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We have previously published an article describing the protocol for a clinical, non-randomized phase II study (Eudract no. 2013-001648-79) [1], which aimed to provide proof of concept for introduci...

The optimal treatment for cancer in the elderly poses problems, partly related to the underrepresentation of elderly patients in clinical trials. Colorectal cancer, especially when metastatic (mCRC...

Background: An aging population will increase the number of older patients with metastatic colorectal cancer (mCRC). However, there is limited knowledge about treatment in older patients as they are under-represented in clinical trials. The oral fluoropyrimidine S-1 is associated with a lower rate of adverse events than capecitabine and may therefore be a suitable drug for elderly. However, data on the use of S-1 in Caucasian mCRC patients are lacking/scarce. Material and methods: In the present study we evaluated safety and the efficacy of S-1 alone or in combination with oxaliplatin (SOx) or irinotecan (IRIS) in older mCRC patients. Patients who received at least one cycle of S-1 (first-line therapy), SOx (mainly first-line therapy) or IRIS (second-line therapy) were included. Results: From June 2012 to December 2014, 71 older patients received ≥1 cycle of either S-1 (n = 9), SOx (n = 44) or IRIS (n = 18) for mCRC. Median age was 76 years and most patients had a WHO performance status of 0 (32%) or 1 (56%). All patients were evaluable for response and safety. In the SOx group, 18 (41%) and 20 patients (45%) had partial response (PR) and stable disease (SD), respectively (disease control rate 86%). Median progression-free survival (PFS) was 8.5 months and median overall survival (OS) was 18.5 months. In the S-1 group (median age 82 years), PR was 22%, median PFS 6.4 months and median OS 15.8 months. In the IRIS group, PR was 28%, median PFS 7.8 months and the median OS 16.5 months. In general, therapy was well tolerated; main non-hematological toxicities were fatigue and diarrhea. Conclusion: S-1 monotherapy, SOx and IRIS were well tolerated for older patients with mCRC and could become alternative regimens in older mCRC patients. These regimens are now further evaluated in the randomized ongoing NORDIC9 trial.

Background Cancers of the liver, bile duct, gall bladder and pancreas (HPB-c) are a heterogeneous group, united almost exclusively by a poor prognosis. As the number of elderly in the Western world continues to rise and HPB-c are associated with age, we wanted to examine changes in incidence, mortality, prevalence and relative survival for these cancers.Materials and methods HBP-c was defined as ICD-10 codes C22 (liver), C23-24 (gall bladder), and C25 (pancreas). Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013.Results The incidence and mortality rates of cancer of the liver and pancreas increased over time while the rates of cancer of the gall bladder and bile duct decreased. All HBP-c were more frequent in persons over the age of 70 than in younger persons. The relative one- and five-year survival rose in most HPB-c, but mainly occurring in the younger population of 0-69 years with only small to no gains in the 80 + group.Conclusion As the number of persons aged 80 years or more will increase dramatically in the following years, and our results show a gap in relative survival, it is important to continue to study this population in order to improve management and outcome.

Background. The use of postoperative adjuvant chemotherapy is controversial for rectal adenocarcinoma. Both international and national guidelines display a great span varying from recommending no adjuvant chemotherapy at all, over single drug 5-fluororuacil (5-FU), to combinations of 5-FU/oxaliplatin.Methods. A review of the literature was made identifying 24 randomized controlled trials on adjuvant treatment of rectal cancer based on about 10 000 patients. The trials were subdivided into a number of clinically relevant subgroups.Results. As regards patients treated with preoperative (chemo) radiotherapy, four randomized studies were found where use of adjuvant chemotherapy showed no benefit in survival. Three trials were found in which a subset of patients received preoperative (chemo) radiotherapy. Two of these trials showed a statistically significant benefit of adjuvant chemotherapy. Twenty trials were identified in which the patients did not receive preoperative (chemo) radiotherapy, including five Asian studies in which a statistically significant benefit from adjuvant chemotherapy was reported.Conclusions. Most of the data found did not support the use of postoperative adjuvant chemotherapy for patients already treated with preoperative (chemo) radiotherapy. For patients not treated preoperatively, several studies support the use of single agent 5-FU chemotherapy. Treatment guidelines seem to differ according to if preoperative chemoradiation is considered of importance for use of adjuvant chemotherapy and if adjuvant colon cancer studies are considered transferrable to rectal cancer patients regardless of the molecular differences.

Consensus is that patients with locally advanced rectal cancer (LARC) should receive long-term chemoradiotherapy (CRT) before surgery. With the intent to offer the patients intensified concomitant chemotherapy (CT) to improve outcome and to assess tolerability and toxicity of oxaliplatin (Ox) a phase I trial of high dose pelvic radiotherapy (RT), fixed dose of oral UFT/l-leucovorin and increasing doses of weekly Ox were performed.Pelvic RT with 48.6 Gy/27 fractions was given to the primary tumour and the regional lymph nodes and a concurrent boost of 5.4 Gy/27 fractions with a final boost of 6 Gy/3 fractions was given to the gross tumour volume (GTV) (60 Gy/30 fractions). Concurrent with RT patients received a daily dose of UFT 300 mg/m(2) plus fixed dose l-leucovorin 22.5 mg 5/7 days and increasing weekly doses of Ox with 10 mg/m(2)/week from a start dose of 30 mg/m(2)/week to a maximum of 60 mg/m(2)/week. In addition, before and after CRT the patients received one course of TEGAFOX (UFT 300 mg/m(2) with l/leucovorin 22.5 mg Days 1-14 and Ox 130 mg/m(2) given on Day 1). Surgery was planned at least six weeks after the completion of the CRT.From May 2005 to March 2009, 18 patients with LARC (16 primary, two recurrent) were included in this phase I trial. Toxicity was low with only 5-17% grade 3-4 toxicity. Fifteen patients (83%) were operated (14 R0 resection and 1 R1 resection) after completion of CRT. Five (33%) patients had a pathological complete response (ypCR). When ypCR was combined with yp few residual cells, the rate was 60%. Thirteen patients are still alive December 2011.Preoperative high-dose RT and concomitant UFT with increasing doses of Ox up to 60 mg/m(2)/week was feasible with low toxicity, high ypCR rates and promising OS in patients with non-resectable LARC.

Results of continuous sunitinib, in combination with cetuximab and irinotecan every other week (SIC) for compassionate use in heavily pre-treated patients with mCRC are presented.Patients with mCRC resistant to oxaliplatin, irinotecan, 5-FU and cetuximab received SIC at two Danish oncologic departments. The regimen consisted of sunitinib given as a continuous-dosing in combination with cetuximab and irinotecan every other week (CetIri). The first six patients started with a daily oral dose of sunitinib of 12.5 mg. Subsequent patients started at a daily dose of 25 mg with the possibility to escalate to 37.5 mg.Twenty-nine patients received SIC. No patient had an objective response, but 13 patients had subjective relief and 42% had stable disease. The median time to progression was 3.2 months and median overall survival was 7.4 months. Fatigue and leukopenia were the most frequently reported severe adverse event (18% grade 3 and 18% grade 3/4, respectively).Sunitinib continuous-dosing with 25 mg/day can safely be combined with CetIri administered every other week.

Udgivelsesdato: 2008-null Background. Preoperative radiochemotherapy is a cornerstone in patients with non- resectable locally advanced rectal cancer (LARC). To improve outcome (number of R0 resections and survival) high-dose radiotherapy (RT) was combined with oral UFT/l-leucovorin to allow tumour regression before radical intended surgery. Methods. Pelvic RT was delivered with megavoltage photons using a 5 field technique. RT was CT-based, given 5 days a week through one posterior field and two lateral fields (48.6 Gy/27 fractions) to encompass the primary tumour and the regional lymph nodes. In addition, the tumour bed received a concurrent boost (5.4 Gy/27 fractions) and a final boost (6 Gy/3 fractions); thus GTV received 60 Gy/30 fractions. Concurrent with RT patients received a daily dose of oral UFT 300 mg/m(2) plus l-leucovorin 22.5 mg 5/7days (divided in three doses). Results. From September 2000 to November 2004, 52 patients (median age 60 years (32-83); median PS 0 (0-2)) with LARC (36 primary, 16 recurrent) were included in this phase II study. All but three patients received the planned 60 Gy, median duration of RT was 42 days (25-49). Toxicity was very modest; only four patients had a dose reduction of UFT. No hematological toxicity of clinical significance was seen. Non-hematological toxicity grade 1 (GI-toxicity, fatigue and/or dysuria) was frequently observed but only four patients experienced grade 3 toxicity (diarrhoea and/or nausea/vomiting). Forty patients (77%) were operated (30 R0, 5 R1, 5 R2) median 55 days (27-112) after completion of RT. Seven (13%) patients had a pathological complete response (pCR). Thirty-one patients (60%) died after median 25.4 months (1.6-45.2 months). Twenty-one patients (40%) are still alive June 2007. Conclusions. Preoperative high-dose RT and concomitant UFT produces major regression in most patients with non-resectable LARC and thus a good chance of cure.

From having been a 'single-drug not very interesting cancer type' from a medical treatment perspective, treatment of colorectal cancer (CRC) has during the past five years become a more complex issue of the appropriate use of several cytotoxic drugs sometimes integrated with advanced metastatic surgery with curative intent. The new drugs have provided significant benefit to the patients, so far mostly in the metastatic setting but also in adjuvant treatment. The significant progress in molecular and tumour biology has produced a great number of new 'targeted' drugs that are now in various stages of clinical development. Two of these drugs, the monoclonal antibodies bevacizumab (Avastin) and cetuximab (Erbitux), directed against VEGF and EGFR, respectively, have recently been approved within the EU for use in metastatic CRC. This Nordic Expert Consensus Report summarizes the current status of chemotherapy in metastatic CRC, overviews the clinical status of targeted drugs in CRC and, finally, provides guidelines for the routine clinical use of bevacizumab and cetuximab based on the most recently available clinical data.

The main objectives of this phase II study were to determine efficacy and safety of the combination of UFT with Leucovorin and mitomycin C in patients with metastatic colorectal cancer. Ninety-seven patients were treated with UFT (91 patients 300 mg/m2, 6 patients 250 mg/m2) + Leucovorin 90 mg days 1-28 q 5 weeks. During the first 4 cycles the patients also received mitomycin C 7 mg/m2 on day 1. At the end of 4 courses patients with benefit from the treatment could receive further courses of UFT and Leucovorin alone. Two patients had a complete response (2%), 20 (21%) had a partial response, 40 (41%) had no change, 19 (20%) had progression, and 16 (17%) were not evaluable for response. The overall response rate by intention to treat was 22/97 (23%). Median time to progression was 5 months and median survival 13 months. Severe (grade 3-4) toxicities included: anorexia 3%, nausea 6%, vomiting 7%, diarrhoea 7%, and fatigue 9%. Febrile neutropenia, renal failure, and thrombocytopenia were seen in 1% of the patients, respectively. The combination of UFT with Leucovorin and mitomycin C shows similar clinical activity with regard to overall response rate (23%) and survival (13 months) to other frontline 5-fluorouracil-based therapies in metastatic colorectal cancer patients. The results indicate that mitomycin C did not increase either efficacy or toxicity. Therefore, phase III trials with this regimen cannot be recommended.

The incidence and latency period of radiation-induced brachial plexopathy (RBP) were assessed in 79 breast cancer patients by a neurological follow-up examination at least 60 months (range 67-130 months) after the primary treatment. All patients were treated primarily with simple mastectomy, axillary nodal sampling and radiotherapy (RT). Postoperatively, pre- and postmenopausal patients were randomly allocated chemotherapy or antiestrogen treatment. All patients were recurrence-free at time of examination. Clinically, 35% (25-47%) of the patients had RBP; 19% (11-29%) had definite RBP, i.e. were physically disabled, and 16% (9-26%) had probable RBP. Fifty percent (31-69%) had affection of the entire plexus, 18% (7-36%) of the upper trunk only, and 4% (1-18%) of the lower trunk. In 28% (14-48%) of cases assessment of a definite level was not possible. RBP was more common after radiotherapy and chemotherapy (42%) than after radiotherapy alone (26%) but the difference was not statistically significant (p = 0.10). The incidence of definite RBP was significantly higher in the younger age group (p = 0.02). This could be due to more extensive axillary surgery but also to the fact that chemotherapy was given to most premenopausal patients. In most patients with RBP the symptoms began during or immediately after radiotherapy, and were thus without significant latency. Chemotherapy might enhance the radiation-induced effect on nerve tissue, thus diminishing the latency period. Lymphedema was present in 22% (14-32%), especially in the older patients, and not associated with the development of RBP. In conclusion, the damaging effect of RT on peripheral nerve tissue was documented. Since no successful treatment is available, restricted use of RT to the brachial plexus is warranted, especially when administered concomitantly with cytotoxic therapy.

(1990). A Prospective Pilot Study on the Effect of Sucralfate Mouth-Swishing in Reducing Stomatitis During Radiotherapy of the Oral Cavity. Acta Oncologica: Vol. 29, No. 4, pp. 471-473.

Oral  uoropyrimidines represent a new treatment option in colorectal cancer. So far, two drugs have drawn major attention. UFT is a combination of tegafur and uracil in a 1 : 4 molar ratio. Tegafur is a pro-drug to 5- uorouracil (5-FU) and uracil inhibits dihydropyrimidindehydrogenase, which is a key enzyme in the catabolism of 5-FU. Combined with leucovorin, the drug appears to have an effect equal to that of 5-FU and leucovorin, as shown in two large randomized trials (1, 2), but with a lower risk of toxicity compared with that in the Mayo schedule. This schedule is probably one of the more toxic bolus 5-FU regimens (3). Capecitabine is activated to 5-FU through a number of steps. Thymidinfosforylase catalyses the Ž nal conversion and this enzyme is present in higher concentrations in tumour tissue than in normal tissue, resulting in a tumour selective generation of 5-FU (4). In randomized trials, capecitabine has an activity in line with 5-FU and leucovorin (5, 6). Both of these oral treatments are attractive for a number of reasons, but they have not been directly compared. We conducted two consecutive phase II trials to elucidate the advantages and disadvantages of the two drugs. The two trials had identical criteria for inclusion, evaluation of response, toxicity and follow-up. The inclusion criteria included histopathologic veriŽ cation of the diagnosis; age 575 years; measurable lesions; performance status (WHO) 52; and informed consent. The patients were required to have a normal bone marrow function as estimated by white blood cell count ]31⁄210:L and thrombocytes ]1001⁄2 10:L. Previous chemotherapy was not allowed, with the exception of adjuvant chemotherapy if terminated at least 12 months before protocol entrance. Patients with a previous malignant disease or serum bilirubin ]40 mmol:L were also excluded. Pretreatment evaluation included full history, physical examination, CT or abdominal ultrasound (UL), chest x-ray and measurement of the lesion(s) chosen for evaluation. The Ž rst phase II trial included 77 patients. The treatment, which lasted 28 days, included UFT in a daily dose of 300 mg:m and l-leucovorin 22.5 mg:m. Both drugs were divided into three daily doses (q 8 h) and hydroxyurea (HU) in a Ž xed daily dose of 0.5 g. The treatment period was followed by a 7-day rest period for a total cycle time of 35 days. Details of this trial have been presented previously (7). The second phase II trial included 63 patients treated with capecitabine in a dose of 2500 mg:m divided into two daily doses for a treatment period of 14 days followed by a 7-day rest period. The total cycle time was thus 21 days. The results are presented in Table 1. In the two trials 63 (82%) and 52 (83%) patients, respectively, were evaluable for response, with an objective response rate of 23% and 22%. The table also indicates a similar progression-free interval of 6.8 and 4.7 months, and an almost identical median survival (11 and 10.6 months). Important side effects are listed in Table 2. We observed no signiŽ cant myelotoxicity. Severe (grade 3) nausea and vomiting were seen in 4% and 2%, respectively, and severe diarrhoea (grade 3) occurred in 9% of patients in the UFT trial and in 3% of patients in the capecitabine trial. A major difference was seen with respect to hand–foot syndrome, which occurred in 54% of the patients in the capecitabine trial. This side effect was not observed