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.

Long-term prognostic impact of surgical complications in the German Rectal Cancer Trial CAO/ARO/AIO-94.

BACKGROUND: The influence of postoperative complications on survival in patients with locally advanced rectal cancer undergoing combined modality treatment is debatable. This study evaluated the impact of surgical complications on oncological outcomes in patients with locally advanced rectal cancer treated within the randomized CAO/ARO/AIO-94 (Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society) trial. METHODS: Patients were assigned randomly to either preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) or postoperative CRT between 1995 and 2002. Anastomotic leakage and wound healing disorders were evaluated prospectively, and their associations with overall survival, and distant metastasis and local recurrence rates after a long-term follow-up of more than 10 years were determined. Medical complications (such as cardiopulmonary events) were not analysed in this study. RESULTS: A total of 799 patients were included in the analysis. Patients who had anterior or intersphincteric resection had better 10-year overall survival than those treated with abdominoperineal resection (63·1 versus 51·3 per cent; P < 0·001). Anastomotic leakage was associated with worse 10-year overall survival (51 versus 65·2 per cent; P = 0·020). Overall survival was reduced in patients with impaired wound healing (45·7 versus 62·2 per cent; P = 0·009). At 10 years after treatment, patients developing any surgical complication (anastomotic leakage and/or wound healing disorder) had impaired overall survival (46·6 versus 63·8 per cent; P < 0·001), a lower distant metastasis-free survival rate (63·2 versus 72·0 per cent; P = 0·030) and more local recurrences (15·5 versus 6·4 per cent; P < 0·001). In a multivariable Cox regression model, lymph node metastases (P < 0·001) and surgical complications (P = 0·008) were the only independent predictors of reduced overall survival. CONCLUSION: Surgical complications were associated with adverse oncological outcomes in this trial.

Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study).

BACKGROUND: Initially, unresectable colorectal liver metastases can be resected after response to chemotherapy. While cetuximab has been shown to increase response and resection rates, the survival outcome for this conversion strategy needs further evaluation. PATIENTS AND METHODS: Patients with technically unresectable and/or ≥5 liver metastases were treated with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated with regard to resectability every 2 months. Tumour response and secondary resection data have been reported previously. A final analysis of overall survival (OS) and progression-free survival (PFS) was carried out in December 2012. RESULTS: Between December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 [95% confidence interval (CI) 27.2-44.2] months [arm A: 35.8 (95% CI 28.1-43.6), arm B: 29.0 (95% CI 16.0-41.9) months, HR 1.03 (95% CI 0.66-1.61), P = 0.9]. The median PFS was 10.8 (95% CI 9.3-12.2) months [arm A: 11.2 (95% CI 7.2-15.3), arm B: 10.5 (95% CI 8.9-12.2) months, HR 1.18 (95% CI 0.79-1.74), P = 0.4]. Patients who underwent R0 resection (n = 36) achieved a better median OS [53.9 (95% CI 35.9-71.9) months] than those who did not [21.9 (95% CI 17.1-26.7) months, P < 0.001]. The median disease-free survival for R0 resected patients was 9.9 (95% CI 5.8-14.0) months, and the 5-year OS rate was 46.2% (95% CI 29.5% to 62.9%). CONCLUSIONS: This study confirms a favourable long-term survival for patients with initially sub-optimal or unresectable colorectal liver metastases who respond to conversion therapy and undergo secondary resection. Both FOLFOX/FOLFIRI plus cetuximab, appear to be appropriate regimens for 'conversion' treatment in patients with K-RAS codon 12/13/61 wild-type tumours. Thus, liver surgery can be considered curative or alternatively as an additional 'line of therapy' in those patients who are not cured. CLINICAL TRIAL NUMBER: NCT00153998, www.clinicaltrials.gov.

Discrepancies between medical oncologists and surgeons in assessment of resectability and indication for chemotherapy in patients with colorectal liver metastases.

BACKGROUND: Multidisciplinary discussion of the treatment of patients with colorectal liver metastases (CRLM) is advocated currently. The aim of this study was to investigate medical oncologists' and surgeons' assessment of resectability and indication for chemotherapy, and the effect of an educational intervention on such assessment. METHODS: Medical histories of 30 patients with CRLM were presented to ten experienced medical oncologists and 11 surgeons at an initial virtual tumour board meeting (TB1). Treatment recommendations were obtained from each participant by voting for standardized answers. Following lectures on the potential of chemotherapy and surgery, assessment was repeated at a second virtual tumour board meeting (TB2), using the same patients and participants. RESULTS: Overall, 630 answers (21 × 30) were obtained per tumour board meeting. At TB1, resectability was expected more frequently by surgeons. Participants changed 56·8 per cent of their individual answers at TB2. Assessment shifted from potentially resectable to resectable CRLM in 81 of 161 and from unresectable to (potentially) resectable CRLM in 29 of 36 answers. Preoperative chemotherapy was indicated more often by medical oncologists, and overall was included in 260 answers (41·3 per cent) at TB1, compared with only 171 answers (27·1 per cent) at TB2. Medical oncologists more often changed their decision to primary resection in resectable patients (P = 0·006). Postoperative chemotherapy was included in 51·9 and 52·4 per cent of all answers at TB1 and TB2 respectively, with no difference in changes between medical oncologists and surgeons (P = 0·980). CONCLUSION: Resectability and indication for preoperative chemotherapy were assessed differently by medical oncologists and surgeons. The educational intervention resulted in more patients deemed resectable by both oncologists and surgeons, and less frequent indication for chemotherapy.

Metastatic recurrence after complete resection of colorectal liver metastases: impact of surgery and chemotherapy on survival.

PURPOSE: Surgery is the standard of care for resectable colorectal liver metastases (CRC-LM). Unfortunately, 60% of patients develop secondary metastatic recurrence (SMR) after R0-resection of CRC-LM. We investigated the impact of surgical re-intervention and chemotherapy (Ctx) on survival in a consecutive series of patients with SMR. METHODS: From 01/2001 to 11/2011, 104 out of 178 consecutive patients with R0-resection of CRC-LM developed SMR and were evaluated. The impact of surgical and Ctx re-interventions on recurrence free (RFS) and cancer-specific survival (CSS) was analyzed. Median follow-up was 28.0 (95%CI: 19.4-37.4) months. RESULTS: SMR occurred in 81 patients at a single site (49× liver, 18× lung, 14× other) and in 23 patients at multiple sites. Forty-two patients were scheduled for primary surgery. Fifty-three patients were classified as non-resectable and treated with median 5.0 [IQR, 3.0-10.0] cycles of Ctx, combined with an EGFR/VEGF-antibody in 27 patients. Nine patients received best supportive care only. R0/R1 resection could be achieved in 35 patients primarily and even in 8 patients secondarily after Ctx. Surgical morbidity and mortality were 16 and 0%, respectively. The 5-year RFS rates for patients with R0 versus R1-resection were 22 and 24% (p = 0.948). The 5-year CSS rate for R0/R1-resected patients was 38% versus 10% for those patients treated by Ctx alone (p < 0.001). CONCLUSION: In SMR, surgical re-intervention is feasible and safe in a remarkable number of patients and offers significantly longer CSS compared to patients without resection.

Bilobar spreading of colorectal liver metastases does not significantly affect survival after R0 resection in the era of interdisciplinary multimodal treatment.

PURPOSE: Bilobar colorectal liver metastases (CRLM) are often considered incurable or associated with poor prognosis even after R0 resection. In this single-center study, we evaluate the impact of CRLM spreading on recurrence-free survival (RFS) and cancer-specific overall survival (CSS) after R0 resection of CRLM with respect to multimodal treatment strategies including perioperative chemotherapy and multistep resections. METHODS: Between January 2001 and December 2010, R0 resection could be achieved in 70 patients with bilobar and 100 with unilobar CRLM. Extent of disease, perioperative chemotherapy, surgical procedures, adjuvant treatment, histopathological workup, RFS, and CSS were compared between both cohorts. RESULTS: Forty-six (66 %) patients with bilobar and 26 (26 %) patients with unilobar CRLM received preoperative chemotherapy (p < 0.001). For bilobar CRLM, more extended and multistep resection including portal vein occlusion were performed (29 % versus 3 %; p < 0.001). Morbidity (39 % versus 28 %, p = 0.183) and mortality (1 % versus 3 %, p = 0.644) rates were comparable in both patients' cohorts. Postoperative therapy was applied in adjuvant intent to 42 (60 %) versus 51 (51 %) patients (p = 0.275). The 5-year RFS and CSS rates were 24 % versus 31 % (p = 0.169) and 42 % versus 55 % (p = 0.131), respectively. CONCLUSIONS: To our single-center experience, there is no significant effect of CRLM spreading (bilobar versus unilobar) on RFS and CSS rates. Bilobar CRLM are more likely to require extended multimodal efforts to achieve R0 resection.

[Rectal cancer: current status of multimodal therapy--when and how?]. / Rektumkarzinom: Aktueller Stand der multimodalen Therapie--wann und wie?

Preoperative 5-fluorouracil-based radiochemotherapy (RCT) followed by quality assessed total mesorectal excision (TME surgery) are the two most important elements of multimodal treatment for patients with locally advanced rectal cancer (UICC stages II and III). The optimum sequence of these neoadjuvant modalities complemented by adjuvant (postoperative) chemotherapy, has been addressed in several randomised trials. Especially within the trials of the German Rectal Cancer Study Group (GRCSG), preoperative RCT has been shown to be superior to postoperative treatment for a variety of endpoints (pathologically confirmed complete tumour remission (pCR), RCT-induced tumour regression, R0 resection rates (including circumferential resection margins) and long-term locoregional control). This neoadjuvant multimodal strategy has decreased the 5-year and 10-year local recurrence rates below 10%, and the development of distant metastases (e.g., 35% to 45% liver metastases) remains the predominant reason for failure. Furthermore, approximately 25% of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients' refusal or the investigator's discretion. Thus, today, integrating more effective systemic therapy into (preoperative) multimodal regimens is the most accepted challenge! But from the clinical point of view this demand is also a dilemma. The question to be addressed is how and when to apply intensified systemic therapy with adequate dosage and intensity as well as acceptable treatment-associated toxicity. The increase of therapeutic options requires valid predictive biomarkers that may help to stratify patients into regimens associated with low toxicity (5-FU monotherapy alone) or into more intensified treatment for better long-term outcome. In summary, the use of biomarkers for individualised risk-adapted treatment is one of the most promising areas of clinical investigations, not only in rectal cancer. The assessment of individual tumour response, toxicity, and prognosis during multimodal treatment of rectal cancer as a model of a very common solid tumour offers radiooncologists, surgeons, pathologists, gastroenterologists as well as oncologists immense insights into the under-standing of tumour biology.

The mesopancreas is the primary site for R1 resection in pancreatic head cancer: relevance for clinical trials.

PURPOSE: The prognosis of patients with pancreatic cancer remains poor, even after potentially curative R0 resection. This discrepancy may be due to the histopathological misclassification of R1 cases as curative resections (R0) in the past. MATERIALS AND METHODS: To test this hypothesis, color coding of all resection margins and organ surfaces as part of a standardized histopathological workup was implemented and prospectively tested on 100 pancreatic head specimens. RESULTS: Thirty-five patients were excluded from the analysis owing to the pathohistological diagnosis; only pancreatic ductal adenocarcinoma, distal bile duct adenocarcinoma, and periampullary adenocarcinoma were included. Applying the International Union Against Cancer criteria, 32 cancer resections were classified R0 (49.2%), while 33 cases turned out to be R1 resections (50.8%). The mesopancreas was infiltrated in 22 of the 33 R1 resection specimens (66.6%). It proved to be the only site of tumor infiltration in 17 specimens (51.5%). Applying the Royal College of Pathologists' criteria, 46 resections were classified R1 (70.8%). As expected, the mesopancreas again was the most frequent site of noncurative resection (n = 27; 58.7%). CONCLUSION: Using the intensified histopathological workup for pancreatic head cancer specimens resulted in an increased rate of R1 resections and the mesopancreas represents the primary site for positive resection margins. Such results are of relevance for patients' stratification in clinical trials.

[Extramural Gastral GIST Manifested by Spontaneous Perforation with Acute Intraabdominal Bleeding and Haemoperitoneum]. / Extramuraler GIST des Magens mit Manifestation durch Spontanruptur und akuter intraabdomineller Blutung mit Hämatoperitoneum.

We report on the case of a 38-year-old male patient with a huge extramural gastrointestinal stromal tumour (GIST) of the stomach, located in the left upper and middle abdominal cavity that was diagnosed on the basis of a spontaneous -rupture and consecutive haemoperitoneum. The lesion was resected completely in an emergency operation. The tumour was classified as a high-risk lesion for aggressive biological behaviour and with regard to tumour rupture with perforation of the serosa, an adjuvant systemic therapy was indicated.

CONKO-006: A randomised double-blinded phase IIb-study of additive therapy with gemcitabine + sorafenib/placebo in patients with R1 resection of pancreatic cancer - Final results.

BACKGROUND: CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles. PATIENTS AND METHODS: This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment. RESULTS: 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021). CONCLUSION: CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients. CLINICAL TRIAL INFORMATION: German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242.

Two-stage hepatectomy (R0) with portal vein ligation--towards curing patients with extended bilobular colorectal liver metastases.

BACKGROUND AND AIMS: Patients with bilobular colorectal liver metastases (CRLM) experience poor prognosis, especially when curative resection cannot be achieved. However, resectability in these patients is often limited by low future remnant liver volume (FRLV). The latter can be enhanced by a two-stage liver resection, using portal vein ligation to induce liver hypertrophy. The aim of this prospective pilot study was to evaluate safety, secondary resectability, and time to recurrence of two-stage hepatectomy with portal vein ligation (PVL) and complete surgical clearance of the FRLV in patients with bilobular CRLM. MATERIALS AND METHODS: Out of 24 patients (63+/-8.26 years) with extended bilobular CRLM (metachronous n=10, synchronous n=14), 18 received preoperative 5-FU-based chemotherapy combined with oxaliplatin or irinotecan. Staging included thoracoabdominal computed tomography and (18)F-fluorodeoxyglucose-positron emission tomography scans. First-stage procedure consisted of PVL, resection of all CRLM in the FRLV, and radiofrequency ablation (RFA) of CRLM situated near the future resection plane. RESULTS: During first-stage procedure, 7x RFA, 4x non-anatomical resections, and 4x bisegmentectomies were performed additionally to PVL. FRLV/body-weight ratio increased from 0.4% to 0.6% within 55 days (median) after PVL. Second-stage hepatectomy was performed in 19 patients without tumor progression. R0 resection was possible in 14 patients. During a median follow-up of 17 months, intrahepatic recurrence occurred in two, and extrahepatic recurrence in nine out of 14 patients. CONCLUSION: Two-stage hepatectomy with PVL and complete surgical clearance of FRLV is safe even after intensified systemic chemotherapy resulting in a curative resection rate of 58.3% (73.7% of re-explored cases).

[Gastrointestinal stromal tumors from the surgical point of view. Laparoscopic therapy]. / Gastrointestinale Stromatumoren aus chirurgischer Sicht. Laparoskopische Therapie.

Gastrointestinal stromal tumors (GIST) are the most frequent soft tissue tumors of the gastrointestinal tract. The demonstration of KIT expression (CD117) defined GIST as a distinct tumor entity. Despite many improvements in the medical therapy, complete tumor resection remains the standard treatment for resectable GIST and is the precondition for cure. Data concerning the role of laparoscopic surgery are sparse, but small gastric GIST (<5 cm) could be a good indication for laparoscopic procedures. In principle laparoscopic GIST resections should be performed only by interdisciplinary teams of surgeons and gastroenterologists experienced in laparoscopy, endoscopy, and oncology.

[Lymph node metastases in ypT1/2 rectal cancer after neoadjuvant chemoradiotherapy : The Achilles heel of organ-preserving operative procedures?]. / Lymphknotenmetastasen beim ypT1/2-Rektumkarzinom nach neoadjuvanter Radiochemotherapie : Die Achillesferse organerhaltender Operationsverfahren?

BACKGROUND: For patients with rectal cancer and complete remission (ypT0) or with good response and residual tumor restricted only to the bowel wall (ypT1-2) after neoadjuvant chemoradiotherapy (CRT), local excision has been suggested as an alternative to avoid the significant morbidity and functional deficits associated with total mesorectal excision (TME). The aim of this investigation was to investigate the incidence, distribution and tumor-related localization of mesorectal lymph node (LN) metastases in TME specimens with complete remission (ypT0), intramural (ypT1-2) and extramural (ypT3-4) residual tumor tissue. PATIENTS AND METHODS: Specimens of TME from 81 patients with locally advanced rectal cancer (UICC II-III) undergoing neoadjuvant CRT within the phase III German rectal cancer trial CAO/ARO/AIO-04 were prospectively evaluated. The entire mesorectal compartment was microscopically screened after complete paraffin embedding. The number and localization of all detectable LN metastases were documented in relation to the primary tumor. RESULTS: Whereas 50 patients (62 %) had ypT3-4 rectal cancer after neoadjuvant CRT, 20 patients (25 %) presented with residual tumor within the bowel wall (ypT1-2), 11 patients (14 %) had pathological complete remission (ypT0), an average of 28 ± 13.7 LN were detected per specimen and 25 patients (31 %) had residual LN metastases after CRT. Although the incidence of LN metastases was higher in the ypT3-4 group (40 %), 25 % of patients in the ypT1-2 group with intramural residual tumor had a mean number of 2.2 residual LN metastases of which 55 % were located far from the primary lesion in the proximal mesorectum. None of the patients with ypT0 status (complete response) had residual LN metastases. CONCLUSION: Even in patients with good response and post-CRT tumor tissue restricted only to the bowel wall (ypT1-2), there is still a considerable risk for residual LN metastases. Local excision of residual rectal cancer was accompanied by a higher rate of local failure and radical surgery with TME should remain the standard treatment in these patients. To date, valid selection criteria for patients eligible for organ-sparing surgery are still lacking.

Radioimmunotherapy of small volume disease of colorectal cancer metastatic to the liver: preclinical evaluation in comparison to standard chemotherapy and initial results of a phase I clinical study.

At the time of surgery, occult metastases (micrometastases) are present in more than 50% of colorectal cancer patients, and the liver is the most frequent site of apparent metastatic disease. Frequently, adjuvant chemotherapy is unable to prevent tumor recurrence. Thus, novel therapeutic strategies are warranted. The aim of this study was to establish a model of human colon cancer metastatic to the liver of nude mice, to assess, in this setting, the therapeutic efficacy of radioimmunotherapy (RAIT) compared to standard chemotherapy and to evaluate, in a Phase I/II trial, the toxicity and therapeutic efficacy of RAIT in colorectal cancer patients with small volume disease metastatic to the liver. Multiple liver metastases of the human colon cancer cell line GW-39 were induced by intrasplenic injection of a 10% tumor cell suspension. Whereas controls were left untreated, therapy was initiated on day 10 or 20 after tumor inoculation with the 131I-labeled, low affinity anticarcinoembryonic antigen (anti-CEA) monoclonal antibody (MAb), F023C5 (Ka = 10(7) liters/mol), or the high-affinity anti-CEA MAb, MN-14 (Ka = 10(9) liters/mol), or chemotherapy (5-fluorouracil/leucovorin (folinic acid) versus irinotecan) at their respective maximum tolerated doses (MTDs). Twelve colorectal cancer patients with small volume disease metastatic to the liver (all lesions < or = 2.5 cm) were entered into a mCi/m2-based Phase I dose escalation study with 131I-labeled humanized version of MN-14, hMN-14. The patients were given single injections, starting at 50 mCi/m2 and escalating in 10-mCi/m2 increments. The MTD was defined as the dose level at which < or = 1 of 6 patients develop grade 4 myelotoxicity. In the mice, untreated controls died from rapidly progressing hepatic metastases at 6-8 weeks after tumor inoculation. The life span of mice treated with 5-fluorouracil/leucovorin was prolonged for only 1-3 weeks, whereas irinotecan led to a 5-8-week prolongation. In contrast, at their respective MTDs, the 131I-labeled low-affinity anti-CEA MAb, F023C5, led to a 20% permanent cure rate, and the high affinity MAb, MN-14, led to an 80% permanent cure rate, when therapy was initiated at 10 days after tumor inoculation. In the 20-day-old tumor stage, although it prolonged life, 131I-F023C5 was unable to achieve cures, whereas 131I-MN-14 was still successful in 20%. Histologically, no remaining viable tumor cells could be demonstrated in these animals surviving > 6 months. In patients, the MTD was reached at 60 mCi/m2 of hMN-14 (at 70 mCi/m2, two of three grade 4 myelotoxicities). Of 11 assessable patients, 2 had partial remissions (corresponding to an objective response rate of 18%), and 5 (45%) had minor/mixed responses or experienced stabilization of previously rapidly progressing disease. These data suggest that in small volume disease, RAIT may be superior to conventional chemotherapy. Antibodies of higher affinity seem to be clearly superior. The clinical response rates in patients with small volume disease are encouraging, being comparable to the response rates of conventional chemotherapeutic regimens but with fewer side effects. Ongoing studies will show whether treatment at the MTD will further improve therapeutic results.

Prognosis factors in incisional hernia surgery: 25 years of experience.

BACKGROUND: Incisional hernia underwent a change from conventional techniques to mesh implantation. The relevance of different factors, like operative technique, mesh material, and patient-related parameters concerning the outcome following mesh repair, are still under debate. METHODS: In a comparative retrospective study of 421 incisional hernia operations on 348 patients, we investigated 241 Mayo procedures and 180 mesh repairs over a 25-year period. In addition to the quality of life following mesh implantation, the prognostic relevance of demographic, preoperative and intraoperative parameters, surgical technique, mesh material, and the surgeon's experience were analysed, both in a univariate and multivariate manner. RESULTS: With a mean follow-up of 9.7+/-8.8 years, the total recurrence rate following Mayo overlap was 37%, in contrast to 15% after mesh implantation (P=0.001). Mesh size was the only significant prognostic factor concerning quality of life following mesh implantation, and 86% of the patients with mesh repair were satisfied. The complication rate was determined significantly by patients' risk factors, size of hernia, operative technique, and the surgeon's experience, whereas the rate of recurrences was significantly influenced by the parameters obesity (BMI>25), size of hernia, and surgical experience. The recurrence rate decreased significantly with surgeon's experience-a minimum of 16 mesh repairs led to a recurrence rate of less than 10%. CONCLUSIONS: Only the mesh repair revealed acceptable recurrence rates with high patient comfort. From a surgical point of view, the most important prognostic factor following mesh repair is the surgeon's experience.

[Present treatment strategies for rectal carcinoma]. / Aktuelle Behandlungsstrategien beim Rektumkarzinom.

In the last ten years, considerable progress has been achieved in the treatment of rectal cancer. According to improved interdisciplinary staging, rectal carcinomas can be treated based on a stage-dependent concept: "low-risk" pT1 (G1/G2) carcinomas can be cured by local full wall excision, while "high-risk" pT1 (G3/G4) and pT2 carcinomas require transabdominal resection. In contrast, locally advanced rectal cancers in cUICC-II/-III stages (T3/T4 or N(+)) should receive long-term, 5-FU-based, neoadjuvant chemoradiotherapy according to the excellent results of the CAO/AIO/ARO-94 trial of the German Rectal Cancer Study Group. High-quality resection must be based on radical oncologic principles such as "no-touch" technique, radicular dissection of vessels, and total mesorectal excision. Multimodal treatment is completed with adjuvant 5-FU-based chemotherapy. This therapeutic approach led to a reduction in the 5-year local recurrence rate to 6% and disease-free survival of approximately 68% in advanced rectal cancer (overall survival: 76%).

Radiation therapy after breast-conserving surgery; first results of a randomised clinical trial in patients with low risk of recurrence.

To study the role of radiotherapy and tamoxifen after breast-conserving surgery (BCS) in patients with a favourable prognosis, a clinical trial was initiated by the German Breast Cancer Study Group. Between 1991 and 1998, 361 patients (pT1pN0M0, aged 45-75 years, receptor positive, grade I-II) were randomised to radiotherapy (yes/no) and tamoxifen for 2 years (yes/no) in a 2x2 factorial design; the exclusion of seven centres (14 patients) left 347 patients in the analysis. After a median follow-up of 5.9 years, 77 events concerning event-free survival have been observed. Since a strong interactive effect between radiotherapy and tamoxifen has been established, the results are presented in terms of the treatment effects for all four treatment groups separately. Mainly due to the presence of local recurrences, the event rate was about three times higher in the group with BCS only than in the other three groups. No difference could be established between the four treatment groups for distant disease-free survival rates. It is concluded that even in patients with a favourable prognosis, the avoidance of radiotherapy and tamoxifen after BCS increases the rate of local recurrences substantially.

Reverse transcriptase/polymerase chain reaction analysis of parathyroid hormone-related protein for the detection of tumor cell dissemination in the peripheral blood and bone marrow of patients with breast cancer.

Tumor cell dissemination in the bone marrow is an independent prognostic marker for relapse and survival for patients with primary breast cancer. Parathyroid-hormone-related protein (PTHrP) is expressed in most primary tumors and bone metastases of patients with breast cancer. PTHrP acts as an autocrine growth factor for breast cancer cells in vitro and there is evidence that it is especially important for osseous metastasis. For a sensitive detection of PTHrP-positive disseminated tumor cells a reverse transcriptase/polymerase chain reaction (RT/PCR) assay for PTHrP transcripts in the peripheral blood (PB) and in the bone marrow (BM) has been established. In mixing studies, the sensitivity of the reverse transcriptase/polymerase chain reaction (RT/PCR) for PTHrP was one tumor cell in 1 x 10(6) mononuclear cells. At this level of sensitivity, transcripts of PTHrP were detected in none of 30 PB samples and in 3 of 25 BM samples of healthy volunteers; there were also no transcripts of PTHrP in the PB and BM of 6 patients with benign breast lesions. The PB samples of 31 patients and the BM samples of 34 patients with predominantly early-stage breast cancer were tested for PTHrP expression along with immunocytology against cytokeratin 18 (CK18) as a standard immunological detection technique. PTHrP expression was shown in 9 of 31 patients in the PB and in 9 of 34 patients in the BM. In 30 patients, PB and BM samples were available simultaneously. There were cases of combined positive findings in the PB and the BM (4/30) and of isolated positivity in the PB (5/30) or in the BM (4/30). Compared to immunocytology, RT/PCR assay of PTHrP assay was significantly more sensitive in the peripheral blood (8/30 by RT/PCR compared to 1/30 by immunocytology). In the bone marrow there were cases of positivity for both markers (2/34), cases of isolated positivity by immunocytology for CK18 (3/34) and cases of isolated positivity for PTHrP transcripts (7/34). In conclusion the RT/PCR assay for PTHrP transcripts is a feasible and very sensitive technique for the detection of tumor cell dissemination in the PB, even in patients with early-stage breast cancer. The specificity of detection of PTHrP transcripts in the bone marrow is limited, possibly because of autochthonous expression of PTHrP in osteoblastic cells. The clinical follow-up of the subgroups of patients at risk, as defined by this assay, will show its prognostic significance for patients with breast cancer.