Lucas Widmer

Cetuximab in Combination With Chemoradiotherapy Before Surgery in Patients With Resectable, Locally Advanced Esophageal Carcinoma : a Prospective, Multicenter Phase IB/II Trial (SAKK 75/06)

PURPOSE This multicenter phase IB/II trial investigated cetuximab added to preoperative chemoradiotherapy for esophageal cancer. PATIENTS AND METHODS Patients with resectable, locally advanced esophageal cancer received two 3-week cycles of induction chemoimmunotherapy (cisplatin 75 mg/m(2) day 1, docetaxel 75 mg/m(2) day 1, cetuximab 250 mg/m(2) days 1, 8,15 [400 mg/m(2) loading dose]) followed by chemoimmunoradiation therapy (CIRT) and surgery. CIRT consisted of 45 Gy radiotherapy (RT) plus concurrent cisplatin 25 mg/m(2) and cetuximab 250 mg/m(2) weekly for 5 weeks in cohort 1. If fewer than three of seven patients experienced limiting toxicity (LT), the next seven patients also received docetaxel (20 mg/m(2) weekly × 5). If fewer than three patients experienced LTs, 13 additional patients were treated at this dose. RESULTS In total, 28 patients (median age, 64 years) with predominantly node-positive (82%) esophageal adenocarcinoma (15 patients) or squamous cell carcinoma (13 patients) were enrolled and 24 (86%) completed the entire trimodal therapy. During CIRT, no LT occurred, rash was not exacerbated within the RT field, and the main grade 3 toxicities were esophagitis (seven patients), anorexia (three), fatigue (three), and thrombosis (two). Surgery (R0 resection) was performed in 25 patients. Anastomotic leakage occurred in three patients: two recovered spontaneously and one successfully underwent re-operation. There were no deaths at 30 days and no treatment-related mortality after 12 months. Nineteen patients (68%) showed complete or near complete pathologic regression. CONCLUSION Adding cetuximab to preoperative chemoradiotherapy is feasible without increasing postoperative mortality. Phase III investigation has begun based on the high histopathologic response and R0 resection rate.

Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02)

BACKGROUND This multicenter phase II study investigated the efficacy and feasibility of preoperative induction chemotherapy followed by chemoradiation and surgery in patients with esophageal carcinoma. PATIENTS AND METHODS Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the esophagus received induction chemotherapy with cisplatin 75 mg/m(2) and docetaxel (Taxotere) 75 mg/m(2) on days 1 and 22, followed by radiotherapy of 45 Gy (25 x 1.8 Gy) and concurrent chemotherapy comprising cisplatin 25 mg/m(2) and docetaxel 20 mg/m(2) weekly for 5 weeks, followed by surgery. RESULTS Sixty-six patients were enrolled at eleven centers and 57 underwent surgery. R0 resection was achieved in 52 patients. Fifteen patients showed complete, 16 patients nearly complete and 26 patients poor pathological remission. Median overall survival was 36.5 months and median event-free survival was 22.8 months. Squamous cell carcinoma and good pathologically documented response were associated with longer survival. Eighty-two percent of all included patients completed neoadjuvant therapy and survived for 30 days after surgery. Dysphagia and mucositis grade 3/4 were infrequent (<9%) during chemoradiation. Five patients (9%) died due to surgical complications. CONCLUSIONS This neoadjuvant, taxane-containing regimen was efficacious and feasible in patients with locally advanced esophageal cancer in a multicenter, community-based setting and represents a suitable backbone for further investigation.

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07

BACKGROUND We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

Limited Predictive Value of FDG-PET for Response Assessment in the Preoperative Treatment of Esophageal Cancer: Results of a Prospective Multi-Center Trial (SAKK 75/02)

Background: Only responding patients benefit from preoperative therapy for locally advanced esophageal carcinoma. Early detection of non-responders may avoid futile treatment and delayed surgery. Patients and Methods: In a multi-center phase ll trial, patients with resectable, locally advanced esophageal carcinoma were treated with 2 cycles of induction chemotherapy followed by chemoradiotherapy (CRT) and surgery. Positron emission tomography with 2[fluorine-18]fluoro-2-deoxy-d-glucose (FDG-PET) was performed at baseline and after induction chemotherapy. The metabolic response was correlated with tumor regression grade (TRG). A decrease in FDG tumor uptake of less than 40% was prospectively hypothesized as a predictor for histopathological non-response (TRG > 2) after CRT. Results: 45 patients were included. The median decrease in FDG tumor uptake after chemotherapy correlated well with TRG after completion of CRT (p = 0.021). For an individual patient, less than 40% decrease in FDG tumor uptake after induction chemotherapy predicted histopathological non-response after completion of CRT, with a sensitivity of 68% and a specificity of 52% (positive predictive value 58%, negative predictive value 63%). Conclusions: Metabolic response correlated with histopathology after preoperative therapy. However, FDG-PET did not predict non-response after induction chemotherapy with sufficient clinical accuracy to justify withdrawal of subsequent CRT and selection of patients to proceed directly to surgery.

Reversible Posterior Leukoencephalopathy Syndrome after Treatment of Diffuse Large B-Cell Lymphoma

Background: We report the case of a patient who experienced a severe neurologic complication after treatment of diffuse large B-cell lymphoma. Case Report: A 62-yearold patient was diagnosed with a diffuse large B-cell lymphoma and treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone under prophylactic G-CSF substitution. After the second cycle she developed severe neurologic complications with generalized seizures and soporous condition. The MRI showed bilateral areas of signal hyperintensity in the subcortical and cortical regions in both hemispheres, consistent with the diagnosis of a reversible posterior leukoencephalopathy syndrome. The patient was under surveillance in intensive care, and a meticulous control of the blood pressure was performed. She fully recovered within a few days, and MRI changes normalized. Antineoplastic treatment had to be continued, and we chose a combination of rituximab, doxorubicin, etoposide, and prednisone. Conclusions: The reversible posterior leukoencephalopathy syndrome is believed to be the result of altered cerebral autoregulation with impaired blood flow control and resultant endothelial damage caused by different situations and agents. Several chemotherapy agents have been described in association with the syndrome. However, little is known about the prevalence of the syndrome and the follow-up of these patients, especially their further treatment.

Oxaliplatin, Irinotecan and Capecitabine (OCX) for First-Line Treatment of Advanced/Metastatic Colorectal Cancer: A Phase I Trial (SAKK 41/03)

Background: A phase I multicentre trial was conducted to define the recommended dose of capecitabine in combination with oxaliplatin and irinotecan (OCX) in metastatic colorectal cancer. Patients and Methods: Patients with performance status (PS) < 2 and adequate haematological, renal and liver function received oxaliplatin 70 mg/m2 on days 1 and 15, irinotecan 100 mg/m2 on days 8 and 22 and one of five dose levels (DL 1–5, between 800 and 1,600 mg/ m2) of capecitabine on days 1–29 every 5 weeks. Results: 23 patients received a median of 3 cycles. 3 dose-limiting toxicities occurred (DL 1: grade 3 (G3) elevated alkaline phosphatase; DL 5: 1 patient G4 hyperglycaemia/G3 diarrhoea and 1 sudden death). The most common severe adverse event was G3 diarrhoea (13%). Severe haematotoxicity was rare. Therapy was stopped mainly due to metastasectomy or tumour progression (7 patients each). 8 patients reached a partial response. Median time to progression and overall survival (OS) were 8.0 and 21.9 months, respectively. Conclusions: The recommended capecitabine dose in this schedule is 1,400 mg/m2 daily. The OCX regimen is well tolerated. The response rate was surprisingly low with progression-free survival (PFS) and OS within the range of a triple combination. Further studies in combination with targeted agents are warranted.

Capecitabine and Oxaliplatin Prior and Concurrent to Preoperative Pelvic Radiotherapy in Patients With Locally Advanced Rectal Cancer: Long-Term Outcome

Background: The risk/benefit ratio of any treatment can only be fully assessed if long‐term results of both efficacy and toxicity are taken into account. Whereas the combined modality treatment of locally advanced rectal cancer (LARC) has considerably improved prognosis, particularly with regard to local control, long‐term results—including patient‐reported outcomes—are underreported. Patients and Methods: Patients with LARC treated within a multicenter single‐arm phase II study were prospectively assessed for at least 5 years after surgery. Study treatment consisted of capecitabine and oxaliplatin prior and concurrent to preoperative pelvic radiotherapy followed by total mesorectal excision. Progression‐free survival time (first endpoint), overall survival time, and pattern of relapse were analyzed in the whole study population and in pre‐planned exploratory subgroups. Patient‐reported outcomes, including overall satisfaction with bowel, stoma, and urinary function, were assessed in 6‐month intervals. Results: Five‐year progression‐free and overall survival rate was 61% (95% confidence interval [CI], 46%‐73%) and 78% (95% CI, 63%‐87%), respectively. Distant to local recurrence rate was 3:1, with only 8% of patients relapsing locally. Main predictors for recurrence in univariate analyses were tumor downstaging (hazard ratio, 0.16; 95% CI, 0.05‐0.56; P = .0011) and nodal downstaging (hazard ratio, 0.17; 95% CI, 0.06‐0.52; P = .0005). The self‐reported burden of symptoms related to bowel function was high in up to one‐third of patients. A total of 28% of patients were dissatisfied with their urinary, bowel, or stoma function for at least 1 observation period. Conclusion: Combined‐modality treatment of LARC results in a high and durable local disease control rate, especially in patients with tumor and/or nodal downstaging, at the cost of relevant long‐term toxicity. Long‐term care is required for a proportion of patients with poor gastrointestinal and/or urinary function after multimodality therapy. Reporting of long‐term follow‐up, including patient‐recorded outcomes should be mandatory for future trials in LARC. &NA; In a prospective long‐term follow‐up of patients with locally advanced rectal cancer treated with radiochemotherapy and surgery, downstaging of tumor and nodal status were significant predictors for longer progression‐free and overall survival. A high local control rate of trimodal treatment comes at the cost of considerable long‐term toxicity, with patient‐reported dissatisfaction of bowel function even years after treatment.

Deutsche Osteoonkologische Gesellschaft gegründet

zudem Dr. Holger Uhthoff, Speyer (Schatzmeister) und Prof. Dr. M. Heinrich Seegenschmiedt, Hamburg (Schriftführer) an. Zu Beisitzern wurden PD Dr. Christian Eberhardt, Hanau, Prof. Dr. Tanja Fehm, Tübingen, Prof. Dr. Franz Jakob, Würzburg, und PD Dr. Florian Schütz, Heidelberg berufen. Die Gesellschaft umfasst derzeit 45 Gründungsmitglieder. Mitglied werden kann jeder, der sich wissenschaftlich mit dem Gebiet der Osteoonkologie beschäftigt. Die Gesellschaft wird als Verein eingetragen und die Gemeinnützigkeit wird beantragt.