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ABSTRACT: Abstract Background. To evaluate the predictive and prognostic value of serum and plasma tumor markers, in comparison with clinical and biomedical parameters for response rate (RR), progression-free survival (PFS) and overall survival (OS) among patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy. Material and methods. One-hundred and six patients with mCRC from three centers, part of a multicenter study, received irinotecan with the Nordic bolus 5-fluorouracil (5-FU) and folinic acid schedule (FLIRI) or the de Gramont schedule (Lv5FU2-IRI). Blood samples for CEA, CA19-9, TPA, TIMP-1, SAA, transthyretin and CRP were taken at baseline and after two, four and eight weeks of treatment. Tumor marker levels at baseline and longitudinally were compared with responses evaluated (CT/MRI) after two and four months of treatment. The correlations to RR, PFS and OS were evaluated with regression analyses. Results. A significant correlation to OS was seen for baseline levels of all markers. In multivariate analyses with clinical parameters, TPA, CRP, SAA and TIMP-1 provided independent information. The baseline values of CEA, TPA and TIMP-1 were also significantly correlated to PFS and TPA to RR. Changes during treatment, i.e. the slope gave with the exception of CA19-9 for OS less information about outcomes. The best correlation to response was seen for CEA, CA19-9 and TPA with AUC values of 0.78, 0.83 and 0.79, respectively, using a combined model based upon an interaction between the slope and the baseline value. Conclusions. Baseline tumor markers together with clinical parameters provide prognostic information about survival in patients with mCRC. The ability of the individual tumor markers to predict treatment response and PFS is limited. Changes in marker levels during the first two months of treatment are less informative of outcome.
Acta oncologica (Stockholm, Sweden) 09/2012; 51(7):849-59. · 2.27 Impact Factor
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ABSTRACT: The optimal chemotherapy in patients with advanced gastric carcinoma (GC) is yet to be determined. We compared sequential administration of docetaxel and irinotecan, both in combination with infused 5-fluorouracil/leucovorin (5-Fu/Lv), and randomly assigned patients to start with either of the two.
Patients with previously untreated locally advanced or metastatic GC and with measurable lesions (response evaluation criteria in solid tumors; RECIST) were randomly assigned to start with docetaxel 45 mg/m(2) (arm T) or irinotecan 180 mg/m(2) (arm C) with bolus/44-h infusion of 5-Fu/Lv (day 1 every 2 weeks). After four courses, there was a prescheduled crossover to the alternative regimen for four additional courses.
Eighty-one patients were randomized and 78 started treatment. Complete and partial responses were seen in 31 (40%) patients after 8 weeks and in 32 (41%) after 16 weeks, with similar results in both study arms. The median overall survival (OS) was 11.5 and 10.6 months in arms T and C, respectively (P = 0.3). The two schedules were feasible and did not differ in the overall rate of severe adverse events (SAEs).
This is the first randomized comparison of two of the newer cytostatic drugs in GC therapy. No differences favoring either arm T or arm C were found with respect to response rate, OS, or toxicity. The median OS of 11 months indicates that sequential administration of the two combinations is effective and is similar to triple combinations. Thus, comparable efficacy to platinum combinations appears to be obtained with newer, less toxic regimens when given sequentially.
Gastric Cancer 08/2010; 13(3):155-61. · 2.42 Impact Factor
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ABSTRACT: To evaluate whether combination chemotherapy leads to early changes in plasma TIMP-1 and serum carcinoembryonic antigen (CEA) levels in patients with metastatic colorectal cancer (mCRC), and whether such changes relate to subsequent objective response, time to progression (TTP) and overall survival.
Eighty-eight patients with mCRC were included. Blood samples were collected before initiation and after 2, 4 and 6 weeks of treatment with an irinotecan-5-fluorouracil combination. Plasma TIMP-1 and serum CEA levels were determined by validated ELISA platforms. The first response evaluation was performed after 8 weeks of chemotherapy.
Median plasma TIMP-1 and serum CEA levels did not change significantly during 6 weeks of treatment. High plasma TIMP-1 and high serum CEA levels before treatment and at weeks 2, 4 and 6 were related to poor objective response. Moreover, high levels of plasma TIMP-1 before treatment and at weeks 2 and 4 were significantly associated with short TTP, while high levels of serum CEA at week 4 were significantly associated with short TTP. Finally, high levels of plasma TIMP-1 before and during treatment were significantly associated with poor overall survival; p < 0.0001 in all 4 determinations. A similar association between serum CEA and overall survival could only be demonstrated before treatment.
Median plasma TIMP-1 or serum CEA levels do not change significantly during the first 6 weeks of chemotherapy for mCRC. The results indicate that plasma TIMP-1 in particular and serum CEA may be valuable biomarkers even in samples collected during treatment with chemotherapy.
Oncology 01/2010; 79(1-2):144-9. · 2.27 Impact Factor
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ABSTRACT: Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials.
A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy.
Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials.
Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low.
Cancer Chemotherapy and Pharmacology 09/2009; 65(6):1165-72. · 2.83 Impact Factor
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ABSTRACT: The feasibility, safety, and efficacy of planned sequential administration of docetaxel and irinotecan with 5-fluorouracil (5-FU)/leucovorin in advanced upper gastrointestinal adenocarcinoma (UGIA) are unknown. Seventy-three patients with gastric (GC; n = 22), pancreatic (PC; n = 28) or biliary cancer (BC; n = 23) were randomised to start with 45 mg/m(2) docetaxel or 180 mg/m(2) irinotecan combined with 5-FU/leucovorin every 2nd week. After every 2nd course, the patients were crossed over to the other combination. Treatment was given for a maximum of 12 courses. Quality-of-life (QoL) was evaluated during the first two months using the EORTC QLQ-C30. Eighteen patients (25%; GC 32%, PC 21%, BC 22%) demonstrated partial response (PR) and 21 (29%) had prolonged stable disease. Mean QoL scores were low at baseline. Twenty-three (32%) patients had improved QoL using a summary measure and 13 were stable. Median time to progression was 4.4 months and overall survival 8.2 months. The treatments were reasonably well tolerated. Grade 3-4 toxicities were slightly more common for the docetaxel combination. There were two treatment-related deaths. Planned sequential treatment with docetaxel or irinotecan with 5-FU/leucovorin is feasible, reasonably tolerable and appears active in advanced UGIA.
Medical Oncology 03/2009; 27(1):65-72. · 2.14 Impact Factor
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ABSTRACT: There are conflicting results on the role of cobalamin and folate for epidemiology and carcinogenesis in colorectal cancer patients and the need of supplementation for prevention of chemotherapy toxicity.
Serum cobalamin, folate, and homocysteine were analysed before and during the treatment of 93 patients with advanced colorectal cancer (ACRC) with first-line chemotherapy treatment. This cohort was compared with a healthy control group of 224 individuals.
Patients with ACRC had similar cobalamin, folate, and homocysteine values as the healthy control group. There were no correlations between serum cobalamin, folate, and homocysteine values and objective response. There were no correlations to anaemia or other severe toxicity for cobalamin and homocysteine. A total of 12 patients had folate deficiency, and 10 of those suffered from severe toxicity (grade 3 or more). All patients had markedly increased folate values after 2 months of treatment. Folate and homocysteine did not predict patient outcome; however, patients with subclinically low cobalamin values (<300 pmol/L) had significant better overall survival and time to progression than patients with normal or high cobalamin values.
Patients with ACRC seem to have fairly adequate cobalamin and folate status before and during chemotherapy treatment. This study indicates that ACRC patients receiving chemotherapy do not need supplementation with vitamin B12 and folate. A minor portion of the patients had folate deficiency, and most of those patients had severe toxicity. Patients with subclinically low cobalamin values had surprisingly better survival.
Upsala journal of medical sciences 01/2009; 114(3):160-4. · 0.73 Impact Factor
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ABSTRACT: Preoperative chemoradiotherapy is considered standard treatment for locally advanced rectal cancer, although the scientific evidence for the chemotherapy addition is limited. This trial investigated whether chemotherapy as part of a multidisciplinary treatment approach would improve downstaging, survival, and relapse rate.
The randomized study included 207 patients with locally nonresectable T4 primary rectal carcinoma or local recurrence from rectal carcinoma in the period 1996 to 2003. The patients received either chemotherapy (fluorouracil/leucovorin) administered concurrently with radiotherapy (50 Gy) and adjuvant for 16 weeks after surgery (CRT group, n = 98) or radiotherapy alone (50 Gy; RT group, n = 109).
The two groups were well balanced according to pretreatment characteristics. An R0 resection was performed in 82 patients (84%) in the CRT group and in 74 patients (68%) in the RT group (P = .009). Pathologic complete response was seen in 16% and 7%, respectively. After an R0 + R1 resection, local recurrence was found in 5% and 7%, and distant metastases in 26% and 39%, respectively. Local control (82% v 67% at 5 years; log-rank P = .03), time to treatment failure (63% v 44%; P = .003), cancer-specific survival (72% v 55%; P = .02), and overall survival (66% v 53%; P = .09) all favored the CRT group. Grade 3 or 4 toxicity, mainly GI, was seen in 28 (29%) of 98 and six (6%) of 109, respectively (P = .001). There was no difference in late toxicity.
CRT improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in patients with nonresectable rectal cancer. The treatments were well tolerated.
Journal of Clinical Oncology 09/2008; 26(22):3687-94. · 18.37 Impact Factor
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ABSTRACT: In the most advanced, non-resectable primary rectal cancers, conventional long-course radiotherapy (RT) (1.8-2Gyx25-28), frequently combined with chemotherapy, has been used since tumour regression is needed in order to allow a radical (R0) resection. In Uppsala, short-course 5x5Gy with planned delayed surgery has been used in patients with contraindications to long-course RT (+/-chemotherapy). The aim is to describe our experience of using this approach in patients not eligible for standard treatment.
During 2002 and 2005, 46 patients with non-resectable rectal cancer (+/-synchronous distant metastases) were treated with 5x5Gy and delayed surgery if possible. The clinical records were retrospectively evaluated. The first group (A) had no metastases (T4NXM0), whereas the other two groups (B+C) had metastases (T4NXM1). In group (B), the patients had predominantly loco-regional disease and were not candidates for combination chemotherapy (high age, co-morbidities), and in group (C) up-front combination chemotherapy was given, with the intention to have surgery of both the primary and the secondaries if sufficient regression at both sites were seen.
The patients in the first two groups (A+B) were old (median 79 and 76 years, respectively), and had several co-morbidities. In group (C), median age was 63 years. The 5x5Gy RT was well tolerated by most patients, but grade IV diarrhoea was recorded in three elderly patients. One patient in the group (C) died from neutropenic fever. Many patients were reported to have less local symptoms after the treatment given. Delayed surgery was performed in all but nine patients. Radical surgery (R0+R1) was performed in 22 (92%) (group A), 4 (44%) (group B), and 6 (46%) (group C) patients, respectively. A pCR was seen in four patients (two in group A and two in group C). No postoperative deaths occurred.
Considering the very high age and presence of co-morbidity, the 5x5Gy schedule is well tolerated. Further, considering the very advanced local stage, the schedule has considerable anti-tumour activity and can result in radical surgery in a high proportion of patients.
Radiotherapy and Oncology 07/2008; 87(3):343-9. · 5.58 Impact Factor
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ABSTRACT: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to protect cells against apoptosis. We raised the hypothesis that elevated tumor tissue levels and thereby plasma levels of TIMP-1 would predict resistance to apoptosis-inducing chemotherapy.
Ninety patients with metastatic colorectal cancer were included in the study. Plasma TIMP-1 and serum carcinoembryonic antigen (CEA) were measured in samples obtained before the first cycle of chemotherapy.
Analysis of best objective response (complete or partial response versus stable or progressive disease) showed that patients with low plasma TIMP-1 had higher probability of obtaining an objective response [odds ratio (OR), 3.5; 95% confidence interval (95% CI), 1.4-8.5, P=0.007]. CEA treated as a continuous variable was also a statistically significant predictor of no response (OR, 1.3; 95% CI, 1.0-1.7, P=0.02, area under the curve 0.66) but much less so. Plasma TIMP-1 was the only significant covariate in a multivariable analysis of best objective response (OR, 3.6; 95% CI, 1.4-9.5; P=0.001). Plasma TIMP-1 scored as a continuous variable on the log scale (log(e)) was significantly associated with overall survival [OS; hazard ratio (HR), 3.8; 95% CI, 2.4-5.9; P<0.0001] and with time to progression (TTP; HR, 1.5; 95% CI, 1.0-2.3; P=0.048). Multivariable analysis showed that plasma TIMP-1 was significant for OS when including routine clinical baseline covariates (HR, 3.5; 95% CI, 2.1-5.8; P<0.0001). A multivariable analysis including TTP instead of OS showed that only plasma TIMP-1 was retained in the model (HR, 1.5). CEA was not significantly associated with TTP or OS when TIMP-1 was included in the model.
This study shows that plasma TIMP-1 levels are significantly and independently associated with objective response, TTP, and OS in patients with metastatic colorectal cancer receiving combination chemotherapy.
Clinical Cancer Research 08/2007; 13(14):4117-22. · 7.74 Impact Factor
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ABSTRACT: Two consecutive studies have evaluated the efficacy of oxaliplatin combined with the Nordic bolus schedule of 5-fluorouracil and folinic acid as first-line treatment in metastatic non-resectable colorectal cancer. One hundred and twelve patients were followed after end of first-line treatment and any secondary therapy registered. Fifty-three patients (47%) did not receive second-line irinotecan-based chemotherapy. The main reason was too poor performance status (59%). These patients had a median survival of only 1.7 months after progression of first-line therapy. The best predictive factors at start of first-line chemotherapy for receiving later second-line chemotherapy were performance status and alkaline phosphatase level. Fifty-nine patients (53%) received irinotecan-based second-line therapy. Four (7%) patients had a partial response, and 28 (52%) had stable disease. Median progression-free survival after second-line chemotherapy was 4.1 months and median survival 9.5 months. Median survival after first-line chemotherapy and secondary liver surgery was 34 months and five-year disease-free survival 8%. Survival among patients receiving both first- and second-line chemotherapy was 20.8 months, but only 8.9 months in patients not receiving second-line irinotecan-based chemotherapy. Poor performance status or elevated alkaline phosphatase level at start of first-line chemotherapy predicts whether second-line chemotherapy will be given or not.
Acta Oncologica 02/2007; 46(7):982-8. · 3.33 Impact Factor
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ABSTRACT: This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil (FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer.
Eighty-five patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1, followed by a 3-minute bolus injection with FU 500 mg/m(2) and, 30 minutes later, by a bolus injection with FA 60 mg/m(2) every second week. The same doses of FU and FA were also given on day 2.
Fifty-one of 82 assessable patients achieved a complete (n = 4) or partial (n = 47) response, leading to a response rate of 62% (95% CI, 52% to 72%). Nineteen patients showed stable disease, and 12 patients had progressive disease. Thirty-eight of the 51 responses were radiologically confirmed 8 weeks later (confirmed response rate, 46%; 95% CI, 36% to 58%). The estimated median time to progression was 7.0 months (95% CI, 6.3 to 7.7 months), and the median overall survival was 16.1 months (95% CI, 12.7 to 19.6 months) in the intent-to-treat population. Neutropenia was the main adverse event, with grade 3 to 4 toxicity in 58% of patients. Febrile neutropenia developed in seven patients. Nonhematologic toxicity consisted mainly of neuropathy (grade 3 in 11 patients and grade 2 in another 27 patients).
Oxaliplatin combined with the bolus Nordic schedule of FU+FA (Nordic FLOX) is a well-tolerated, effective, and feasible bolus schedule as first-line treatment of metastatic colorectal cancer that yields comparable results compared with more complex schedules.
Journal of Clinical Oncology 02/2004; 22(1):31-8. · 18.37 Impact Factor
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Lakartidningen 07/2003; 100(26-27):2312-3.
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Ake Berglund,
Bengt Glimelius,
Jonas Bergh,
Ola Brodin,
Marie-Louise Fjällskog,
Hans Hagberg,
Anne von Heideman,
Rolf Larsson,
Bengt Tholander,
Manuel de la Torre,
Gunnar Aström,
Kjell Oberg,
Gunnar Parö,
Peter Nygren
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ABSTRACT: The feasibility of tumor sampling followed by ex vivo assessment of drug sensitivity, using the short-term fluorometric microculture cytotoxicty assay (FMCA), for selection of chemotherapy was investigated prospectively in patients with advanced cancer not amenable to standard treatment. Taxol (175 mg/m2 every 3 wk) was given to patients with tumor samples being low drug resistant (LDR) to Taxol ex vivo, to patients with no LDR drug, and if other drugs were unsuitable. The remaining patients received the most optimal drug(s) based on the FMCA results. Gastrointestinal cancer was dominating among the 61 eligible patients. Tumor sampling was safely performed in 75% by ultrasound-guided core biopsy. Eighty-two percent of the patients had Taxol. Five patients (8%) had a partial remission and 18 (30%) had stable disease. Tumor response was poorly predicted, probably because the Taxol excipient Cremophor EL is cytotoxic exclusively ex vivo. However, patients with tumor cells being LDR to at least one drug ex vivo lived significantly longer than those with no such drug.
Medical Oncology 02/2002; 19(3):151-9. · 2.14 Impact Factor
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Anders Jakobsen, Ake Berglund,
Bengt Glimelius,
Jan-Erik Frödin,
Flemming Hansen,
Mogens Kjaer,
Ebbe Lindegaard Madsen,
Erik Sandberg,
Jan Peter Poulsen,
Göran Carlsson,
Bengt Gustavsson
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ABSTRACT: The effect of different dose intensities of 5-fluorouracil (5-FU) in advanced colorectal cancer was investigated. A total of 312 patients were randomized to receive 400 mg/m2 (group A), 500 mg/m2 (group B) or 600 mg/m2 (group C) of 5-FU with leucovorin 60 mg/m2 on two consecutive days every second week. Treatment continued to progression. Pharmacokinetic analyses with calculation of the area under the concentration (AUC) were performed in 91 patients. The primary endpoint was survival, and secondary endpoints were time to disease progression, toxicity and, if the disease was measurable, tumour response. The study was well balanced in the three groups with respect to a number of patient characteristics. Crude survival as estimated by Kaplan-Meier plots was not statistically significantly different (p = 0.07) but tended to show the best results in the intermediate dose group (median survival 10, 12.5 and 10 months, respectively). Analyses of time to progression or death showed significant differences among the three groups (p = 0.02) with the longest progression-free interval in the intermediate group receiving 500 mg/m2. The objective response rates were 23%, 39% and 28%, respectively (p = 0.02). The actual/projected dose intensity (mg/m2/week) was 92%, 92% and 84%, respectively. AUC did not correlate with response or survival. The frequency of severe side effects in group C was significantly higher than that of groups A and B. The study indicated that an increase from 800 to 1000 mg/m2 of bolus 5-FU fortnightly improved the treatment results but a further increase only worsened the toxicity.
Acta Oncologica 02/2002; 41(6):525-31. · 3.33 Impact Factor
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ABSTRACT: Thymidylate synthase (TS) and p53 expression have been reported to predict the results of palliative chemotherapy in advanced colorectal carcinoma (ACRC), but the knowledge is still limited and partly conflicting.
One hundred and twenty-two patients with ACRC were treated with 5-fluorouracil (5-FU)-based therapy at the University Hospital in Uppsala, Sweden, in four different randomised phase III studies between 1989 and 1997. Fifty-nine (48%) of the patients were initially diagnosed with advanced disease. There were 32 (26%) complete or partial radiological responders. The paraffin-embedded tumours at primary diagnosis were retrospectively analysed with immunohistochemical techniques (IHC) for TS using the specific monoclonal antibody, TS 106, and for p53 with the mouse monoclonal antibody DO-7.
All analyses were independently reviewed. High TS values were seen in 78% and p53 positivity in 60% of the tumours. None of the markers predicted the outcome of the later palliative treatment, either in terms of an objective response or survival. However, for the subgroup who initially had curative resection (Dukes' A-C), TS expression had prognostic information and significantly predicted time to recurrence (median for low TS tumours 30 months and for high TS tumours 11 months, p = 0.001).
Immunohistochemical investigation of TS and p53 of the primary tumour is not useful to predict the outcome of palliative chemotherapy in ACRC. Instead, TS can be regarded as a marker for prediction of time to recurrence.
Anticancer research 22(6B):3653-9. · 1.73 Impact Factor
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ABSTRACT: Despite more than four decades of fluoro-pyrimidine treatment in different cancers, the optimal schedule is still not known. The plasma half-life of 5-fluorouracil (5-FU) is extremely short and continuous infusion has gained popularity. In this study we explored whether repeated bolus 5-FU injections could improve the results.
Forty-three patients with advanced gastrointestinal carcinoma, where no standard treatment was available, were included in the phase I study. The initial dose of 5-FU was 250 mg/m2 with 30 mg/m2 leucovorin, repeated three hours later. Treatments were repeated every week. Twenty-six patients were recruited in the following phase II after maximal-tolerated dose (MTD) was reached. Plasma was collected for 5-FU pharmacokinetics.
Diarrhoea was the dose-limiting toxicity (DLT), and was reached at 450 mg/m2. One complete and three partial responses (24%) were seen in the phase II study at 400 mg/m2. In addition, several patients had lasting subjective improvements. The treatments were well-tolerated but accumulated toxicity was seen after several months. Dose intensity was 89% after four months of treatment. A great interpatient variability was seen in 5-FU pharmacokinetics. The plasma AUC correlated with the 5-FU dose and toxicity, but not with the tumour response.
A split of the 5-FU push bolus injection is possible with maintained treatment activity and surprisingly high doses can be tolerated; a weekly dose intensity of 800 mg/m2 could be reached compared with 500 mg/m2 in the standard Nordic FLv schedule.
Anticancer research 23(2C):1789-94. · 1.73 Impact Factor
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ABSTRACT: Cancer of unknown primary (CUP) is relatively common, approximately 3-5% of all cancers. Diagnostic evaluation must include adequate tumor biopsies for pathology evaluation (PAD) as well as abdominal and chest CT. Prognosis is generally poor, but subgroups occur where long-term survival is possible, and a few patients can even be cured. If patients do not belong to any of these subgroups, diagnostic evaluation and treatment should be considered in relation to possible benefits. CUP diagnosed patients should, if possible, be cared for by experienced hospital units with access to a multi-disciplinary network. New radiological methods, such as PET and whole-body MRI, may in certain cases provide important information for diagnosis.
Lakartidningen 102(41):2946-8, 2950-2.
