A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer.

BACKGROUND: 5-fluorouracil (5-FU) combined with a folate remains an essential treatment component for metastatic colorectal cancer (mCRC). Leucovorin is the folate most often used, but requires intracellular conversion to a reduced folate, and has high pharmacokinetic variability and limited bioavailability in patients with low folate pathway gene expression. Arfolitixorin is an immediately active form of folate, [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF), and may improve outcomes. PATIENTS AND METHODS: This open-label, multicenter, phase I/II study in patients with mCRC (NCT02244632) assessed the tolerability and efficacy of first- or second-line arfolitixorin (30, 60, 120, or 240 mg/m2 intravenous) with 5-FU alone, or in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan, every 14 days. Safety, efficacy, and pharmacokinetics were assessed before and after four cycles (8 weeks) of treatment. RESULTS: In 105 treated patients, investigators reported 583 adverse events (AEs) in 86 patients (81.9%), and 256 AEs (43.9%) were potentially related to arfolitixorin and 5-FU. Dose adjustments were required in 16 patients (15.2%). At 8 weeks, 9 out of 57 patients assessed for efficacy achieved an objective response (15.8%), and all 9 achieved a partial response. Six of these nine patients had received arfolitixorin as a first-line treatment. A further 33 patients (57.9%) achieved stable disease. Pharmacokinetics were assessed in 35 patients. The average tmax was 10 min, and area under the plasma concentration-time curve from time 0 to 1 h increased linearly between 30 and 240 mg/m2. No accumulation was observed for [6R]-MTHF following repeated administration, and there were no major pharmacokinetic differences between cycle 1 and cycle 4 at any dose. CONCLUSIONS: Arfolitixorin is a well-tolerated moderator of 5-FU activity. It is suitable for further investigation in mCRC and has the potential to improve treatment outcomes in patients with low folate pathway gene expression. Arfolitixorin can easily be incorporated into current standard of care, requiring minimal changes to chemotherapy regimens.

Radical prostatectomy for locally advanced primary or recurrent rectal cancer.

AIM: Three papers including five patients have described en bloc radical prostatectomy for locally advanced rectal cancer. METHODS: Six patients (median age 63 years) underwent en bloc radical prostatectomy for locally advanced (3) or recurrent (3) rectal cancer involving the prostate. Quality of life questionnaires were answered postoperatively and the data prospectively entered in a database. RESULTS: One primary case had low anterior resection (LAR), the others abdominoperineal resections (APR) of R0 stage. Two recurrent cases had APRs and one tumour resection-all R1 stage. Anastomotic leakage led to construction of an ileal conduit in one patient and in two healed on conservative treatment. Follow up was 10-50 months. One patient died from distant metastases at 29 months postoperatively, one was operated for a single lung metastasis and one has disseminated lung metastases. None has developed local recurrence. Four of the five with anastomoses had good quality of life and none wanted an ileal conduit. CONCLUSION: In spite of a relatively high urinary leak rate the total complication rate seems to be lower than after pelvic exenteration. En bloc radical prostatectomy seems an option in selected patients otherwise needing pelvic exenteration for locally advanced or recurrent rectal cancer.

[Radiotherapy of skeletal metastases]. / Strålebehandling av skjelettmetastaser.

INTRODUCTION: Patients with skeletal metastases represent a large cohort in clinical oncology, and the single most frequent indication for palliative radiotherapy. Patients with cancer of the breast, lung, prostate and those with myelomatosis, constitute approximately 80% of this group. MATERIAL AND METHODS: This paper summarizes data from relevant published clinical trials employing external irradiation for painful skeletal metastases. More recent randomised trials support the view that a single radiation dose of 8-10 Gy is equally efficient as ten treatments of 3 Gy delivered over two weeks. However, some still believe that fractioned regimes to a higher total dose provide better pain relief of a longer duration than a single fraction. RESULTS: We review the current diagnosis and treatment of patients with skeletal metastases and discuss some aspect of tumour biology. The etiology of pain and the pathogenesis of tumour cells affecting bone tissue, resulting in osteolysis and/or osteosclerosis, are discussed. Associated leukocyte-derived osteoclast-activating cytokines that stimulate pain receptors locally, can in part explain why radiotherapy gives such rapid pain relief. INTERPRETATION: The aims of radiotherapy must be assessed in relation to the life expectancy of the patient. Based on actual publications and own experiences, we suggest treatment with 8 Gy x 1 for the majority of patients, and reserve 3 Gy x 10 for patients with longer life expectancy. Both regimes allow retreatment, if and when pain eventually reoccur in previously irradiated areas.

Clinical significance of routine pre-cystectomy bone scans in patients with muscle-invasive bladder cancer.

OBJECTIVE: To evaluate the clinical significance of bone scans taken routinely before total cystectomy in patients with bladder cancer of clinical stage > or = T2. PATIENTS AND METHODS: Of 227 consecutive patients with stage > or = T2 bladder cancer diagnosed between 1980 and 1990 but with no clinical suspicion of bone metastases, 91 had a pre-cystectomy bone scan performed at the Norwegian Radium Hospital. The medical records of these patients were reviewed to examine the subsequent development of distant metastases and survival. RESULTS: Of the 91 patients, 37 (41%) developed skeletal bone metastases after cystectomy, unrelated to the clinical T category. In 35 patients, the pre-cystectomy bone scan showed pathological uptake of isotope which was interpreted by the specialist in nuclear medicine as suspicious of (13 patients) or probably caused by (22 patients) skeletal metastases. In either circumstance, the clinician decided that total cystectomy was precluded, particularly as most of the changes could be explained radiologically as being degenerative. In the individual patient, there was no clinically useful correlation between the findings on the pre-cystectomy bone scan and the clinical course of disease, nor if serum alkaline phosphatase (SAP) level was included as an additional predictive factor. However, although not statistically significant, the follow-up of all patients revealed an association between the degree of change on the pre-cystectomy bone scan and the subsequent development of skeletal metastases and cancer-corrected survival. CONCLUSION: Unless further investigations, particularly magnetic resonance imaging (MRI), can be performed, the findings of a routine pre-operative bone scan are usually unable to identify patients with bladder cancer of stage > or = T2 who will not be cured by total cystectomy. An increased level of SAP did not improve the predictive accuracy of a pre-cystectomy bone scan. However, the results indicate that future clinical research should be directed at combining the findings of bone scans and MRI in the search for micrometastases.