Surveillance of megakaryocytic function by measurement of CD61-exposing microparticles in allogeneic hematopoietic stem cell recipients.

Increasing evidence suggests that circulating microparticles (MP) exposing CD61 originate predominantly from megakaryocytes. Dramatic changes in megakaryocytic homeostasis are regularly observed following allogeneic hematopoietic stem cell transplantation (HSCT) and associated with transplantation-associated complications. We studied MP plasma levels prospectively in healthy subjects (n = 10) and allogeneic HSCT recipients (n = 19) twice weekly from the start of conditioning therapy up to day 30. A total of 224 measurement points were evaluated. MP were isolated, double-stained with annexin V and anti-CD61, and analyzed by flow cytometry. In uncomplicated HSCT, we found a correlation between platelet and CD61-exposing MP count, which resulted in a constant ratio of MP per platelet. The ratio was increased in patients with active hematological malignancies before transplantation and normalized during conditioning therapy. After take, the MP ratio increased, whereas infections and microangiopathic hemolytic anemia did not affect the ratio. In patients with GvHD, a decreased MP ratio was observed depending on the grade of GvHD, possibly indicating megakaryocytic damage. The MP ratio was able to discriminate between toxic, septic, and GvHD-induced hyperbilirubinemia. We first describe CD61+ MP levels during allogeneic HSCT and postulate that the MP ratio might be a useful biomarker for the surveillance of megakaryocytes during HSCT.

Prognostic relevance of CA 19-9, CEA, CRP, and LDH kinetics in patients treated with palliative second-line therapy for advanced pancreatic cancer.

The objective of this study was to define prognostic serum biomarkers that could serve as surrogate survival endpoints during second-line treatment for advanced pancreatic cancer. This retrospective single-center study included patients treated with second-line therapy for advanced exocrine pancreatic cancer. A pretreatment value and at least one serial measurement during the first two cycles of second-line chemotherapy for CA 19-9, CEA, CRP, and LDH had to be available in order to evaluate the prognostic role of kinetics on overall survival. A cutoff of a >20% increase from baseline during treatment was defined in order to form groups with suspected different outcomes. The effect of serial biomarker changes on survival was modeled by Cox proportional hazards regression in univariate and multivariate analyses. Overall, 70 patients treated with second-line therapy for advanced disease were included; 94% had distant metastases at treatment initiation. Median time to progression was 2.7 months and median survival 5.4 months. Univariate analysis found that an increase of >20% during treatment was significantly associated with a worse overall survival for CA 19-9 (HR 2.00, p = 0.018), CEA (HR 2.38, p = 0.004), and CRP (HR 3.06, p < 0.001). These associations remained significant within multivariate analysis for CEA (HR 2.86, p = 0.001) and CRP (HR 3.20, p = 0.001). Serum biomarker kinetics might serve as useful prognostic tools during second-line chemotherapy in advanced pancreatic cancer.

Antiangiogenic therapy with mammalian target of rapamycin inhibitor RAD001 (Everolimus) increases radiosensitivity in solid cancer.

PURPOSE: Radiotherapy exerts direct antivascular effects in tumors and also induces a proangiogenic stress response in tumor cells via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. Therefore, the combination of radiotherapy and antiangiogenic therapy with mTOR inhibitor RAD001 (Everolimus) might exert additive/synergistic effects on tumor growth. EXPERIMENTAL DESIGN: Effects of radiation combined with mTOR inhibitor RAD001 were studied on proliferation of murine colon cancer CT-26, human pancreatic cancer L3.6pl, and human umbilical vascular endothelial cells in vitro. In vivo tumor growth of subcutaneous colon cancer CT 26 and orthotopic pancreatic cancer L3.6pl was assessed after fractionated radiotherapy (5 x 2 or 5 x 4 Gy) with or without the addition of the mTOR inhibitor RAD001. RAD001 (1.5 mg/kg/d) was administered until the end of experiments beginning before or after radiotherapy. RESULTS: A single dose of 2 Gy reduced in vitro proliferation of L3.6pl (-16%), CT-26 (-70%), and human umbilical vascular endothelial cells (HUVEC; -72%). The mTOR inhibitor RAD001 (10 ng/mL) suppressed proliferation of HUVEC (-83%), L3.6pl (-8%), and CT-26 (-82%). Combination of even low concentrations of 0.01 ng/mL RAD001 and 0.25 Gy radiation significantly reduced proliferation of HUVECs (-57%), whereas additive effects of RAD001 and radiation on tumor cells were seen only at the highest concentrations tested. In vivo, RAD001 introduced before radiotherapy (5 x 2 Gy) improved tumor growth control in mice (L3.6pl: 326 mm(3) versus 1144 mm(3); CT-26: 210 mm(3) versus 636 mm(3); P < 0.05 versus control). RAD001 turned out to possess a dose-modifying effect on radiotherapy. CONCLUSION: Endothelial cells seem to be most sensitive to combination of mTOR inhibition and radiotherapy. Additive tumor growth delay using the mTOR inhibitor RAD001 and radiotherapy in vivo therefore might rely on combined antiangiogenic and antivascular effects.

Oral capecitabine in gemcitabine-pretreated patients with advanced pancreatic cancer.

OBJECTIVE: To date, no standard regimen for salvage chemotherapy after gemcitabine (Gem) failure has been defined for patients with advanced pancreatic cancer (PC). Oral capecitabine (Cap) has shown promising activity in first-line chemotherapy trials in PC patients. METHODS: Within a prospective single-center study, Cap was offered to patients who had already received at least 1 previous treatment regimen containing full-dose Gem (as a single agent, as part of a combination chemotherapy regimen or sequentially within a chemoradiotherapy protocol). Cap was administered orally at a dose of 1,250 mg/m(2) twice daily for 14 days followed by 7 days of rest. Study endpoints were objective tumor response rate by imaging criteria (according to RECIST), carbohydrate antigen 19-9 (CA19-9) tumor marker response, time to progression, overall survival and toxicity. RESULTS: A median of 3 treatment cycles (range 1-36) was given to 39 patients. After a median follow-up of 6.6 months, 27 patients were evaluable for response: no complete or partial responses were observed, but 15 patients (39%) had stable disease. A CA19-9 reduction of >20% after 2 cycles of Cap was documented in 6 patients (15%). Median time to progression was 2.3 months (range 0.5-45.1) and median overall survival (since start of Cap treatment) was 7.6 months (range 0.7-45.1). Predominant grade 2 and 3 toxicities (per patient analysis) were hand-foot syndrome 28% (13% grade 3); anemia 23%; leg edema 15%; diarrhea 13%; nausea/vomiting 10%, and leukocytopenia 10%. CONCLUSION: Single-agent Cap is a safe treatment option for Gem-pretreated patients with advanced PC. Further evaluation of Cap in controlled clinical trials of Gem-pretreated patients with advanced PC is recommended.

Importance of performance status for treatment outcome in advanced pancreatic cancer.

Despite progress in the treatment of advanced and metastatic pancreatic cancer (PC), the outcome of this disease remains dismal for the majority of patients. Given the moderate efficacy of treatment, prognostic factors may help to guide treatment decisions. Several trials identified baseline performance status as an important prognostic factor for survival. Unfit patients with a Karnofsky performance status (KPS) below 70% only have a marginal benefit from chemotherapy with gemcitabine (Gem) and may often benefit more from optimal supportive care. Once, however, the decision is taken to apply chemotherapy, KPS may be used to select either mono- or combination chemotherapy. Patients with a good performance status (KPS = 90%-100%) may have a significant and clinically relevant survival benefit from combination chemotherapy. By contrast, patients with a poor performance status (KPS < or = 80%) have no advantage from intensified therapy and should rather receive single-agent treatment.

Combined chemoradiotherapy for isolated local recurrence after primary resection of pancreatic cancer.

CONTEXT: Primary resectability is expected in up to 20% of pancreatic cancer patients. While most patients relapse with distant metastases, approximately 30% of patients show isolated local recurrence without evidence of distant metastases. OBJECTIVE: The present analysis investigates the efficacy of chemoradiotherapy in this particular patient group. DESIGN: Retrospective study. PATIENTS: Eighteen consecutive pancreatic cancer patients presenting with isolated locoregional recurrence after surgical resection. The median interval between primary surgery and diagnosis of local recurrence was 10.4 months (range: 2.0-19.3 months). INTERVENTIONS: Patients received 3-D conformal radiation with 45 Gy in 25 fractions of 1.8 Gy/day. Simultaneous chemotherapy was employed either with continuous 5-FU infusion, partly in combination with gemcitabine, or with gemcitabine and cisplatin. Sequential chemotherapy with gemcitabine and cisplatin was given to some patients before and after the chemoradiotherapy. RESULTS: In 17 of the 18 patients included, radiotherapy was employed at the intended dose. While WHO grade 3-4 gastrointestinal toxicity was not reported, hematotoxicity was more pronounced. Grades 3 and 4 leukocytopenia occurred in 4 patients (22.2%) and 1 (5.6%) patient, respectively, and grades 3 and 4 thrombocytopenia occurred in 4 patients (22.2%) and 1 patient(5.6%), respectively. Six (37.5%) complete remissions, 6 (37.5%) partial remissions, and 4 (25.0%) stable diseases were noted in 16 evaluable patients. Median progression-free survival calculated from the start of the chemoradiotherapy was 14.7 months (range: 8.4-21.0 months) . Seven (28.9%) patients had another local relapse, while 11 (61.1%) patients developed distant metastases. Median overall survival from the start of the chemoradiotherapy was 17.5 months (95% CI: 15.6-19.4 months) and median survival from the initial diagnosis was 27.2 months (95% CI: 23.9-30.6 months). CONCLUSION: The data provide a first indication that chemoradiotherapy is feasible and may be an effective treatment option in those patients who present with local metastasis after primary surgery for pancreatic cancer.

Chemoradiotherapy with gemcitabine and continuous 5-FU in patients with primary inoperable pancreatic cancer.

CONTEXT: Gemcitabine and 5-fluorouracil (5-FU) sensitize tumor cells to radiation. Furthermore, 5-FU enhances the cytotoxic effect of gemcitabine. OBJECTIVE: We report the efficacy and the toxicity of concurrent chemoradiation with gemcitabine and 5-FU in the treatment of patients with locally advanced, unresectable pancreatic cancer. PATIENTS: Thirty-two patients (20 men, 12 women; median age 69.9 years) with histologically proven advanced pancreatic carcinoma were included in the study. INTERVENTIONS: The patients received chemotherapy with gemcitabine 300 mg/m2 on days 1, 15, 29 and 5-FU as continuous infusion 350 mg/m2/day of radiation while concurrent radiation (45-50 Gy) was given to the tumor and regional lymph nodes (1.8-2.0 Gy/fraction on 5 days/week). Subsequent to chemoradiotherapy, the treatment was continued with an additional two cycles of gemcitabine (1,000 mg/m2) and cisplatin (50 mg/m2) applied on days 1 and 15 of a four-week cycle. MAIN OUTCOME MEASURES: Patient survival, time to progression, and toxicity of chemoradiation. Tumor responses (complete resolution; partial response; stable disease, and progressive disease) were also evaluated. RESULTS: After the completion of chemoradiotherapy, 2 patients (6.3%) achieved complete resolution and 18 patients (56.3%) a partial response, for an overall response rate of 62.5%. Twelve patients (37.5%) were considered resectable and 9 underwent laparotomy, 7 of whom had definitive pancreatic resection. Four patients had negative surgical margins. With a median follow-up of 49.7 months (95% CI: 48.6-60.8 months) after the completion of chemoradiation, distant metastasis occurred in 25 patients (78.1%) while local recurrence was seen only in 4 of 32 patients (12.5%). Median time to progression was 9.2 months (95% CI: 8.2-10.2 months). Median survival amounted to 13.6 months (95% CI: 12.7-14.6 months) for all patients while it was prolonged to 16.4 months (95% CI: 13.4-19.4 months) for those undergoing secondary resection. In addition, performance status proved to be another prognostic factor for overall survival. The main toxicity of chemoradiation included grade 3-4 leukopenia in 18 patients (56.3%) and thrombocytopenia in 8 patients (25.0%). Episodes of cholangitis were observed in 7 patients (21.9%). CONCLUSION: Gemcitabine and 5-FU can safely be combined with external beam radiation. This preoperative treatment approach is highly effective and appears to improve survival in patients with good performance status and in those who are eligible for a secondary resection.

Chemoradiation for ductal pancreatic carcinoma: principles of combining chemotherapy with radiation, definition of target volume and radiation dose.

Review of the role of chemoradiotherapy in the treatment of locally advanced pancreatic cancer with a specific focus on the technical feasibility and the integration of chemoradiotherapy into multimodal treatment concepts. Combined chemoradiotherapy of pancreatic cancer is a safe treatment with an acceptable profile of side effects when applied with modern planning and radiation techniques as well as considering tissue tolerance. Conventionally fractionated radiation regimens with total doses of 45-50 Gy and small-volume boost radiation with 5.4 Gy have found the greatest acceptance. Locoregional lymphatic drainage should be included in the planning of target volumes because the risk of tumor involvement and local or loco-regional recurrence is high. Up to now, 5-fluorouracil has been considered the "standard" agent for concurrent chemoradiotherapy. The role of gemcitabine given concurrently with radiation has not yet been defined, since high local efficacy may also be accompanied by enhanced toxicities. In addition, no dose or administration form has been determined to be "standard" up to now. The focus of presently ongoing research is to define an effective and feasible regimen of concurrent chemoradiotherapy. While preliminary results indicate promising results using gemcitabine-based chemoradiotherapy, reliable data derived from mature phase III trials are greatly needed. Intensity-modulated radiotherapy has been developed to improve target-specific radiation and to reduce organ toxicity. Its clinical relevance still needs to be defined.

Concurrent chemoradiotherapy with gemcitabine and cisplatin after incomplete (R1) resection of locally advanced pancreatic carcinoma.

PURPOSE: To analyze, in a prospective clinical trial, the efficacy and toxicity of concurrent radiotherapy and chemotherapy with gemcitabine and cisplatin in patients with incompletely (R1) resected pancreatic cancer. METHODS AND MATERIALS: Between 2000 and 2002, a total of 30 pancreatic cancer patients were treated. Radiotherapy was performed in 15 patients up to a total dose of 45.0 Gy. An additional 15 patients received a total dose of 50.0 Gy according to the International Commission on Radiation Units and Measurements (ICRU) Report 50 reference point (equivalent to 45.0 Gy at the isodose, including 90% covering the former tumor area and local lymph nodes). Concurrent with radiotherapy, four applications of gemcitabine (300 mg/m(2)) and cisplatin (30 mg/m(2)) were administered. After chemoradiotherapy, patients received four additional courses of gemcitabine (1000 mg/m(2)) and cisplatin (50 mg/m(2)) on Days 1 and 15 in a 4-week cycle. RESULTS: The median progression-free survival was 10.6 months, and the median overall survival was 22.8 months. The 1-, 2-, and 3-year survival rate was 81%, 43%, and 26%, respectively. After completion of chemoradiotherapy, distant metastasis was observed in 14 patients during a median follow-up of 15.0 months (range, 4.6-30.0). One patient developed both local recurrence and distant metastases. Hematologic toxicities were the most prominent side effects (leukopenia Grade 3 and 4 in 53% and 7% and thrombocytopenia Grade 3 and 4 in 33% and 7% of patients, respectively). Grade 3 and 4 GI toxicity was not observed. CONCLUSION: Postoperative chemoradiotherapy with gemcitabine and cisplatin after incomplete (R1) resection of pancreatic carcinoma is safe and feasible. A prolonged progression-free survival suggests high local efficacy, translating into a benefit of overall survival. On the basis of the favorable outcome of patients receiving gemcitabine/cisplatin-based chemoradiotherapy, testing this combined treatment strategy appears warranted in a comparative trial.

Feasibility and effects of high-dose hypofractionated radiation therapy and simultaneous multi-kinase inhibition with sunitinib in progressive metastatic renal cell cancer.

OBJECTIVES: Radiotherapy (RT) is considered oncologically ineffective in metastatic renal cell cancer (mRCC). Inhibition of angiogenetic pathway may lead to radiosensitization in mRCC. The aim of this study was to evaluate the efficacy of the simultaneous combination of RT with systemic treatment of bulky (mRCC) using sunitinib. METHODS AND MATERIALS: We included 22 patients with progressive mRCC between 04/2007 and 08/2008 at the University Hospital Munich Großhadern. All patients underwent high-dose hypofractionated RT while they were simultaneously treated systemically with sunitinib 50 mg. RESULTS: Median age was 63.0 years (range 26.7-84.4). Median dose of radiation was 40 Gy (range 25-50) in a median of 8 fractions (range 5-30). Treatment sites were brain, retroperitoneal and mediastinal lymph nodes, spinal cord, bones, liver, and kidney. Median follow-up was 14.3 months. After 3 months, 2 patients had complete remission (CR), 9 patients showed partial remission (PR) as measured by response evaluation criteria in solid tumors (RECIST) criteria, 2 patients had minor response (MR), and 8 patients had stable disease (SD). Only 1 patient did not respond to therapy. Toxicity was very low with only 1 grade 4 hypertension. Skin toxicities were manageable with no grade 3 event during the combination period. CONCLUSIONS: The combination of RT with simultaneous systemic treatment using sunitinib is effective in patients with progressive mRCC. With high dose RT, complete response seems to be possible. Further evaluation should be based upon combination of RT with systemic therapy, rather than sequential RT regiments.

Cellular origin of platelet-derived microparticles in vivo.

INTRODUCTION: Microparticles (MP), presumably of platelet origin, are the most abundant microparticles in blood. To which extent such MP may also directly originate from megakaryocytes, however, is unknown. During hematopoietic stem cell transplantation, patients undergo total body irradiation which leads to an irreversible destruction of hematopoiesis. MATERIAL AND METHODS: We studied the levels of "platelet-derived" MP (PMP) in 13 patients before and after total body irradiation with 12 Gy (4 Gy for 3 days, dose rate 4.5 cGy/min). PMP were isolated and double-stained with annexin V and anti-CD61. In 6 patients, we additionally analyzed MP exposing P-selectin or CD63. RESULTS: PMP rapidly declined upon total body irradiation, which was 2.4-fold faster than platelet disappearance. In contrast, the kinetics of MP exposing P-selectin or CD63 was comparable to platelets. CONCLUSIONS: Since CD61-positive MP disappear faster than platelets or MP exposing P-selectin or CD63, our data indicate that MP exposing P-selectin or CD63 are likely to originate from platelets, whereas at least a major fraction of CD61-exposing MP is likely to originate from megakaryocytes in vivo.

Application of a time-varying covariate model to the analysis of CA 19-9 as serum biomarker in patients with advanced pancreatic cancer.

PURPOSE: The clinical relevance of CA 19-9 as surrogate biomarker in advanced pancreatic cancer is a matter of debate. EXPERIMENTAL DESIGN: This retrospective multicenter study included patients with histologically confirmed advanced pancreatic cancer treated with first-line therapy. Analysis of CA 19-9 was done using the Elecsys assay (Roche Diagnostics). For an analysis of CA 19-9 kinetics, at least three measurements during first-line chemotherapy had to be available. The effect of pretreatment CA 19-9 levels on time-to-progression (TTP) and overall survival (OS) was modeled by Cox proportional hazards regression. The effect of CA 19-9 kinetics was also modeled by Cox proportional hazards regression where CA 19-9 was treated as a time-varying covariate. RESULTS: One hundred and fifteen patients from five German centers were included; 73% of them were treated within prospective clinical trials. Median TTP was 4.4 months and median OS was 9.4 months; univariate analysis indicated that pretreatment CA 19-9 [as continuous variable, log (CA 19-9)] was significantly associated with TTP [hazard ratio (HR), 1.24; P < 0.001] and OS (HR, 1.16; P = 0.002). These associations remained significant within multivariate analysis. For CA 19-9 kinetics during chemotherapy, data from 69 patients (TTP) and 84 patients (OS) were available, respectively; log (CA 19-9) kinetics after start of treatment were found to be a significant predictor for TTP in univariate (HR, 1.48; P < 0.001) and multivariate (HR, 1.45; P < 0.001) analyses, and also for OS (univariate: HR, 1.34; P < 0.001; multivariate: HR, 1.38; P < 0.001). CONCLUSION: Pretreatment CA 19-9 and CA 19-9 kinetics may serve as a useful serum biomarker in advanced pancreatic cancer.

Radiochemotherapy in combination with regional hyperthermia in preirradiated patients with recurrent rectal cancer.

BACKGROUND AND PURPOSE: Encouraging results of phase II studies combining chemotherapy with radiotherapy have been published. In this study, the results of a multimodal salvage therapy including radiochemotherapy (RCT) and regional hyperthermia (RHT) in preirradiated patients with recurrent rectal cancer are reported. PATIENTS AND METHODS: All patients enrolled had received previous pelvic irradiation (median dose 50.4 Gy). The median time interval between prior radiotherapy and the onset of local recurrence was 34 months. The combined treatment consisted of reirradiation with a median dose of 39.6 Gy (30.0-45.0 Gy), delivered in fractions of 1.8 Gy/day. 5-fluorouracil was given as continuous infusion 350 mg/m(2)/day five times weekly, and RHT (BSD-2000 system) was applied twice a week within 1 h after radiotherapy. The primary endpoint was local progression-free survival (LPFS); secondary endpoints were overall survival, symptom control, and toxicity. RESULTS: 24 patients (median age 59 years) with a previously irradiated locally recurrent adenocarcinoma of the rectum were enrolled. The median LPFS was 15 months (95% confidence interval 12-18 months] with a median follow-up of 27 months (16-37 months). The overall 1-year and 3-year survival rates were 87% and 30%, respectively. Pain was the main symptom in 17 patients. Release of pain was achieved in 12/17 patients (70%). No grade 3 or 4 hematologic or skin toxicity occurred. Grade 3 gastrointestinal acute toxicity was observed in 12.5% of the patients. Paratumoral thermometry revealed a homogeneous distribution of temperatures. CONCLUSION: RCT combined with RHT is an efficient salvage therapy showing high efficacy with acceptable toxicity and can be recommended as treatment option for this unfavorable group of preirradiated patients with local recurrence of rectal cancer.

Clinical relevance of circulating nucleosomes in cancer.

Nucleosomes, complexes of DNA and histone proteins, are released during cell death into the blood circulation. Elevated serum and plasma levels have been found in various forms of cancer, but also in autoimmune diseases and acute situations such as stroke, trauma, and during sepsis. Here, the clinical relevance of circulating nucleosomes for diagnosis, staging, prognosis, and therapeutic monitoring of cancer is reviewed. Several studies have shown that levels of nucleosomes are significantly higher in serum and plasma of cancer patients in comparison to healthy controls. However, because of elevations of nucleosome levels in patients with benign diseases relevant for differential diagnosis, they are not suitable for cancer diagnosis. Concerning tumor staging, nucleosome levels correlate with tumor stage and presence of metastases in gastrointestinal cancer, but not in other tumor types. Prognostic value of circulating nucleosomes is found in lung cancer in univariate analyses, but not in multivariate analyses. Circulating nucleosomes are most informative for the monitoring of cytotoxic therapy. Strongly decreasing levels are mainly found in patients with remission of disease, whereas constantly high or increasing values are associated with progressive disease during chemo- and radiotherapy. In addition, therapy outcome is already indicated by the nucleosomal course during the first week of chemo- and radiotherapy in patients with lung, pancreatic, and colorectal cancer as well as in hematologic malignancies. Despite their non-tumor-specificity, kinetics of nucleosomes are valuable markers for the early estimation of therapeutic efficacy and may be helpful to adapting early cancer therapy in the future.

Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer.

In pancreatic cancer (PC) accurate determination of treatment response by imaging often remains difficult. Various efforts have been undertaken to investigate new factors which may serve as more appropriate surrogate parameters of treatment efficacy. This review focuses on the role of carbohydrate antigen 19-9 (CA 19-9) as a prognostic tumor marker in PC and summarizes its contribution to monitoring treatment efficacy. We undertook a Medline/PubMed literature search to identify relevant trials that had analyzed the prognostic impact of CA 19-9 in patients treated with surgery, chemoradiotherapy and chemotherapy for PC. Additionally, relevant abstract publications from scientific meetings were included. In advanced PC, pretreatment CA 19-9 levels have a prognostic impact regarding overall survival. Also a CA 19-9 decline under chemotherapy can provide prognostic information for median survival. A 20% reduction of CA 19-9 baseline levels within the first 8 weeks of chemotherapy appears to be sufficient to define a prognostic relevant subgroup of patients ('CA 19-9 responder'). It still remains to be defined whether the CA 19-9 response is a more reliable method for evaluating treatment efficacy compared to conventional imaging.

Nucleosomes in colorectal cancer patients during radiochemotherapy.

Apoptotic markers and tumor-associated antigens might be suitable to indicate the response to radiochemotherapy early. We analyzed the courses of nucleosomes, CEA, CA 19-9 and CYFRA 21-1 in 25 colorectal cancer patients during radiochemotherapy (4 postoperative, 13 preoperative, 8 local relapse therapy). Blood was taken before therapy, daily during the first week, once weekly during the following weeks, and at the end of the radiochemotherapy. After a temporary decline 6 h after the first irradiation, nucleosomes rose in most patients rapidly reaching a maximum during the first days which was followed by a subsequent decrease. In patients receiving postoperative therapy after complete resection of tumor, nucleosome levels generally were lower than in patients with preoperative or relapse therapy. Correspondingly, CEA, CA 19-9 and CYFRA 21-1 levels of postoperatively treated patients were the lowest whereas those with tumor relapse had the highest ones. During preoperative therapy, lower nucleosome concentrations were found in patients with response to therapy resulting in a smaller area under the curve of days 1-3 (AUC) than in those with progressive disease (p = 0.028). The other parameters did not indicate the response to therapy at the initial treatment phase. In conclusion, the course of nucleosomes (AUC) might be valuable for the early prediction of therapy response in preoperatively treated colorectal cancer patients.

Feasibility of photofrin II as a radiosensitizing agent in solid tumors--preliminary results.

BACKGROUND: Photofrin II has been demonstrated to serve as a specific and selective radiosensitizing agent in in vitro and in vivo tumor models. We aimed to investigate the feasibility of a clinical application of Photofrin II. MATERIAL AND METHODS: 12 patients were included in the study (7 unresectable solid tumors of the pelvic region, 3 malignant gliomas, 1 recurrent oropharyngeal cancer, 1 recurrent adenocarcinoma of the sphenoid sinus). The dose of ionizing irradiation was 30-50.4 Gy; a boost irradiation of 14 Gy was added for the pelvic region. All patients were intravenously injected with 1 mg/kg Photofrin II 24 h prior to the commencement of radiotherapy. Magnetic resonance imaging (MRI) controls and in some cases positron emission tomography (PET) were performed in short intervals. The mean follow-up was 12.9 months. RESULTS: No major adverse events were noted. Minor adverse events consisted of mild diarrhea, nausea and skin reactions. A complete remission was observed in 4/12 patients. A reduction in local tumor volume of >45% was achieved in 4/12 patients. Stable disease was observed in 4/12 patients. 1 patient showed local disease progression after 5 months. CONCLUSION: The early follow- up results are encouraging regarding the feasibility of the application of Photofrin II as a radiosensitizing agent.

Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer.

PURPOSE: To compare the effectiveness and tolerability of gemcitabine plus cisplatin with single-agent gemcitabine as first-line chemotherapy for locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with advanced adenocarcinoma of the pancreas were randomly assigned to receive either gemcitabine 1,000 mg/m2 and cisplatin 50 mg/m2 given on days 1 and 15 of a 4-week cycle (GemCis arm) or gemcitabine alone at a dose of 1,000 mg/m2 on days 1, 8, and 15 of a 4-week regimen (Gem arm). The primary end point was overall survival; secondary end points were progression-free survival, response rate, safety, and quality of life. RESULTS: One hundred ninety-five patients were enrolled and showed baseline characteristics well balanced between treatment arms. Combination treatment in the GemCis arm was associated with a prolonged median progression-free survival (5.3 months v 3.1 months; hazard ratio [HR] = 0.75; P = .053). Also, median overall survival was superior for patients treated in the GemCis arm as compared with the Gem arm (7.5 v 6.0 months), an advantage which did not, however, reach statistical significance (HR = 0.80; P = .15). Tumor response rates were comparable between treatment arms (10.2% v 8.2%). The rate of stable disease was, however, greater in the combination arm (60.2% v 40.2%; P < .001). Grade 3 to 4 hematologic toxicity did not exceed 15% in both treatment arms. CONCLUSION: These results support the efficacy and safety of an every-2-weeks treatment with gemcitabine plus cisplatin. Median overall survival and progression-free survival were more favorable in the combination arm as compared with gemcitabine alone, although the difference did not attain statistical significance.

A new concurrent chemotherapy with vinorelbine and mitomycin C in combination with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: The purpose of this pilot study was to evaluate the feasibility and toxicity of concurrent chemotherapy with vinorelbine and mitomycin C in combination with accelerated radiotherapy (RT) in patients with locally advanced cancer of the head and neck. PATIENTS AND METHODS: Between January 2003 and March 2004, 15 patients with T4/N2-3 squamous cell carcinoma (12/15) and with N3 cervical lymph node metastases of carcinoma of unknown primary (3/15) were treated with chemotherapy and simultaneous accelerated RT. RESULTS: 11 patients completed therapy without interruption or dose reduction. Grade 3-4 acute mucosal toxicity was observed in 9/15 patients, grade 4 hematologic toxicity in 6/15 patients. At a median follow-up of 7.5 months, 2 patients have died of intercurrent disease, 2 patients have experienced local relapse; 5 patients are alive with no evidence of disease at the primary tumor site. DISCUSSION: The described regimen is highly effective, but led to remarkable side effects.

Nucleosomes in pancreatic cancer patients during radiochemotherapy.

Nucleosomes appear spontaneously in elevated concentrations in the serum of patients with malignant diseases as well as during chemo- and radiotherapy. We analyzed whether their kinetics show typical characteristics during radiochemotherapy and enable an early estimation of therapy efficacy. We used the Cell Death Detection Elisa plus (Roche Diagnostics) and investigated the course of nucleosomes in the serum of 32 patients with a local stage of pancreatic cancer who were treated with radiochemotherapy for several weeks. Ten of them received postsurgical therapy, 21 received primary therapy and 1 received therapy for local relapse. Blood was taken before the beginning of therapy, daily during the first week, once weekly during the following weeks and at the end of radiochemotherapy. The response to therapy was defined according to the kinetics of CA 19-9: a decrease of CA 19-9 > or =50% after radiochemotherapy was considered as 'remission'; an increase of > or =100% (which was confirmed by two following values) was defined as 'progression'. Patients with 'stable disease' ranged intermediately. Most of the examined patients showed a decrease of the concentration of nucleosomes within 6 h after the first dose of radiation. Afterwards, nucleosome levels increased rapidly, reaching their maximum during the following days. Patients receiving postsurgery, primary or relapse therapies did not show significant differences in nucleosome values during the time of treatment. Single nucleosome values, measured at 6, 24 and 48 h after the application of therapy, could not discriminate significantly between patients with no progression and those with progression of disease. However, the area under the curve of the first 3 days, which integrated all variables of the initial therapeutic phase, showed a significant correlation with the progression-free interval (p=0.008). Our results indicate that the area under the curve of nucleosomes during the initial phase of radiochemotherapy could be valuable for the early prediction of the progression-free interval.