Oncological outcome after hyperthermic isolated limb perfusion for primarily unresectable versus locally recurrent soft tissue sarcoma of extremities.

INTRODUCTION: The management of locally advanced extremity soft tissue sarcomas, particularly in terms of a limb salvage strategy, represents a challenge, especially in recurrent tumors. In the context of a patient-tailored multimodal therapy, hyperthermic isolated limb perfusion (ILP) is a promising limb-saving treatment option. We report the outcome of patients with primarily irresectable and locally recurrent soft tissue sarcoma (STS) treated by ILP. PATIENTS AND METHODS: Data about patient demographics, clinical und histopathological characteristics, tumor response, morbidity and oncological outcome of all patients with STS, who underwent an ILP at our institution in a 10-year period, were retrospectively detected and analyzed. RESULTS: The cohort comprised 30 patients. Two patients were treated with ILP for palliative tumor control, 13 patients because of a local recurrent soft tissue sarcoma (rSTS) and 15 patients because of primarily unresectable soft tissue sarcoma (puSTS). 25 of the 28 patients with curative intention received surgery after ILP (11 pts with rSTS and 14 pts with puSTS). Histopathologically we observed complete response in 6 patients (24%) and partial responses in 19 patients (76%) with a significant better remission in patients with puSTS (p = 0,043). Limb salvage rate was 75%. Mean follow-up was 69 months [range 13-142 months]. Seven (7/11; 64%) patients with rSTS and one (1/14; 7%) patient with puSTS developed local recurrence after ILP and surgery, whereas eight (8/13; 62%) rSTS patients and seven (7/15; 47%) puSTS patients developed distant metastasis. During follow-up, eight patients (28.5%) died of disease (5/13; 38%) rSTS and 3/15 (20%) puSTS. ILP in the group of previously irradiated sarcoma patients (n = 13) resulted in a limb salvage rate of 69% and was not associated in an increased risk for adverse events. DISCUSSION: ILP for advanced extremity STS is a treatment option for both puSTS and rSTS resulting in good local control and should be considered in multimodal management. ILP is also a good option for patients after radiation history.

Impact of age on the efficacy of oxaliplatin in the preoperative chemoradiotherapy and adjuvant chemotherapy of rectal cancer: a post hoc analysis of the CAO/ARO/AIO-04 phase III trial.

Background: The German rectal cancer trial CAO/ARO/AIO-04 has shown a significant benefit in 3-year disease-free survival (DFS) of adding oxaliplatin to a standard preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) and adjuvant chemotherapy in patients with locally advanced rectal cancer. The use of oxaliplatin as adjuvant treatment in elderly patients with colon cancer is controversial. We therefore investigated the impact of age on clinical outcome in the CAO/ARO/AIO-04 phase III trial. Patients and methods: We carried out a post hoc analysis of the CAO/ARO/AIO-04 phase III trial evaluating primary and secondary end points according to age. Patient and tumor characteristics, NCI CTC adverse events grades 3-4 (version 3.0), dose intensities as well as survival and recurrence data were analyzed in three specified age groups (<60, 60-70, and ≥70 years). The influence of age as a continuous variable on DFS was modeled using a subpopulation treatment effect pattern plot (STEPP) analysis. Results: A total of 1232 patients were assessable. With the exception of Eastern Cooperative Oncology Group status (P < 0.001), no differences in patient and tumor characteristics were noticed between age groups. Likewise, toxicity pattern, dose intensities of CRT and surgical results were similar in all age groups. After a median follow-up of 50 months, in patients aged <60 years a significant benefit of adding oxaliplatin to 5-FU-based CRT and adjuvant chemotherapy was observed for local (P = 0.013) and systemic recurrences (P = 0.023), DFS (P = 0.011), and even overall survival (OS; P = 0.044). The STEPP analysis revealed improved hazard ratios for DFS in patients aged 40-70 years compared with elderly patients treated with oxaliplatin. Conclusion: The addition of oxaliplatin significantly improved DFS and OS in younger patients aged <60 years with advanced rectal cancer. Patients aged ≥70 years had no benefit. Clinical Trials Number: NCT00349076.

Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial.

Background: Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods: Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results: After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4. Conclusion: Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.

Effective local control of advanced soft tissue sarcoma with neoadjuvant chemoradiotherapy and surgery: A single institutional experience.

PURPOSE: There is a sound theoretical basis but little clinical evidence substantiating the benefits of concurrent chemoradiotherapy with two-drug chemotherapy for locally advanced soft tissue sarcomas. Our five-year data on the feasibility and effectiveness of neoadjuvant chemoradiotherapy with systemically effective doses of adriamycin and ifosfamide combined is presented here. PATIENTS AND METHODS: Between 2000 and 2011, 53 patients with UICC (2010) stage I (n=1, 1.9%), II (n=12, 22.7%) or III (n=40, 75.5%) nonmetastatic soft tissue sarcoma received neoadjuvant chemoradiotherapy with ifosfamide (1.5 g/m(2)/day, d1-5, q28) and doxorubicin (50mg/m(2)/day, d3, q28) plus concurrent radiotherapy with a target dose of 50-64 Gy (median 60 Gy). The treatment of 34 patients (64.2%) was combined with hyperthermia. RESULTS: At five years, the local control rate was 89.9% (± 5.7%), distant metastasis-free survival 66.6% (± 7.6%), and survival 83.3% (± 6%). The R0 resection rate was 81.1%. Radiotherapy was completed as planned in all patients and chemotherapy in 42/53 (70.2%). Grades III (n=21, 29.6%) and IV (n=18, 34%) leukopenia was the main acute adverse event. All acute and chronic non-hematologic toxicities were moderate. CONCLUSION: Neoadjuvant chemoradiotherapy for soft tissue sarcoma is associated with good feasibility, manageable acute and late toxicities, and high local efficacy.

[Surgical Indications for Diverticulitis in Germany: Are All Operations Justified?]. / Operationsindikation der Sigmadivertikulitis in Deutschland: Sind alle Operationen gerechtfertigt?

INTRODUCTION: Pathological changes of preexisting sigma diverticulosis into a state of sigma diverticulitis are possible. Treatment of sigma diverticulitis accounts for a significant proportion of emergency treatments in clinics. The number of patients treated for sigma diverticulitis has risen steadily in recent years. Although it can be observed that operated cases making 7 % compared with 14 % to all stationary admissions, there is a less marked increase. Nevertheless, the question should be clarified as to how high the proportion of complicated surgical cases is in relation to non-complicated cases. It is important to clarify, in this context, if each operation is justified or whether in some cases there is over-treatment. MATERIAL AND METHODS: All data relating to Germany, were prospectively collected by the treating hospitals using the DRG and evaluated by the Federal Statistical Office. The treatment numbers from Erlangen were prospectively collected from the encrypted DRG and analysed retrospectively by the coding officer. The investigated period lasted from 2005 to 2010. To demonstrate some treatment options, the following possible forms of therapy were examined with reference to the Hansen/Stock classification. RESULTS: In Germany, about 40 % of stationary patients with sigma diverticulitis are treated surgically. It is striking that in about two thirds of all operated patients uncomplicated forms of diverticulitis were present. The remainder consisted of covered or free perforations. For these complicated forms, various treatment approaches have been established. Ultimately, in dependence of timing these are always surgically treated. In the milder forms the general indication for surgery has come into discussion as the recommendation for a surgical approach after the second relapse in the symptom-free interval is being questioned by several groups based on the age of the studies on which the recommendations are based. CONCLUSION: A significant increase in hospital admissions and surgically treated patients is demonstrated. Striking was that a closer analysis of data revealed that mainly non-complicated cases were surgically treated. This should be seen as a clear indication for an over-treatment. Therefore, possibly not all surgeries performed are justified. In the case of complicated forms, in consideration of various treatment paths, surgery is inevitable in most cases.

[Rational diagnostics of acute abdomen]. / Rationelle Diagnostik des "akuten Abdomens"

BACKGROUND: In view of the threat that comes with an acute abdomen, it is of major importance that diagnostics are executed quickly and efficiently. In the course of this two tendencies can be differentiated: 1) general use of complex examination (e.g. CT, MRT) of all potential patients and 2) step-by-step-diagnostics with advanced diagnostics as and when required. MATERIAL AND METHODS: A total of 444 patients with an acute abdomen as admission diagnosis were investigated. All data were evaluated prospectively and analyzed retrospectively. All patients had the same basic diagnostics consisting of aclinical history, clinical examination, laboratory examination, abdominal sonography and x-ray overview images. These examinations were supplemented when required by advanced measures, such as CT, colon enema with contrast fluid, endoscopic examination and diagnostic laparotomy. RESULTS: Three different disease groups of unequal diagnostic need could be identified. The first group, presented in the form of an appendicitis showed that in 80% of all patients a basic diagnosis was sufficient. Advanced examination such as CT affected 14%. The negative appendectomy rate amounted to 8%. Other diseases belonging to the first group were ileus, acute biliary diseases, perforation etc. In the second group presented in the form of a diverticulitis, an advanced radiological examination was required in 84% of all cases. Similar results are also expected in cases of pancreatitis. In the third group presented in the form of coprostasis, inflammatory etiology was found in 39% of all secondary diseases. However the symptoms became clinically apparent after treatment of the coprostasis. In this group a basic diagnosis was satisfactory in 84% of cases, however, a diagnostic laparotomy was inevitable for 3% of these patients. CONCLUSION: Generally step-by-step diagnostic approach has proven itself to be efficient. For 80% of all patients it makes advanced diagnostic measures unnecessary. The exceptions are diseases in which it is necessary to know not only the diagnosis but also the disease stage. In these cases (e.g. pancreatitis, diverticulitis etc.) advanced diagnostics should be pursued from the onset. The necessity of a diagnostic laparotomy has lost importance for 1% of all patients.

A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer.

BACKGROUND: Studies indicate that adjuvant 5-fluorouracil (5-FU) with folinic acid (FA) in colorectal cancer patients with completely resectable liver-limited metastases (LMCRC) offers clinical benefit over surgery alone. This phase III trial compared FOLFIRI with simplified 5-FU/FA in this setting. PATIENTS AND METHODS: LMCRC patients were randomized to receive every 14 days, FA, 400 mg/m2 infused over 2 h, followed by 5-FU as a 400 mg/m2 i.v. bolus, followed by continuous 5-FU infusion, 2400 mg/m2 over 46 h (LV5FUs) with or without irinotecan: 180 mg/m2 infusion (FOLFIRI). The primary end point was disease-free survival (DFS); secondary end points included overall survival (OS) and safety. RESULTS: Treated patients (n = 306) were balanced for critical prognostic factors in each arm. Median DFS in patients receiving LV5FUs was 21.6 versus 24.7 months for FOLFIRI [hazard ratio (HR) 0.89, log-rank P = 0.44]. No significant differences were found in OS. A trend was observed for improved DFS in patients receiving FOLFIRI within 42 days of surgery (HR 0.75, P = 0.17). Grade 3/4 toxic effects were more common in patients treated with FOLFIRI versus LV5FUs (47% versus 30%) with neutropenia being most common (23% versus 7%). CONCLUSION: FOLFIRI in the adjuvant treatment of LMCRC showed no significant improvement in DFS compared with LV5FUs.

Long-term functional outcome after hyperthermic isolated limb perfusion (HILP).

BACKGROUND: One of the biological characteristics of melanoma is the locoregional development of metastases that are difficult to treat by conventional tumour mass reduction. Locoregionally metastasised melanoma of the limb can effectively be treated by hyperthermic isolated limb perfusion (HILP). Postoperative complication rates are acceptable. Only few studies have examined long-term complications. This is the reason why we followed up patients in respect of long-term physical and psychological complications after HILP. MATERIALS AND METHODS: 312 patients with melanoma of the limb underwent HILP in our department between 1977 and 1983. Eighty-two patients that were still alive and no older than 80 years at the time of follow-up were contacted and invited to a physical examination. On average, follow-up took place 20 years after HILP. Thirty-nine patients were willing to participate in the study. Twelve of these patients were male and 27 female. The average age was 63.1 years (range 41 to 79). The average age at the point of perfusion was 42.1 years (range 19 to 59). In 10 cases the upper extremity was involved, in 29 patients the lower extremity. Patients were questioned on impairment of daily life and their health status using a standardised questionnaire. A physical examination was performed to document the impairments quantitatively. Ranges of motion, circumference and neurological deficits of the operated limbs were compared to the healthy limbs. RESULTS: At the time of follow-up examination all patients were without recurrent disease. A definite correlation between impairment of the general health condition and the operation could only be found in one patient with persisting lymph oedema. Thirteen patients still wore elastic stockings during the day, 9 of which regularly underwent lymphatic drainage. Most of the patients (58%) saw an improvement of their condition due to the treatment. 67% of the patients reported not having any or only slight impairment of everyday life. Only a few cases had disadvantages in their social and working life due to the perfusion. The physical examination of the upper limb showed an impaired range of motion of the shoulder in all planes in 50% of the patients. Relevant decrease in range of motion in the elbow was seen in two patients. The other examination results showed no significant differences in comparison to the healthy arm. The analysis of the lower limb showed relevant clinical reduction of range of motion in all three major joints. Significant differences were also found in the circumference of the leg compared to the healthy side. SUMMARY: According to our results and results from the literature it was possible to show that hyperthermic isolated limb perfusion is associated with an elevated risk of persisting impairment of range of motion of the treated limb. The impaired function is due to a persistent swelling of the limb because of lymph oedema on the one hand and local toxicity to the ligaments of the joints on the other. Response rates and results of HILP have greatly improved in the last years due to numerous modifications so that this treatment is the method of choice in locoregionally metastasised melanoma of the limb in spite of the long-term complication rate.

Hyperthermic intraperitoneal chemoperfusion is an option for treatment of peritoneal carcinomatosis in children.

BACKGROUND: Gastrointestinal carcinomas in childhood are rare and frequently present at an advanced stage. Besides lymphatic and distant organ metastasis, peritoneal carcinomatosis may be detected and has a poor prognosis. In addition to surgery and intravenous chemotherapy, hyperthermic intraperitoneal chemoperfusion (HIPEC) may be an option for selected patients. Our aim was to demonstrate the feasibility of the method and to discuss possible indications. METHODS: After treating a series of adult patients, HIPEC for peritoneal carcinomatosis from a signet cell carcinoma of the colon was performed intraoperatively in a 12-year-old boy. We gave mitomycin C at a dose of 30 mg/m2 over 90 minutes at maximum temperature of 41.2 degrees C. We performed intraoperative drug level monitoring and daily postoperative liver and kidney function tests and differential blood counts. RESULTS: Hyperthermic intraperitoneal chemoperfusion was performed according to protocol without complications. Perfusate and venous drug levels were similar to those in an adult case. The patient had an uneventful recovery, and serum chemistry and blood count returned to normal after a week. The boy lived for 36 months after initial presentation. Sixteen months after HIPEC, still with excellent quality of life, an elevated carcinoembryonic antigen (CEA) indicated recurrence. Thirty months after HIPEC, he died of progressive recurrent disease. CONCLUSIONS: Hyperthermic intraperitoneal chemoperfusion as performed in adults may be beneficial to children with peritoneal carcinomatosis and merits further study.

Histological response of peritoneal carcinomatosis after hyperthermic intraperitoneal chemoperfusion (HIPEC) in experimental investigations.

BACKGROUND: In selected patients with peritoneal carcinomatosis from colorectal cancer prognosis can be improved by hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery. The aim of this study was to evaluate the tumor response of peritoneal carcinomatosis in tumor-bearing rats treated with HIPEC. METHODS: CC531 colon carcinoma (2,5 x 106 cells), implanted intraperitoneally in Wag/Rija rats, was treated by hyperthermic intraperitoneal chemotherapy. After 10 days of tumor growth the animals were randomized into five groups of six animals each: group I: control (n = 6), group II: sham operated animals (n = 6), group III: hyperthermic intraperitoneal perfusion (HIP) without cytostatic drugs, group IV: HIPEC with mitomycin C in a concentration of 15 mg/m2 (n = 6), group V: mitomycin C i.p. alone in a concentration of 10 mg/m2 (n = 6). After 10 days the extent of tumor spread and histological outcome were analysed by autopsy. RESULTS: All control animals developed extensive intraperitoneal tumor growth. Histological tumor load was significantly reduced in group III and group V and was lowest in group IV. In group II tumor load was significantly higher than in group I. Implanted metastases were significantly decreased in group IV compared with group I and group II. CONCLUSION: These findings indicate that HIPEC is an effective treatment for peritoneal carcinomatosis in this animal model. HIPEC reduced macroscopic and microscopic intraperitoneal tumor spread.

Cerebral representation of the anorectum using functional magnetic resonance imaging.

BACKGROUND: Anorectal continence depends not only on the organs of continence but also on cerebral control. There are relatively few data regarding cerebral processing of anorectal continence. METHODS: Thirteen healthy subjects underwent rectal distension to cause urge increasing to discomfort during functional magnetic resonance imaging (fMRI). In addition, a painful heat stimulus was applied to the skin of the anterior abdominal wall in the dermatome corresponding to the rectum. Voluntary contraction of the anal sphincter was also performed. Subjective rating of stimulus intensity was recorded. Evaluation of the data used a general linear model with Brain Voyager(trade mark). RESULTS: Subjective sensation of discomfort increased during repeated rectal distension and caused activation in the anterior cingulate gyrus, insula, thalamus and secondary somatosensory cortex seen on fMRI. Perception of rectal urge and discomfort activated the same cerebral regions with differing intensity. Application of a painful thermal stimulus in the corresponding dermatome showed a modification of the response. Voluntary contraction of the anal sphincter led to activation of the motor cortex and increased activity in the supplementary motor cortex and the insula. CONCLUSION: Cerebral representation of the anorectum as mapped by fMRI is intricate and reflects the complexity of the continence mechanism.

Hyperthermic isolated limb perfusion (HILP) in malignant melanoma. Experience with 101 patients.

AIMS: To analyse results with a standardized HILP procedure in terms of response rate, recurrence pattern and complication rate. PATIENTS AND METHODS: From 1992 to 2003 HILP with melphalan and dactinomycin was performed in 101 patients with loco-regional metastases of malignant melanoma of the limbs. Among these were 66 women and 35 men with a median age of 62 years. Forty patients were in M. D. Anderson stage IIIA, 51 patients in stage IIIAB and 9 had stage IV disease at the time of perfusion. If not been done before, regional lymph node dissection preceded limb perfusion in the same setting. RESULTS: A complete response (CR) was observed in 58 out of 87 evaluable patients. Twenty-one patients achieved a partial response (PR) and eight patients were non-responders. The overall response rate was 90.8%. The median recurrence-free interval after CR was 21 months. Severe toxicity (Wieberdink IV/V) was observed in five patients necessitating fasciotomy in four of them and above knee amputation in one patient. All further cases presented with grade II-III toxicity. The overall survival was 42 months, with a 5-year survival rate of 38%. Survival significantly differed according to stage of disease. CONCLUSION: HILP is an effective treatment for loco-regional tumour relapse of malignant melanoma of the extremities and has improved by modification of technique. In the absence of regional lymph node and distant metastases long-term survival can be achieved in responders.

Innovations in fecal incontinence: sacral nerve stimulation.

OBJECTIVE: The aim of this study was to present an overview of sacral nerve stimulation in the treatment of fecal incontinence. We describe the evolution in technique, patient selection, and indications, and review results and complications. METHODS: All articles on sacral nerve stimulation for fecal incontinence that were recovered on MEDLINE search were reviewed. With multiple articles from an institution, the most recent reports with the longest follow-up and largest cohort of patients were selected, unless information from earlier reports was relevant. RESULTS: The technique of sacral stimulation is well established, carries little risk, and continues to be refined (e.g., a less invasive approach has been proposed). Patient selection is based on a two-stage diagnostic test stimulation (acute and subchronic), for which the predictive value is high. On this basis, permanent sacral nerve stimulation has proved effective in both single-center and multicenter trials in patients with a functional deficit but limited morphologic lesions or no morphologic lesions. The clinical benefit derives from multiple symptomatic improvements contributing to better bowel control and from substantially improved quality of life. The underlying mechanism of action remains undefined, but both somatic and autonomic function appears affected. CONCLUSION: Sacral nerve stimulation offers a safe treatment mode in a patient population in whom conservative treatment has failed and traditional surgical approaches would have limited success. The high predictive value of the diagnostic approach offers a unique therapeutic advantage.

Palliative second-line treatment with weekly high-dose 5-fluorouracil as 24-hour infusion and folinic acid (AIO) plus oxaliplatin after pre-treatment with the AIO-regimen in colorectal cancer (CRC).

BACKGROUND AND AIMS: The aim of this work was to evaluate the efficacy and safety of second-line treatment with weekly high-dose 5-Fluorouracil (5-FU) as a 24-hour infusion (24-h inf.) and folinic acid (FA) (AIO-regimen) plus Oxaliplatin (L-OHP) after pre-treatment with the AIO regimen, focusing in particular on the efficacy of palliative first- and second-line treatment in colorectal carcinoma (CRC). PATIENTS AND METHODS: Patients with non-resectable distant CRC metastases were enrolled in a prospective phase II study for palliative second-line treatment after previous palliative first-line treatment in accordance with the AIO regimen. On an outpatient basis, the patients received a treatment regimen comprising biweekly 85 mg/m2 L-OHP in the form of a 2-hour intravenous (i.v.) infusion and 500 mg/m2 FA as a 1 to 2-hour i.v. infusion, followed by 2,600 mg/m2 5-FU administered as a 24-h inf. i.v. once weekly. A single treatment cycle comprised 6 weekly infusions followed by 2 weeks of rest. RESULTS: During second-line treatment, a total of 26 patients received 340 chemotherapy applications. As the main symptom of toxicity, diarrhoea (NCI-CTC toxicity grade 3+4) presented in 5 patients (19%; 95% CI: 4-34), followed by nausea (CTC grade 3) in one patient (4%; 95% CI: 0-11). Twenty-three patients were evaluable for treatment response. The remission data can be summarised as follows: Complete remission (CR): n=1 (4%; 95% CI: 0-13); partial remission (PR): n=3 (13%; 95% CI: 0-27); stable disease (SD): n=11 (48%; 95% CI: 27-68) and progressive disease (PD): n=8 (35%; 95% CI: 15-54). The median progression-free survival (PFS) rate (n=26) was 3.3 months (range 0-11.5), the median survival time counted from the start of second-line treatment (n=26) 11.6 months (range 2.1-33.0) and the median survival time counted from the start of first-line treatment (n=26) 19.9 months (range 7.7-49.8). CONCLUSION: Palliative second-line treatment according to the AIO regimen plus L-OHP is feasible in an outpatient setting and well tolerated by the patients. Tumour control (CR + PR + SD) was achieved in 65% of the patients, the median survival time being 11.6 months. The AIO regimen followed by the 'AIO regimen plus L-OHP' therapy sequence led to a promising median survival time of 19.9 months (range 7.7-49.8).

Adjuvant vs. neoadjuvant radiochemotherapy for locally advanced rectal cancer: the German trial CAO/ARO/AIO-94.

AIM: The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy (RCT) is recommended for advanced disease (pT3/4 or pN+). In recent years, encouraging results of pre-operative radiotherapy have been reported. This prospective randomized phase-III-trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant RCT to standard postoperative RCT. We report on the design of the study and first results with regard to toxicity of RCT and postoperative morbidity. PATIENTS AND METHODS: Patients with locally advanced operable rectal cancer (uT3/4 or uN+, Mason CS III/IV) were randomly assigned to pre or postoperative RCT: A total dose of 50.4 Gy (single dose 1.8 Gy) was applied to the tumour and the pelvic lymph nodes. 5-FU (1000 mg/m2/d) was administered concomitantly in the 1th and 5th week of radiation as 120 h-continuous infusion. Four additional cycles of 5-FU-chemotherapy (500 mg/m2/d, i.v.-bolus) were applied. RCT was identical in both arms except for a small-volume boost of 5.4 Gy postoperatively. The time interval between RCT and surgery was 4-6 weeks in both arms. Techniques of surgery were standardized and included total mesorectal excision. Primary endpoints of the study are 5-year survival and local and distant control. Secondary endpoints include the rate of curative (R0) resection and sphincter saving procedures, toxicity of RCT, surgical complications and quality of life. RESULTS: As of July 2002, 805 patients were randomized from 26 participating institutions. Acute toxicity (WHO) of RCT was low, with less than 15% of patients experiencing grade 3 or higher toxicity: The principal toxicity was diarrhea, with 12% in the postoperative RCT-arm and 11% in the pre-operative RCT-arm having grade 3-, and 1% in either arm having grade 4-diarrhea. Erythema, nausea and leukopenia were the next common toxicities, with less than 3% of patients in either arm suffering grade 3 or greater leukopenia or nausea. Postoperative complication rates were similar in both arms, with 12% (postop. RCT) and 12% (pre-op. RCT) of patients, respectively, suffering from anastomotic leakage, 3% (postop. RCT) and 3% (pre-op. RCT) from postoperative bleeding, and 6% (postop. RCT) and 4% (pre-op. RCT) from delayed wound healing. CONCLUSION: The patient accrual to the trial is satisfactory. Neoadjuvant RCT is well tolerated and bears no higher risk for postoperative morbidity.

Relationship between microsatellite instability, response and survival in palliative patients with colorectal cancer undergoing first-line chemotherapy.

BACKGROUND AND AIMS: The aim of this work was to investigate the relationship between microsatellite instability (MSI), treatment response and survival in palliative patients with colorectal cancer (CRC) undergoing first-line treatment with weekly 24-hour infusion (24-h inf.) of high-dose 5-fluorouracil (5-FU) and folinic acid (FA). PATIENTS AND METHODS: Tumour material from the colorectal primary carcinomas was analysed for 43 patients. MSI analysis was carried out and immunohistochemistry was performed with hMLH1 and hMSH2. RESULTS: Tumours of 7 patients (16%) were highly instable (MSI-H). These patients had a better response rate (72% vs. 41%; p = 0.072) and a significantly better median survival (33 months, [95% CI 20-46] vs. 19 months, [95% CI 10-28]; p = 0.021) than microsatellite stable (MSS) patients (n = 36). Furthermore, MSI status was shown to be an independent predictive marker for survival (p = 0.037). CONCLUSION: These data provide further support for the hypothesis that MSI-H CRC might have a better response and survival than (MSS) CRC in palliative first-line treatment.

Neoadjuvant treatment with weekly high-dose 5-Fluorouracil as 24-hour infusion, folinic acid and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer.

PURPOSE: To evaluate the efficacy and safety of neoadjuvant treatment comprising weekly high-dose 5-fluorouracil (5-FU) as a 24-hour infusion, folinic acid (FA) and biweekly oxaliplatin (L-OHP), followed by metastatic resection in patients with primarily resectable liver metastases of colorectal cancer (CRC). PATIENTS AND METHODS: 20 patients with primarily resectable liver metastases of CRC were enrolled in a prospective phase II study. On an outpatient basis, the patients received a treatment regimen comprising biweekly 85 mg/m(2) L-OHP in the form of a 2-hour intravenous infusion and 500 mg/m(2) FA as a 1- to 2-hour intravenous infusion, followed by 2,600 mg/m(2 ) 5-FU administered as a 24-hour intravenous infusion once weekly. A single treatment cycle comprised one infusion per week during a period of 6 weeks followed by a 2-week rest. Two cycles were administered, with a third being added when the treatment was well tolerated. Thereafter, curative resection of the liver metastases was attempted, and the patients were followed up. RESULTS: After neoadjuvant therapy, 2 of the original 20 patients showed complete remission (CR; 10%) and 18 patients partial remission (PR; 90%). As the main symptom of toxicity, diarrhea (CTC toxicity grade 3-4) was observed in 6 patients (30%), followed by vomiting in 3 patients (15%). The curative resectability rate was 80% (16 of 20). In 9 of 18 patients (50%) undergoing surgical intervention, mild postoperative complications, mainly wound healing disturbances (n = 5), occurred. No postoperative mortality was observed. Over a median follow-up of 23 months (12-38) 6 of 16 curatively resected patients developed distant metastases and 1 patient a local pelvic recurrence. The 2-year disease-free survival rate was 52% and the 2-year cancer-related survival rate 80%. CONCLUSION: The neoadjuvant treatment with weekly high-dose 5-FU in the form of a 24-hour infusion combined with FA and L-OHP is very effective and well tolerated. Surgical morbidity does not appear to be increased by the neoadjuvant treatment.

[Sacral nerve stimulation in the treatment of faecal incontinence]. / Sakralnervstimulation in der Behandlung der Stuhlinkontinenz.

BACKGROUND: Sacral nerve stimulation is a recent development in the treatment of faecal incontinence. This paper reports the experiences of a single center on the use of this technique since its first application. PATIENTS AND METHOD: Based on the functional results of a temporary test stimulation phase, 16 patients underwent operative implantation of a permanent neurostimulation device. Due to a functional deficit of the morphologically intact anal sphincter, all patients suffered from incontinence for liquid and solid stool. The aetiology varied among the patients. The median duration of symptoms was 8.5 years (2-30). Clinical function was evaluated by standardized questionnaires, the Cleveland Clinic incontinence score and the disease specific quality of life instrument (FIQL-ASCRS) before and during stimulation. Anorectal physiology was tested by anorectal manometry. RESULTS: Functional improvement was achieved in 94% of the patients. At a median follow-up of 32.5 months (3-99) treatment was successful in 81%. The percentage of incontinent bowel movements decreased from a median of 40% (5-100) before stimulation to 0% (0-20) with stimulation ( P=0.001). The Cleveland Clinic incontinence score improved from a median of 17 (11-20) to 5 (0-15) ( P=0.003). The quality of life index was improved in all categories.Mean squeeze pressure was increased form a median of 44 to 75 mmHg with stimulation ( P=0.003) and maximal squeeze pressure from a median of 69 to 97 mmHg (P=0.009). Resting pressure, perception, urge threshold and maximum tolerable volume were not significantly changed. CONCLUSION: Sacral nerve stimulation is an effective treatment for faecal incontinence. Morbidity is low. Sacral nerve stimulation is indicated, if conservative treatment fails and more conventional surgical approaches are of limited success.

[Palliative second-line treatment with oxaliplatin, gemcitabine and weekly high-dose 5-fluorouracil as 24-h infusion in patients with metastatic pancreatic adenocarcinoma]. / Palliative Zweitbehandlung mit Oxaliplatin, Gemcitabin und wochentlich hochdosiert 5-Fluorouracil als 24-h-Infusion beim metastasierten Adenokarzinom des Pankreas.

The most commonly used treatment in the palliative first-line therapy of metastatic pancreatic adenocarcinoma is the Gemcitabine (Gem) monotherapy, while several combination therapies are currently being tested in clinical trials. With regard to pancreatic cancer, a palliative second-line therapy has not been established, yet. The four patients presented in this paper received a palliative second-line therapy with Oxaliplatin (L-OHP), Gem and high-dose 5-Fluorouracil (5-FU) as a 24-h infusion after a first-line therapy with Gem and weekly high-dose 5-FU as a 24-h infusion. During second-line therapy, four patients received 67 chemotherapy applications, which were well tolerated. As severe symptom of toxicity, thrombocytopenia (CTC toxicity grade 4) was observed in one patient. As a result of second-line therapy, stable disease (SD) with a significant decrease of CA 19 - 9 was achieved in three patients and partial remission (PR) in one patient. After palliative first- and second-line treatment the survival time of the patients was 9, 9, 15 and 20 months. Currently, a multicentre phase I study has been started aiming at an optimisation of the three-drug combination dosage.

Small bowel resection in the rat: the effect upon bone and mineral metabolism.

BACKGROUND AND AIMS: We analyzed bone and mineral metabolism after long-segment small bowel resection in the rat to detect functional and morphological alterations and to determine the development of osteopathy. METHODS: Twelve-week-old male Lewis rats were randomized into short (8-week) or long (16-week) follow-up groups. Sham operation, resection of the proximal third of the small bowel, resection of the distal third of the bowel and resection of the entire jejunum and ileum were carried out. Nineteen days before the end of the experiment the animals were transferred into a metabolic cage to analyze weight gain/loss, food intake, and fecal excretion/24 h. At the end of the experiment the animals were killed; blood samples and bowel and bone specimens were collected, length, weight, volume, density, mineral content, and fracturing energy were determined, and bone histology was examined. The calcium/phosphorus ratio, nonmineralized tissue content and the ratio fracturing energy/mean bone density were calculated. RESULTS: After 8 weeks there were significant differences to the control group in body weight, weight gain, food efficiency, femur length, weight, volume, mineral content, mineral density, fracturing energy per bone volume, and bone density but not in bone calcium or magnesium. After 16 weeks there were differences in body weight, weight gain, food efficiency, femur length, weight, volume, bone mineral content and density, bone minerals, and nonmineralized tissue but not in fracturing energy; the average values of all these parameters were lower in the resected groups, and lowest in the group after resection of the entire jejunum and ileum. Bone histology showed a reduction in trabecular bone mass after long-segment small bowel resection. CONCLUSIONS: Long-segment small bowel resection causes a significant loss of body weight despite of a comparable mean chow ingestion resulting in a significant decreased food efficiency. We conclude that there is no inverse relationship of bone calcium content and the fracture risk, and that there is no severe mineralization defect after long-segment small bowel resection.