| 1. |
- Glimelius, Bengt, et al.
(författare)
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Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx®) : a placebo-controlled randomised phase II study (PLIANT)
- 2018
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 57:3, s. 393-402
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Oxaliplatin causes disabling acute and chronic peripheral neuropathy. We explored the preventive effects of calmangafodipir, mimicking the mitochondrial enzyme manganese superoxide dismutase, thereby protecting cells from oxidative stress, in a placebo-controlled, double-blinded randomised phase II study (ClinicalTrials.gov.NCT01619423) in patients with metastatic colorectal cancer (mCRC).Patient and methods: mCRC patients treated with modified FOLFOX-6 (folinic acid 200 mg/m2, 5-fluorouracil bolus 400 mg/m2, oxaliplatin 85 mg/m2 and 5-fluorouracil 2400 mg/m2 continuous infusion for 46 h) every fortnight for 8 cycles in first or second line were eligible. Calmangafodipir was given in a phase I dose-finding and in a phase II placebo-controlled study, as a 5-min infusion 10 min prior to oxaliplatin. Neurotoxicity was evaluated by the physician using the Oxaliplatin Sanofi Specific Scale and by the patient using the cold allodynia test and the Leonard scale.Results: Eleven patients were included in phase I without any detectable toxicity to calmangafodipir. In the phase II study, 173 patients were randomised to placebo (n = 60), calmangafodipir 2 µmol/kg (n = 57) and calmangafodipir 5 µmol/kg (n = 45, initially 10 µmol/kg, n = 11). Calmangafodipir-treated patients (all three doses pooled) had less physician graded neurotoxicity (odds ratio (90% confidence interval one-sided upper level) 0.62(1.15), p = .16), significantly less problems with cold allodynia (mean 1.6 versus 2.3, p < .05) and significantly fewer sensory symptoms in the Leonard scale (cycle 1–8 mean 1.9 versus 3.0, p < .05 and during follow-up after 3 and 6 months, mean 3.5 versus 7.3, p < .01). Response rate, progression-free and overall survival did not differ among groups.Conclusions: Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes.
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| 2. |
- Karlberg, Mia
(författare)
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Prognostic factors in colorectal cancer : studies of thymidylate synthase expression, mismatch repair protein expression, tumor budding and t-cell infiltration
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is a major health problem in the Western world. CRC is treatable with surgery and often curable when the disease is diagnosed at an early stage. With improved surgery and adjuvant chemotherapy treatment, the disease-free-survival (DFS) rate for colon cancer is approximately 80% for stage II and for stage III close to 65%. There is a continual need for the established risk stratification of CRC based on the tumor, node, metastasis (TNM) staging to evolve. The overall aim of this thesis was to detect new potential prognostic and predictive factors for molecular and clinical responses in primary CRC. One specific aim was to establish whether thymidylate synthase (TS) expression in a large group of patients with stage II and stage III CRC is a prognostic and/or predictive factor alone or in combination with mismatch repair (MMR) status in the colon cancer subgroup. Another aim was to explore in primary CRC the potential association between tumor budding and MMR status and the impact of tumor budding as a factor of tumor recurrence and development of distant metastases. The last aim was to investigate the prognostic and predictive value of tumor budding, tumor border configuration and T-cell infiltration in primary colon cancer with known MMR status. Tumor material for the studies was derived from the adjuvant Nordic trials which randomized from 1991 to 1997, 2224 patients with stage II or stage III CRC to surgery alone or surgery plus adjuvant 5-FU-based chemotherapy. Immunohistochemistry (IHC) was used to detect and evaluate TS expression, MMR-status, tumor budding and infiltration of CD3+ and CD8+ T-cells. Paper I. TS expression was assessed in tumors from 1,389 patients with stage II and III CRC. TS expression with the classification of TS grade 0-1 versus 2-3 as well as TS 1-2 versus TS 3 was prognostic in the surgery alone group. A high TS expression was associated with a shorter overall survival (OS). Among patients with TS grade 3, the subgroup treated with adjuvant chemotherapy had a significant longer OS compared with the group treated with surgery alone. Paper II. Primary colon cancer with a deficient MMR status (dMMR) is associated with an improved prognosis. Data indicates that colon cancer with a proficient MMR status (pMMR) and with high TS expression has an improved response to adjuvant 5-FU-based chemotherapy. This study evaluated if a combined analysis of MMR status and TS expression in 716 colon cancer patients added prognostic value and better predicted response to adjuvant 5-FU-based chemotherapy. In the group of patients treated with surgery alone, patients with dMMR tumors and low TS grade had a trend to a better OS compared to patients with pMMR tumors and high TS grade. In stage III, patients with pMMR tumors and high TS grade who received adjuvant 5-FU-based chemotherapy had a significantly improved OS compared to patients treated with surgery alone. No relationship was found between MMR status and TS expression. Paper III. A pMMR status compared to a dMMR status and tumor budding are considered adverse prognostic factors in primary CRC. This exploratory study included 134 patients with primary CRC. It assessed tumor budding grade in tumors with pMMR status compared to dMMR status to see if it differed as to whether local recurrence or metastases did or did not develop. The 29 available dMMR cases which developed recurrence or distant metastases (met+) were matched with a dMMR group with no recurrence or metastases (met-), and the pMMR/met+ group with pMMR/met- cases. A significantly higher percentage of high-grade tumor budding was only found in the dMMR/met+ group compared to the pMMR/met+ group. Paper IV. Tumor budding is correlated to the development of local and distant metastases in CRC while high density of tumor infiltrating immune cells is associated with an improved prognosis. In this study, tumors from 478 patients with stage II-III colon cancer and known MMR status were examined to determine the prognostic value of tumor budding, tumor border configuration and CD3+ / CD8+ T-cell infiltration. An association was found between high grade tumor budding and more advanced stage, higher N-stage, pMMR status, an infiltrating tumor border configuration and lower levels of high score CD3+ and CD8+ T-cells. High grade tumor budding was correlated to worse OS in univariate analysis but not in multivariate. In the entire study population, an infiltrative tumor border configuration was an adverse prognostic factor for OS and a dense infiltration of CD8+ T-cells was independently associated with a better OS. In conclusion, TS is a prognostic factor in CRC patients treated with surgery alone and patients with the highest level of TS expression had an improved clinical outcome following adjuvant 5-FU-based chemotherapy. In stage III colon cancer, a combined rather than a single marker analysis of MMR-status and TS expression, can improve the prediction of response to 5-FU-based chemotherapy. Whether tumor budding can provide prognostic information for patients with primary CRC and a dMMR status should be further explored in larger studies. An independent prognostic impact was found for CD8+ T cell infiltration and tumor border configuration as well as an association between them and tumor budding. Our study supports the inclusion of tumor border configuration, tumor budding, CD8+ T cell infiltration in the risk assessment for stage II-III colon cancer patients.
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| 3. |
- Mezheyeuski, Artur, et al.
(författare)
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Stroma-normalised vessel density predicts benefit from adjuvant fluorouracil-based chemotherapy in patients with stage II/III colon cancer
- 2019
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Ingår i: British Journal of Cancer. - : NATURE PUBLISHING GROUP. - 0007-0920 .- 1532-1827. ; 121:4, s. 303-311
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Identification of biomarkers associated with benefit of adjuvant chemotherapy in stage II/III colon cancer is an important task. METHODS: Vessel density (VD) and tumour stroma were analysed in a randomised-trial-derived discovery cohort (n = 312) and in a stage II/III group of a population-based validation cohort (n = 85). VD was scored separately in the tumour centre, invasive margin and peritumoral stroma compartments and quantitated as VD/total analysed tissue area or VD/stroma area. RESULTS: High stroma-normalised VD in the invasive margin was associated with significantly longer time to recurrence and overall survival (OS) (p = 0.002 and p = 0.006, respectively) in adjuvant-treated patients of the discovery cohort, but not in surgery-only patients. Stroma-normalised VD in the invasive margin and treatment effect were significantly associated according to a formal interaction test (p = 0.009). Similarly, in the validation cohort, high stroma-normalised VD was associated with OS in adjuvant-treated patients, although statistical significance was not reached (p = 0.051). CONCLUSION: Through the use of novel digitally scored vessel-density-related metrics, this exploratory study identifies stroma-normalised VD in the invasive margin as a candidate marker for benefit of adjuvant 5-FU-based chemotherapy in stage II/III colon cancer. The findings, indicating particular importance of vessels in the invasive margin, also suggest biological mechanisms for further exploration.
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| 4. |
- Pfeiffer, Per, et al.
(författare)
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Maintenance Therapy With Cetuximab Every Second Week in the First-Line Treatment of Metastatic Colorectal Cancer : The NORDIC-7.5 Study by the Nordic Colorectal Cancer Biomodulation Group
- 2015
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Ingår i: Clinical colorectal cancer. - : Elsevier BV. - 1533-0028 .- 1938-0674. ; 14:3, s. 170-176
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Tidskriftsartikel (refereegranskat)abstract
- In the NORDIC-7.5 trial, cetuximab administered every 2 weeks in 152 patients with Kirsten rat sarcoma viral oncogene homolog wild type metastatic colorectal cancer was investigated. After 4 months of induction therapy with Nordic FLOX (oxaliplatin, bolus 5-fluorouracil, and bolus folinic acid) and cetuximab, patients continued with cetuximab monotherapy. Cetuximab might have added to a longer chemotherapy-free interval, but needs to be validated in clinical trials. Background: In the NORDIC-7.5 trial, how cetuximab might safely and conveniently be added to an intermittent treatment strategy in patients with prospectively selected Kirsten rat sarcoma viral oncogene homolog wild type (KRASwt) metastatic colorectal cancer (mCRC) was investigated. Patients were treated in a multicenter phase II trial with cetuximab in combination with the Nordic bolus FLOX (oxaliplatin, 5-fluorouracil, and folinic acid) for 4 months followed by maintenance cetuximab. Patients and Methods: Patients had KRASwt, nonresectable mCRC, no previous chemotherapy, and Eastern Cooperative Group performance status of 0 to 2. Patients received 8 courses of Nordic FLOX (oxaliplatin 85 mg/m(2) over 1 hour on day 1, and 5-fluorouracil 500 mg/m(2) as a bolus injection, followed 30 minutes later with bolus folinic acid 60 mg/m(2) on days 1 and 2). Cetuximab was administered every 2 weeks at a dose of 500 mg/m(2) for 16 weeks followed by cetuximab as maintenance therapy until disease progression. Results: Between July 2008 and September 2010, 152 KRASwt patients were included. The response rate was 62% (95% confidence interval [CI], 54%-69%), median progression-free survival was 8.0 months (95% CI, 7.5-8.9) and median overall survival was 23.2 (95% CI, 18.1-27.4) months. Twenty-one patients (14%) had later R0-resection of metastasis. FLOX with cetuximab was reintroduced in 47 of 85 patients (55%). The most common Grade 3/4 nonhematologic adverse events were diarrhea in 14 patients (9%), skin rash in 13 patients (9%), infection without neutropenia in 11 patients (7%), and fatigue in 11 patients (7%). Conclusion: In a prospectively selected KRASwt population, biweekly cetuximab was safely integrated in an intermittent chemotherapy strategy and might have added to a longer chemotherapy-free interval. However, the combination of biweekly cetuximab with chemotherapy needs to be validated in trials using FOLFOX (oxaliplatin, fluorouracil, and leucovorin) or FOLFIRI (irinotecan, fluorouracil, and leucovorin).
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