Bengt Glimelius

Combined chemo- and radiotherapy vs. radiotherapy alone in the treatment of primary, nonresectable adenocarcinoma of the rectum

PURPOSE In a randomized study in primarily inextirpable rectal cancer, conventional radiotherapy to reduce the tumor mass was compared with combined chemotherapy and radiotherapy. METHODS AND MATERIALS The combined treatment (CRT) was given every other week, four times, during a 7-week period. The drugs used were methotrexate, 5-fluorouracil in bolus injection followed by continuous infusion and leucovorin rescue. Radiotherapy (RT) was given simultaneously with five 2-Gy fractions in 3 days to a dose of 10 Gy to a total dose in the four courses of 40 Gy. This regimen was compared with radiotherapy in 2-Gy fractions to a total dose of 46 Gy in the radiotherapy group. Surgery was performed 3-4 weeks after finished treatment. Seventy patients were included between November 1988 and August 1996; 36 patients were allocated to RT and 34 to CRT. RESULTS Twenty-five (74%) of the patients in the CRT group underwent a locally radical resection with 20 (59%) patients without any known metastases. The corresponding figures in the RT group were 23 (64%) and 18 (50%), respectively. Among the patients who underwent any tumor resection, 5/29 (17%) in the CRT group and 12/27 (44%, p = 0.05) in the RT group have had a local recurrence. After a locally radical resection, the corresponding figures are 4% and 35% (p = 0.02), respectively. Local disease-free survival was significantly superior in the CRT group (66% at 5 years) compared with the RT group (38%, p = 0.03 log-rank test). Five-year survival was 29% (9 patients) in the CRT group and 18% (6 patients) in the RT group, a nonsignificant difference (p = 0.3). Five patients in the RT group did not complete planned treatment, mainly due to the appearance of metastatic disease. In this group toxicity was usually of Grade 0-1. In the experimental group, the toxicity usually was Grade 2 or higher, and 6 patients did not manage to fulfill the planned treatment due to toxicity. CONCLUSION In this study, with fewer included patients than intended, resectability rates were high in both groups. The addition of chemotherapy to radiotherapy significantly improved local control rates, but no statistically significant difference was found in survival between the groups. The acute toxicity after CRT was higher than after RT alone, but manageable.

The cytotoxic activity of Taxol in primary cultures of tumour cells from patients is partly mediated by Cremophor EL.

In patient tumour samples the activity in vitro of Taxol corresponded fairly well to the known clinical activity and Taxol showed low cross-resistance to standard cytotoxic drugs. However, the Taxol solvent Cremophor EL--ethanol was considerably active alone, whereas paclitaxel formulated in ethanol was less active. Taxol thus seems to contain two components active against patient tumour cells in vitro.

The circular stapling device as a risk factor for anastomotic leakage

Aim  To investigate the relation between the type of circular stapler and anastomotic leak in rectal cancer surgery.

A novel B-cell line (U-2932) established from a patient with diffuse large B-cell lymphoma following Hodgkin lymphoma.

Little is known about mechanisms leading to secondary non-Hodgkin lymphomas (NHL) in patients treated for Hodgkin lymphoma (HL). Our aim was to characterise in detail a cell line derived from a diffuse large B-cell lymphoma (DLBCL) that had developed in a patient with relapsing HL. The cell line U-2932 was established from ascites in a patient suffering from DLBCL previously treated for HL with multiple chemotherapy regimens. Characterisation was based on morphology, immunophenotype, Epstein-Barr virus (EBV)-status, IgH gene rearrangement status, tumourigenicity, p53 sequencing, and immunohistochemical expression of p53, BCL-2 and BCL-6. The karyotype was investigated using G-banding, comparative genomic hybridisation (CGH) and spectral karyotype (SKY) analysis. This cell line shows typical morphological features of a DLBCL and grows as colonies in nude mice. It expresses a B-cell phenotype with a somatically hypermutated V H 4-39 gene and is negative for EBV. The origin of U-2932 was confirmed by demonstrating an identical V H 4 rearrangement in ascites from the patient. A point mutation of the tumour-suppressor gene p53 was detected in amino acid position 176 and immunohistochemical over-expression of the p53 protein was also demonstrated. U-2932 carries a complex karyotype including high-level amplifications of the chromosomal bands 18q21 and 3q27 and expresses aberrant BCL-2 and BCL-6 immunohistochemically. We were unable to investigate the clonal relationship between the original HL and U-2932. In conclusion, U-2932 is a unique B cell line established from a patient suffering from HL followed by NHL. Overexpression of BCL-2, BCL-6 and p53 may play a role in the tumourigenesis and drug resistance. This cell line may become a useful tool to better understand the mechanisms responsible for development of secondary NHL in patients treated for HL.

Induction chemotherapy and radiotherapy in loco-regionally advanced epidermoid carcinoma of the anal canal.

PURPOSE To evaluate the efficacy of induction chemotherapy in combination with radiotherapy for treatment of loco-regionally advanced epidermoid anal carcinoma. METHODS AND MATERIALS Thirty-one patients diagnosed during the period 1989-1994 with loco-regionally advanced cancer of the anal canal (phiTmax > or = 4 cm or T4 or N+) were treated with induction chemotherapy consisting of one to three courses of carboplatin (300-375 mg/m2 i.v.) and 5-fluorouracil [5,000 mg/(m2 x 120 h) i.v.] followed by external beam irradiation +/- surgery. RESULTS The toxicity of the chemotherapy was low. Twenty-nine patients were tumor free after the primary therapy. Kaplan-Meier analyses were made for overall survival, tumor-specific survival, freedom from recurrence, preservation of sphincter, and event-free survival. For these end points the 5-year data were 67, 85, 80, 69, and 51%, respectively. CONCLUSION The results are promising but a well-designed randomized trial is needed to further elucidate the role of induction chemotherapy in the treatment of loco-regionally advanced anal carcinoma.

Lower treatment intensity and poorer survival in metastatic colorectal cancer patients who live alone

Background:Socioeconomic status (SES) and social support influences cancer survival. If SES and social support affects cancer treatment has not been thoroughly explored.Methods:A cohort consisting of all patients who were initially diagnosed with or who developed metastatic colorectal cancer (mCRC, n=781) in three Scandinavian university hospitals from October 2003 to August 2006 was set up. Clinical and socioeconomic data were registered prospectively.Results:Patients living alone more often had synchronous metastases at presentation and were less often treated with combination chemotherapy than those cohabitating (HR 0.19, 95% CI 0.04–0.85, P=0.03). Surgical removal of metastases was less common in patients living alone (HR 0.29, 95% CI 0.10–0.86, P=0.02) but more common among university-educated patients (HR 2.22, 95% CI 1.10–4.49, P=0.02). Smoking, being married and having children did not influence treatment or survival. Median survival was 7.7 months in patients living alone and 11.7 months in patients living with someone (P<0.001). Living alone remained a prognostic factor for survival after correction for age and comorbidity.Conclusion:Patients living alone received less combination chemotherapy and less secondary surgery. Living alone is a strong independent risk factor for poor survival in mCRC.

Bulky disease is the most important prognostic factor in Hodgkin lymphoma stage IIB.

Abstract: The aim of this study was to evaluate treatment results for Hodgkin lymphoma (HL) patients younger than 60 yr in stage IIB, treated according to the Swedish National Care Programme. The intention was also to identify specific subgroups depending on the number of negative prognostic factors the patients have, in order to optimise and differentiate future treatment. In total, 99 patients with HL stage IIB, diagnosed between 1985 and 1994, have been analysed. There were 47 men and 52 women and the median age was 33 yr (range 17–59). Eighty‐six patients presented with supradiaphragmatic disease and 13 with infradiaphragmatic. The HL specific and overall 10‐yr survival was 73 and 65%, respectively. The HL‐specific survival for patients in pathological stage IIB tended to be better, although not statistically significant than for clinical stage IIB, despite less chemotherapy (P = 0.1). The patients in stage IIB who were selected for laparotomy were, however, younger and with fewer negative prognostic factors. The only significant negative prognostic factor was bulky disease (P = 0.001). The following factors also tended to have a negative influence on the prognosis although not statistically significant: the International Prognostic Score, the number of involved lymph node stations, extranodal involvement and leucocyte count >15 × 109/L. In conclusion, we suggest that bulky disease should be taken into account when treating patients with stage IIB HL.

Patients above sixty years of age with Hodgkin's lymphoma treated with a new strategy

In the Swedish National Care Programme for Hodgkins lymphoma (HL) a less intensive chemotherapy regimen with individualized dosing (LVPP/OEPA) was introduced in 1989. In total, 139 patients, 77 between 1985 and 1988 and 62 between 1989 and 1992, were studied. Mean ages were 72 and 71 years, respectively. One hundred and nineteen patients were treated with curative intention, 63 (82%) between 1985 and 1988 vs. 56 (90%) between 1989 and 1992 (p = 0.11). All patients (13 vs. 20) treated with radiotherapy only achieved a complete remission (CR). The CR rates (67% vs. 65%) for patients treated with 6-8 cycles of chemotherapy were also similar in the two time periods. The 5-year survival rate was 45% in the period 1985-1988 and 48% in 1989-1992. The survival of elderly HL patients was thus not improved from 1985-1988 to 1989-1992. Thus efforts to improve the chemotherapy regimen with individualized dosing did not change the outcome. Many patients experienced myelosuppression and opportunistic infections that may have contributed to the poor treatment results.In the Swedish National Care Programme for Hodgkins lymphoma (HL) a less intensive chemotherapy regimen with individualized dosing (LVPP/OEPA) was introduced in 1989. In total, 139 patients, 77 between 1985 and 1988 and 62 between 1989 and 1992, were studied. Mean ages were 72 and 71 years, respectively. One hundred and nineteen patients were treated with curative intention, 63 (82%) between 1985 and 1988 vs. 56 (90%) between 1989 and 1992 (p=0.11). All patients (13 vs. 20) treated with radiotherapy only achieved a complete remission (CR). The CR rates (67% vs. 65%) for patients treated with 6-8 cycles of chemotherapy were also similar in the two time periods. The 5-year survival rate was 45% in the period 1985-1988 and 48% in 1989-1992. The survival of elderly HL patients was thus not improved from 1985-1988 to 1989-1992. Thus efforts to improve the chemotherapy regimen with individualized dosing did not change the outcome. Many patients experienced myelosuppression and opportunistic infections that may have contributed to the poor treatment results.

Methyl-Gag, Ifosfamide, Methotrexate and Etoposide (Mime) as Salvage Therapy for Hodgkin's Disease and Non-Hodgkin's Lymphoma

One hundred and three patients with recurrent or refractory Hodgkins disease (HD) or non-Hodgkins lymphoma (NHL) treated with MIME (methyl-GAG, ifosfamide, methotrexate, etoposide) were retrospectively studied. Thirty-seven of the 44 patients with HD, 34/47 with high-grade malignant and 9/12 with low-grade malignant NHL were evaluable for response. Of the 37 evaluable patients with HD, 16 (43%) achieved complete remission (CR) and 4 partial remission (PR), giving a total response rate of 54%. Of the 34 evaluable patients with high-grade NHL, 5 achieved CR and 8 PR, giving a response rate of 38%. Of 9 evaluable patients with low-grade NHL, 2 achieved CR. The main toxicity was leukopenia, thrombocytopenia and infections. Twenty-six per cent of the patients developed septicaemia, which was fatal in 6 cases (6%). We conclude that MIME as salvage regimen can induce complete remissions in lymphoma patients, particularly in HD with previous heavy treatment, and that it is relatively well tolerated.

Methyl-GAG, ifosfamide, methotrexate and etoposide (MIME) as salvage therapy for Hodgkin's disease: a prospective study.

Abstract: This study presents the results of a prospective study of methylgag, ifosfamide, methotrexate and etoposide (MIME) as salvage regimen for Hodgkins disease (HD) in Sweden. Sixty‐four patients with recurrent or refractory HD were treated with MIME between July 1988 and December 1993. All patients except one had, earlier, been treated with and failed consecutive or alternating MOPP and ABVD. Median age was 37 yr (range 14–73). Twenty patients (31%) achieved a complete remission (CR) and 17 (27%) a partial remission (PR), giving an overall response rate of 58%. The 5‐yr survival for all patients was 43%. In a multivariate analysis, the most important factors predicting a poor survival were the presence of extranodal disease at relapse, male gender and high age. Twenty‐nine patients were treated with high‐dose chemotherapy with stem‐cell rescue after MIME. Those patients had a similar survival compared to the patients responding to MIME but not treated with high‐dose chemotherapy. We conclude that MIME induces remissions in a high proportion of patients with recurrent and refractory HD with acceptable toxicity. The remissions probably need consolidation, but the nature of this consolidation is still controversial.