| 1. |
- Gustafsson Liljefors, Maria
(author)
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Immunotherapy with the anti-EpCAM monoclonal antibody and cytokines in patients with colorectal cancer : a clinical and experimental study
- 2005
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Doctoral thesis (other academic/artistic)abstract
- The tumor-associated antigen EpCAM (epithelial cell-adhesion molecule) (C017-1A) is over expressed by various human carcinomas, including colorectal carcinoma (CRC). This antigen can be used as a target structure for specific immunotherapy with vaccines and monoclonal antibodies (MAb). Addition of cytokines to MAb therapy may augment immune effector functions and chemotherapeutic agents may also add to therapeutic efficacy. In this thesis, we have analysed clinical and immunological responses of patients with advanced CRC treated with either the murine anti-EpCAM MAb (anti-EpCAM mMAb) or its chimeric counterpart (antiEpCAM cMAb) in combination with cytokines and chemotherapeutics. Additionally, sequential analysis of cytokeratin positive (CK+) cells in the bone marrow (BM) were made in CRC patients receiving MAb based therapy for advanced disease or as adjuvant therapy. Pretreatment natural killer (NK) cell cytotoxicity in vitro of peripheral blood mononuclear cells was an independent prognostic factor for overall survival and progression free survival (PFS) in patients receiving anti-EpCAM MAb based therapy as first-line therapy. The results from this study might be used for future patient selection and indicate that agents that activate NK cells should be considered to MAbbased treatment regimens. The addition of GM-CSF, alpha-interferon and 5-fluorouracil to anti-EpCAM mMAb seemed to improved the antitumor response rate compared to historical control patients treated with anti-EpCAM mMAb alone (54% vs 15%) as well as PFS (15 vs 7 weeks). Clinical effects were mainly stable disease > 3months (11 of 14 responders) and responding patients survived longer than non-responders. The clinical efficacy of antiEpCAM cMAb and GMCSF was not better than in a historical control group who had received the antiEpCAM mMAb and GM-CSF (overall response rates=21% vs 27%, respectively). Anti-idiotypic antibody (Ab2) concentrations as well as the frequency of patients mounting an Ab2response in antiEpCAM eMAb treated patients were lower as compared to anti-EpCAM mMAb-treated patients (69% vs 100%). Following repeated daily subcutaneous (s.c.) injections of exogenous non-glycosylated E.coli-derived GM-CSF (molgramostim), the peak serum GM-CSF concentrations declined days 5 and 10 as compared to day 1. A dose-dependent increment in total white blood cell count was observed, the total numbers of GM-CSF receptor expressing cells increased during treatment while a transient decline in expression intensity was observed at day 5. The majority of patients developed binding but not neutralizing antiGM-CSF antibodies. These results might support a receptor-mediated clearance of GM-CSF from the circulation. Importantly, high dose of GM-CSF resulted in lower antibody-dependent cellular cytotoxicity that may reflect immune suppression. Further studies are required to establish the optimal biological dose of different cytokines. CK+ cells in BM were examined by immunohistochemistry on routinely processed BM clots, and CK+ cells were divided into different subtypes; Group A (CK+ probably malignant epithelial cells), Group B (CK+ morphologically non-epithelial cells) and Group C (CK+ contaminating cells). The presence of Group A cells did not adversely affect the prognosis while the presence of Group B cells probably indicates a poor prognosis in patients receiving adjuvant therapy. Sequential BM aspirations do not seem to add to the existing methods to follow the effect of treatment in CRC. These results might provide further clinical studies with MAbs, combined with other agents with different modes of action to increase the clinical efficacy of MAb. Ideally, patients with a well preserved immune system and low or minimal tumor burden should be selected to MAb-based therapy.
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| 2. |
- Labori, Knut Jørgen, et al.
(author)
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Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1) : a multicentre, randomised, phase 2 trial
- 2024
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In: The Lancet Gastroenterology & Hepatology. - : The Lancet Group. - 2468-1253. ; 9:3, s. 205-217
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Journal article (peer-reviewed)abstract
- BackgroundIn patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.MethodsNORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.FindingsBetween Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.InterpretationThis phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.
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| 3. |
- Labori, Knut Jørgen, et al.
(author)
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Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1) : a multicentre, randomised, phase 2 trial
- 2024
-
In: The Lancet Gastroenterology & Hepatology. - : Elsevier. - 2468-1253. ; 9:3, s. 205-217
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Journal article (peer-reviewed)abstract
- Background: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.Methods: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.Findings: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.Interpretation: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.
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| 4. |
- Tsekrekos, Andrianos, et al.
(author)
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Impact of Laparoscopic Gastrectomy on the Completion Rate of the Perioperative Chemotherapy Regimen in Gastric Cancer : A Swedish Nationwide Study
- 2023
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In: Annals of Surgical Oncology. - 1068-9265. ; 30:1112, s. 7196-7205
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Journal article (peer-reviewed)abstract
- Background: Omission of prescheduled chemotherapy following surgery for gastric cancer is a frequent clinical problem. This study examined whether laparoscopic gastrectomy (LG) had a positive impact on compliance with adjuvant chemotherapy compared with open (OG). Methods: Patients with cT2-4aN0-3M0 adenocarcinoma treated with gastrectomy and perioperative chemotherapy between 2015 and 2020 were identified in the Swedish national register. Additional information regarding chemotherapy was retrieved from medical records. Regression models were used to investigate the association between surgical approach and the following outcomes: initiation of adjuvant chemotherapy, modification, and time interval from surgery to start of treatment. Results: A total of 247 patients were included (121 OG and 126 LG, conversion rate 11%), of which 71.3% had performance status ECOG 0 and 77.7% clinical stage II/III. In total, 86.2% of patients started adjuvant chemotherapy, with no significant difference between the groups (LG 88.1% vs OG 84.3%, p = 0.5). Reduction of chemotherapy occurred in 37.4% of patients and was similar between groups (LG 39.4% vs OG 35.1%, p = 0.6), as was the time interval from surgery. In multivariable analysis, LG was not associated with the probability of starting adjuvant chemotherapy (OR 1.36, p = 0.4) or the need for reduction (OR 1.29, p = 0.4). Conversely, major complications had a significant, negative impact on both outcomes. Conclusions: This nationwide study demonstrated a high rate of adjuvant chemotherapy initiation after curative intended surgery for gastric cancer. A beneficial effect of LG compared with OG on the completion rate was not evident.
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