Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer.

BACKGROUND: There is an unmet need for predictive markers for the antiangiogenic agent bevacizumab in metastatic colorectal cancer (mCRC). We aimed to assess whether the location of the primary tumor is associated with bevacizumab effectiveness when combined with capecitabine and oxaliplatin (CAPEOX) in the first-line treatment of patients with mCRC. PATIENTS AND METHODS: A cohort of 667 consecutive patients with mCRC from the general community treated from 2006 to 2011 with CAPEOX and bevacizumab as standard first-line therapy was compared with a cohort of 213 patients treated with CAPEOX from 2003 to 2006, before bevacizumab was approved. Main outcome measures were progression-free survival (PFS) and overall survival (OS). Differences in outcome were tested using Kaplan-Meier curves and log-rank tests, and multivariate analyses were carried out using Cox Proportional Hazards models. RESULTS: Patients treated with CAPEOX and bevacizumab with primary tumors originating in the sigmoid colon and rectum had a significantly better outcome than patients with primary tumors originating from the cecum to the descending colon, both for PFS (median PFS 9.3 versus 7.2 months; hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.56-0.82) and for OS (median OS 23.5 versus 13.0 months; HR 0.47, 95% CI 0.38-0.57). This difference was confirmed in multivariate analyses after adjustment for other potentially prognostic factors. For patients treated with CAPEOX, there was no association between primary tumor location and outcome, neither in unadjusted nor adjusted analyses. CONCLUSIONS: The addition of bevacizumab to CAPEOX in first-line treatment of patients with mCRC may primarily benefit patients with primary tumors originating in the rectum and sigmoid colon. This hypothesis needs to be validated in data from completed randomized trials. CLINICALTRIALSGOV IDENTIFICATION NUMBER: NCT00212615.

A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial.

BACKGROUND: The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with untreated mCRC received doublet chemotherapy + bevacizumab during 18 weeks and those without tumor progression were eligible for randomization to bevacizumab + erlotinib (arm A) or bevacizumab alone (arm B), until progression or unacceptable toxic effect. RESULTS: Of the 249 patients enrolled, 80 started maintenance treatment in arm A and 79 in arm B. The rate of any grade 3/4 toxic effect was 53% in arm A and 13% in arm B. Median PFS was 5.7 months in arm A and 4.2 months in arm B (HR = 0.79; 95% confidence interval 0.55-1.12; P = 0.19). Overall survival (OS) from start of induction chemotherapy was 26.7 months in the randomized population, with no difference between the two arms. CONCLUSIONS: The addition of erlotinib to bevacizumab as maintenance treatment after first-line chemotherapy in mCRC did not improve PFS significantly. On-going clinical and translational studies focus on identifying subgroups of patients that may benefit from erlotinib in the maintenance setting. CLINICAL TRIALS NUMBER: NCT00598156.

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer.

The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h⁻¹ (range 176-726 l h⁻¹). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P=0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P=0.04) and ABCC1 g.7356253C>G (P=0.04).

Plasma TIMP-1 levels and treatment outcome in patients treated with XELOX for metastatic colorectal cancer.

BACKGROUND: The aim was to evaluate the association between plasma tissue inhibitor of metalloproteinase-1 (TIMP-1) and serum carcinoembryonic antigen (CEA) levels and outcome in patients with metastatic colorectal cancer (mCRC) receiving XELOX (combination chemotherapy with capecitabine and oxaliplatin) as first-line treatment. PATIENTS AND METHODS: One hundred and twenty patients were included. Blood samples were collected before treatment and 3 weeks later before the next treatment cycle. Plasma TIMP-1 and serum CEA levels were correlated to treatment outcome. RESULTS: No significant associations between baseline TIMP-1 or CEA levels and best response to treatment or progression-free survival (PFS) could be demonstrated. In contrast, high baseline plasma TIMP-1 levels were associated with poor overall survival (OS), P = 0.008, hazard ratio (HR) = 1.80 [95% confidence interval (CI): 1.17-2.78]. Furthermore, increase in TIMP-1 levels from baseline to immediately before the second cycle of chemotherapy had a significant negative effect on survival (P = 0.03, HR = 1.30, 95% CI: 1.02-1.65) while a decrease in TIMP-1 was significantly associated with a higher objective response rate (P = 0.03). CONCLUSIONS: Both high baseline and subsequent increase in TIMP-1 levels were associated with shorter OS in patients with mCRC receiving XELOX as first-line treatment, whereas baseline TIMP-1 levels were not associated with response or PFS following XELOX treatment.

A randomized study comparing short-time infusion of oxaliplatin in combination with capecitabine XELOX(30) and chronomodulated XELOX(30) as first-line therapy in patients with advanced colorectal cancer.

BACKGROUND: Chronotherapy is one of the several approaches to increase efficacy and reduce toxicity of chemotherapy. In a phase II study in the second-line in patients with metastatic colorectal cancer (mCRC), we found that chronomodulated XELOX (XELOX(30Chron)) was a well-tolerated regimen with potentially reduced toxicity. PATIENTS AND METHODS: One hundred and forty-one patients with unresectable mCRC were enrolled in a randomized study comparing standard XELOX (XELOX(30)), arm A, and XELOX(30Chron), arm B-both with short-time infusion of oxaliplatin-with the primary aim of reducing overall toxicity. RESULTS: Overall toxicity grade 2-4 was 90% versus 85%, P = 0.47 and grade 3-4 was 31% versus 37%, P = 0.6 in arm A and B, respectively. We found no significant differences in median overall survival (17.6 versus 15.5 months; P = 0.068) and median progression-free survival (8.9 versus 8.8 months; P = 0.7). The incidence of grade 3 neuropathy was 16% in arm A and 19% in arm B (P = 0.7) after a cumulative dose of oxaliplatin of 1000 mg/m(2). CONCLUSION: XELOX(30Chron) does not reduce toxicity or improve efficacy. A 30-min infusion of oxaliplatin is safe and does not increase the severity of chronic neuropathy.

A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer.

BACKGROUND: To compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m(2) on day 1, 5-FU 500 mg/m(2) and FA 60 mg/m(2) on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m(2) on day 1, FA 200 mg/m(2), 5-FU bolus 400 mg/m(2) and infused 5-FU 600 mg/m(2) on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan. PATIENTS AND METHODS: Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS). RESULTS: Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%. CONCLUSIONS: Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

[Cancer of the endometrium following radiotherapy of cervical cancer]. / Endometriecancer udviklet efter strålebehandlet cervixcancer.

We describe three cases of women who have been treated with radiotherapy for cervical cancer and then many years later develop cancer of the uterine endometrium. Apparently there may be active endometrium left in the uterus after radiotherapy, for which reason we recommend combined hormone therapy with oestrogen and progesterone.

[Chemotherapy and radiotherapy as part of curative management of esophageal cancer]. / Kemoterapi og strålebehandling som led i kurativ behandling af cancer esophagi.

Chemotherapy and irradiation it combination or alone have been employed in the treatment of oesophageal carcinomas for many years. However, their place in curative treatment is not definitively clarified. Several non-randomized studies indicate an effect from combined chemotherapy and irradiation possibly followed by surgery. Randomized studies published during the last few years confirm an increased curability in patients who have received combined treatment. New multicentre trials show that a more aggressive attitude is indicated in selected groups of patients with oesophageal carcinoma. Due to the variable spectrum of the disease and complexity of the treatment the treatment should be given in centres which master the different modalities.

Oral treosulfan as second-line treatment in platinum-resistant ovarian cancer: a phase II study. The Danish Ovarian Cancer Study Group.

OBJECTIVE: To evaluate the effect of oral treosulfan in patients with platinum-resistant ovarian cancer. METHODS: A phase II trial of oral treosulfan 500 mg per day in 30 females with platinum resistant ovarian cancer. All patients had measurable or evaluable disease. RESULTS: The treatment was well tolerated. One patient (3%) achieved a partial response lasting 12+ months. Seven patients had stable disease for 5.3 months (median) range 4.4-7.5 months. Median time to progression was 11.5 weeks (95% C.L. 11-12 weeks). Median survival was 31 weeks (95% C.L. 30-35 weeks). CONCLUSION: Oral treosulfan in the present schedule is not recommended in platinum resistant ovarian cancer.

[Anus cancer]. / Cancer ani.

The pathology, etiology and epidemiology of anal cancer (CA) and the treatment and prognostic factors are reviewed. CA is a rare disease. However, the incidence is rising and is now 0.7 per 100,000 women and 0.4 per 100,000 men in Denmark. The median age is 60 years. Smoking and infection with human papillomavirus or HIV increases the risk of CA. The most important prognostic factors are tumour size, depth of invasion, inquinal lymph node involvement, differentiation and DNA ploidy. Previously CA was treated with abdominoperineal resection. Now sphincter preserving treatment with radiotherapy either alone or in combination with chemotherapy is preferred in most centers. Its is unsettled whether combined treatment is superior to radiotherapy only. Careful follow-up is warranted in order to perform salvage surgery in case of recurrent disease.

Risk factors for central nervous system involvement in non-Hodgkins-lymphoma--a multivariate analysis.

A consecutive cohort of patients with NHL was examined to identify the factors predictive of CNS-involvement with Cox's proportional hazards model in a multivariate analysis. Twenty-seven cases of CNS-involvement were found among 498 patients with NHL. Only 3 of 96 patients with low-grade lymphomas had CNS involvement, all occurring after transformation into high-grade lymphoma. In univariate analysis of 402 patients with intermediate or high-grade lymphoma, lymphoblastic histology (including Burkitt's lymphoma), age <35 years, B-symptoms, stage IV disease, testis involvement and bone marrow involvement were found to be statistically significant risk factors. Lymphoblastic histology was found to be strongly correlated to age younger than 35 years. In the multivariate analysis only lymphoblastic histology, stage IV disease and B-symptoms were found to be significantly associated with CNS involvement. It is concluded that CNS prophylaxis should be considered in all patients with lymphoblastic histology and in patients with stage IV B lymphomas other than those of low-grade types.

[Attitudes to autopsy among critically ill patients and the general population]. / Holdninger til obduktion blandt alvorligt syge samt i befolkningen.

Attitudes towards autopsy were investigated by a questionnaire given to 60 cancer patients, 30 patients with severe cardiac disease and 132 healthy people without known disease. Eighty-five percent of the patients and 82% of the healthy people had a positive attitude towards autopsy. A majority (65-72%) found that permission should be given by the patient rather than the family. Only 6% of patients and 13% of the healthy people would refuse to give permission to autopsy, 71% and 47% would give permission and 10% and 25% would consent to autopsy under certain conditions. both groups were more reluctant to give consent to the performance of an autopsy on a relative. It is concluded that hospital routine should be changed so that patients should be asked whether they would permit an autopsy to be performed in event of their decease.

Multiple myeloma treated with mitoxantrone in combination with vincristine and prednisolone (NOP regimen) versus melphalan and prednisolone: a phase III study. Nordic Myeloma Study Group (NMSG).

One-hundred-and-fifty-one patients with previously untreated multiple myeloma were allocated to treatment with either NOP regimen (mitoxantrone 16 mg/m2 and vincristine 2 mg day 1 and prednisolone 250 mg day 1-4 and 17-20) or M+P regimen (melphalan 0.25 mg/kg and prednisolone 100-200 mg/day day 1-4). Both regimens were repeated every 4 weeks and were scheduled for 1 year. Seventy-seven patients were treated with NOP and 74 patients with M+P. No major clinical differences were recorded between the groups before treatment. Sixty percent of the patients responded (CR+PR) to NOP versus 64% to M+P (NS). The time to progression was 16 months (95% C.L. 14-51) in the NOP group versus 21 months (95% C.L. 15-27) in the M+P group (NS). The median survival was 14 months (7-21) in the NOP group and 31 months (21-43) in the M+P group (p = 0.02). NOP was significantly more toxic than M+P. Seven patients treated with NOP died due to infection and neutropenia and 1 patient died of cardiac toxicity, in contrast to 1 death due to infection and neutropenia in the M+P group. Gastrointestinal toxicity was acceptable in both groups. In conclusion, NOP was inferior to M+P as primary treatment of multiple myeloma.

[Surgical treatment of pulmonary sarcoma metastases]. / Kirurgisk behandling af pulmonale sarkommetastaser.

During the ten-year period from 1.1.1980 to 31.12.1989, thoracotomy was found performed on 22 patients with malignant sarcoma on account of suspected pulmonary metastases. Fourteen patients were submitted to operation on one occasion, nine patients were submitted to operation twice and one patient was operated upon six times. The median age was 21 years (range 7-68 years). The median interval without illness from the primary treatment was 65 weeks (range 7 weeks to 5.8 years). At the first operation, 13 patients had one metastasis, seven had two metastases and one had five metastases. In one patient, a benign lesion was found. Six patients were submitted to renewed thoracotomy on account of pulmonary metastases from 16 to 75 weeks after the first recurrence. The median survival after the first operation was 1.4 years (range 0.4-5.7 years). Five patients (24%) are still free from recurrences from 0.9 to 5 years after the last operation. It is concluded that patients with malignant sarcoma should be followed-up regularly with radiography of the thorax and should be offered operation in cases of pulmonary metastases.

[Intracavitary irradiation of esophageal cancer]. / Intrakavitaer strålebehandling af cancer esophagi.

Intracavitary irradiation (ICI) of esophageal cancer is a technique where the radioactive source is placed in the lumen of the esophagus thereby delivering a high local radiation dose to the tumor. ICI is used as single modality therapy for palliation of dysphagia or as a supplement to external irradiation. Dysphagia is hereby relieved in more than 90% of the patients and it appears that survival is improved. The side effects are dose dependent and consist of esophagitis, esophageal ulceration and benign stricture. Fistulae do not seem to occur with increased frequency after ICI, but an existing fistula is claimed to be a contraindication to ICI. The mortality connected with ICI is considerably lower than with tubulation or laser extirpation. It is concluded that ICI is a promising treatment in esophageal cancer both as palliative and curative treatment in combination with other treatment modalities.

Refractory myelomatosis treated with mitoxantrone in combination with vincristine and prednisone (NOP-regimen): a phase II study. The Nordic Myeloma Study Group (NMSG)

In a phase II study, patients with refractory myelomatosis were treated with a combination chemotherapy (NOP regimen): mitoxantrone (bolus injection of 4 mg/m2 on days 1-4), vincristine (continuous infusion of 0.4 mg/24 h on days 1-4) and prednisone (250 mg/d on days 1-4 and 17-20). The treatment was repeated every 4 weeks. Ninety-two patients were treated after they were found refractory to treatment with melphalan and prednisone (and occasionally vincristine) (n = 50) or more intensive treatment regimens (n = 42) including anthracyclines (n = 18). Response (greater than or equal to 50% reduction of M protein) was obtained in 23 patients and minor response (clinical improvement but less than 50% reduction in M protein) in 22 patients. The median duration of the response was 7.5 months. Equal response rates were observed irrespective of the type of previous treatment. The major toxicity was myelosuppression with severe granulocytopenia and infections. However, the frequency decreased throughout the cycles. The NOP treatment is recommended in refractory myelomatosis, especially in patients refractory to other intensive regimens. Patients in a poor clinical condition or with thrombocytopenia before treatment should have a reduced mitoxantrone dose in the first treatment cycles.

Cisplatin and tegafur in recurrent head and neck cancer. A phase II study.

A phase II study of cisplatin and tegafur in recurrent epidermoid head and neck cancer is presented. All patients were treated with cisplatin 100 mg/m2 every 4 weeks. Twenty-nine received tegafur 750 mg/m2 days 2-28 orally and 18 patients, who were unable to take tegafur orally, were treated with tegafur 1,500 mg/m2 intravenously days 2-5. The response rate in the oral group was 28.5% and the median survival 29 weeks. The response rate in the intravenous group was 6% and the median survival was 17 weeks. We conclude that cisplatin and oral tegafur is active against head and neck cancer.

Haematological effects from radioiodine treatment of thyroid carcinoma.

The changes in peripheral blood counts and number of colony forming cells (CFU-c) in the bone marrow after 131I treatment for thyroid cancer were followed in 24 patients. The median WBC declined to 78% and the median blood platelet count to 69% of the pretreatment values after 4 treatments. In 4 patients a moderate pancytopenia developed and in 1 patient additionally treated with chemotherapy and preleukaemia was suspected. In 19 bone marrow samples obtained from 13 patients no difference in number of CFU-c could be found related to cumulated 131I activities given to those patients. In 5 of 7 patients examined between the 9th and the 19th day afer a treatment the number of CFU-c had declined by 50% or more. It is concluded that radioiodine exerts a protracted suppressive effect on the bone marrow which is seldom severe. Agar culture of bone marrow cells with counting of CFU-c was not found to be more sensitive than the peripheral blood counts in predicting bone marrow damage and cannot be recommended for routine use.