All tumors were classified UICC stage III (TxN1M0). Regional chemotherapy consisted of Mitoxantrone 10 mg/m2 day 1, Folinic Acid 170 mg/m2 and 5-FU 600 mg/m2 days 2-4, and cis-Platinum 60 mg/m2 day 5 for up to 6 cycles. In a total of 101 cycles toxicities WHO III occurred in 6%, WHO IV in 0%. RESULTS: The median survival times, compared to institutional historical controls (treated vs. controls) were 18.5 vs. 9.3 months (p < 0.0006). Hepatic disease progression seemed to be suppressed. CONCLUSION: In conclusion regional chemotherapy seems to be effective for adjuvant treatment in resected pancreatic cancer.

Multimodal therapy in rectal cancer.

The possibilities and results of multimodal treatment in rectal cancer were reviewed with respect to the results of surgical treatment only. Based on the results of 4 studies, reducing local relapse rates and increasing long-term survival rates significantly, postoperative radiochemotherapy (RCT) + chemotherapy (CT) should remain the recommended standard for R0 resected UICC II and III rectal cancers. Preoperative neoadjuvant radiotherapy (RT) reduced local relapse rates in 8 studies, and extended survival in one study that evaluated all eligible patients. Preoperative RT may evolve as standard, if the patient selection is improved and postoperative morbidity and long-term toxicity are reduced. Postoperative adjuvant RT reduced local relapses significantly in a single trial, and no impact on survival time is reported. Since postoperative RT is inferior to preoperative RT, this treatment cannot be recommended, if RT is chosen as a single treatment modality as an adjunct to surgery. Preoperative RCT + CT downstages resectable and nonresectable tumors and induces a higher sphincter preservation rate. This treatment may be routinely applied in nonresectable primary tumors or local relapses. Intraoperative RT could be added to this concept or be used together with preoperative/postoperative RT with the same indications. The results of local tumor excisions may be improved with pre- or postoperative RCT + CT.

Palliative and adjuvant regional chemotherapy in pancreatic cancer.

To improve the dismal prognosis of patients (pts) with pancreatic cancer we treated 32 patients with non-resectable (UICC III, 17 pts; UICC IV, 15 pts--group 1) and 20 patients with resected (UICC I, 1 pt; UICC II, 3 pts; UICC III, 16 pts--group 2) pancreatic cancer with palliative (group I) and adjuvant post-operative (group II) coeliac axis intra-arterial cyclic infusions (CAI). CAI consisted of mitoxantrone 10 mg/m2 on day 1, folinic acid 170 mg/m2 and 5-FU 600 mg/m2 during days 2-4, and cis-platinum 60 mg/m2 on day 5 for up to 11 (group I) or six (group II) cycles. In a total of 211 cycles toxicities at the level of WHO III occurred in 0-6% and of WHO IV in 0%. The median survival times, compared with institutional historical controls (treated vs controls), were 12 vs 4.8 months in UICC III (P < 0.006) and 4 vs 2.9 months in UICC IV (P < 0.05) group I pts, and 21 vs 9.3 months in group II (P < 0.0003). Hepatic disease progression appeared to be suppressed with CAI, which also appears to be effective for palliative and adjuvant treatment in non-resectable and resected pancreatic cancer.

[Adjuvant regional chemotherapy in resected advanced pancreas carcinoma]. / Adjuvante regionale Chemotherapie beim resezierten fortgeschrittenen Pankreascarcinom.

Systemic chemotherapy in patients who underwent resection of pancreatic carcinoma has not been significantly improved median survival times. We investigated whether regional chemotherapy administered via celiac trunc infusion increases survival rates in patients with locally advanced pancreatic carcinoma after resection of the primary. From 12/1992 to 2/1995 we treated 18 patients with regional chemotherapy consisting of mitoxantrone (d1), 5-FU + folinic acid (d2-4) and CDDP (d5) on five consecutive days. This cycle was repeated up to 6 times. Besides non-symptomatic GI-ulcerations (3/18) no severe side effects were observed. The median survival is actually 17.8 months (regression analysis). Compared to a historical control of our department survival times are significantly prolonged (17.8 vs. 9.3 months, p < 0,0003). In conclusion we state that adjuvant regional chemotherapy in patients with advanced pancreatic cancer is well tolerated and prolongs survival significantly.

[Reduction of postoperative edema following isolated hyperthermic perfusion of the extremities with prophylactic administration of aprotinin. Preliminary results]. / Reduktion des postoperativen Odems nach der isolierten hyperthermen Extremitätenperfusion durch prophylaktische Anwendung von Aprotinin. (Vorläufige Ergebnisse).

Experience from more than 380 operations resulted in the standardisation of isolated hyperthermic perfusion with cytostatic drugs for the treatment of malignancies of the extremities. A side-effect of this procedure is postoperative oedema in varying degrees of severity. The influence of prophylactic intraoperative administration of aprotinin (Trasylol) was investigated under experimental and clinical conditions. In these preliminary studies aprotinin distinctly reduced maximum extent and duration of the postoperative oedema. An investigation concerning interaction of aprotinin with the cytotoxic activity of the drugs used in perfusion showed only minor inhibition which does not limit clinical usefulness.