Tarja Ruotsalainen

High pre‐treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small‐cell lung cancer

Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and vascular permeability. Increased serum VEGF concentrations (S‐VEGF) have been found in patients with various types of human cancer, including cancer of the lung. However, the clinical and prognostic significance of S‐VEGF in cancer is unknown. We measured S‐VEGF, using enzyme‐linked immunosorbent assay, in sera taken from 68 untreated patients with small‐cell lung cancer (SCLC) at the time of diagnosis. The patients were treated with 6 cycles of cisplatin and etoposide, and were randomly assigned to receive recombinant interferon, leukocyte interferon or neither. S‐VEGF ranged from 70 to 1 738 pg/ml (mean, 527 pg/ml). The patients who achieved partial or complete response to treatment had lower pre‐treatment S‐VEGF than the non‐responding patients (p = 0.0083, Mann‐Whitney test). High (>527 pg/ml) S‐VEGF was associated with poor survival (p = 0.012, Log Rank Test), and all 3‐year survivors had lower than mean pre‐treatment S‐VEGF. In a multivariate analysis, S‐VEGF and stage were the only independent prognostic factors, and the estimated 3‐year survival of the patients with limited stage disease and low pre‐treatment S‐VEGF (n = 17, 25% of all patients) was 41% (p = 0.0055, log rank test). These data show that high pre‐treatment S‐VEGF is associated with poor response to treatment and unfavourable survival in patients with SCLC treated with combination chemotherapy with or without interferon. Int. J. Cancer (Pred. Oncol.) 79:144–146, 1998.© 1998 Wiley‐Liss, Inc.

Pretreatment serum syndecan-1 levels and outcome in small cell lung cancer patients treated with platinum-based chemotherapy

Syndecan-1 is a multifunctional transmembrane heparan sulphate proteoglycan (HSPG) that is present on a variety of cell types. The extracellular syndecan domains can be shed from the cell surface in a highly regulated process called ectodomain shedding. We studied the influence of soluble syndecan-1 on outcome in 88 small cell lung cancer (SCLC) patients treated within the context of two randomised clinical trials with platinum-based therapy. Serum syndecan-1 concentrations were determined using enzyme-linked immunosorbent assay (ELISA) from sera taken prior to initiation of chemotherapy. Patients with the serum syndecan-1 level within the highest tertile (>212 microg/l) had only 38% 1-year and 3% 2-year survival, whereas 58% of those with a lower serum level survived for 1 year and 25% for 2 years following the diagnosis (P=0.0034). A high serum syndecan-1 level (>212 microg/l) was associated with a high pretreatment lactate dehydrogenase (LDH) level (P=0.0024) and a poor Karnofskys performance status (P=0.021), but not with the clinical stage or the presence of distant metastases at diagnosis. A high serum syndecan-1 level had independent influence on survival also in a multivariate analysis (the relative risk, RR, 1.68; 95% CI, 1.02-2.77; P=0.044) together with the clinical stage (RR, 1.72; 95% CI, 1.05-2.82; P=0.032). We conclude that high pretreatment serum syndecan-1 level is associated with poor prognosis in SCLC treated with platinum-based chemotherapy.

Lactose intolerance associated with adjuvant 5-fluorouracil-based chemotherapy for colorectal cancer☆

BACKGROUND & AIMS Bowel mucosal injury associated with 5-fluorouracil (5-FU) treatment might result in secondary lactose intolerance. The frequency and clinical significance of 5-FU-related hypolactasia are unknown. METHODS One hundred fifty patients randomly assigned to receive 1 of 2 adjuvant 5-FU-based chemotherapy regimens, the Mayo regimen or the simplified de Gramont regimen, were studied for lactose tolerance by using an oral lactose absorption test, a symptom questionnaire, treatment-related toxicity, and Subjective Global Assessment of Nutritional Status questionnaire before, during, and 2 and 6 months after chemotherapy for colorectal cancer. RESULTS The frequency of hypolactasia increased from 24% before treatment to 35% during treatment (P < 0.0001). Therapy-related hypolactasia was reversible on discontinuation of chemotherapy. Symptoms compatible with lactose intolerance occurred in 94% of patients with an abnormal lactose absorption test result during chemotherapy. The frequency of hypolactasia increased during chemotherapy in both treatment groups, but was detected more commonly in those for whom therapy included continuous 5-FU infusions (the de Gramont regimen; 45% vs. 25%; P = 0.006). The presence of hypolactasia during chemotherapy was associated with flatulence, diarrhea, and poor nutritional status. CONCLUSIONS Reversible chemotherapy-related hypolactasia and lactose intolerance are not infrequent in patients treated with 5-FU-based adjuvant chemotherapy for colorectal cancer. Avoidance of lactose during chemotherapy may improve treatment tolerability in these patients.

Concomitant chemotherapy and IFN-alpha for small cell lung cancer : a randomized multicenter phase III study

Patients with any stage of small cell lung cancer were given low-dose interferon-alpha (IFN-alpha) from the first day of treatment as long as possible irrespective of changes in treatment dictated by disease progression. All patients received 6 cycles of the chemotherapy (CT): cisplatin 70 mg/m2 i.v. day 1 and etoposide 100 mg/m2 i.v. days 1, 2, 3 every 28 days. Seventy-eight patients were assigned to arm 1: CT alone, 75 patients to arm 2: CT + natural IFN-alpha (3 MU three times a week i.m.), and 66 patients to arm 3: CT + recombinant IFN alpha-2a (3 MU three times a week i.m.). There was no difference in median survival between the arms (10.2 months, 10.0 months, 10.1 months, respectively), p = 0.32. The 2-year survival rates were 15%, 3%, and 11%, respectively. Grade 3 and 4 leukopenia occurred more frequently in the IFN arms than in the CT alone arm and resulted in dose reductions. Antibodies occasionally developed to recombinant IFN. We conclude that IFN-alpha can be administered concomitantly with chemotherapy but is probably better kept for maintenance therapy so that optimal full doses of induction CT can be given.

Interferon-alpha and 13-cis-retinoic acid as maintenance therapy after high-dose combination chemotherapy with growth factor support for small cell lung cancer--a feasibility study.

This randomized phase II multi-center study was designed to determine the time to progression, duration of response and the feasibility of an intensified maintenance regime consisting of a combination of interferon (IFN)-alpha and retinoic acid after high-dose combination chemotherapy and radiotherapy in patients with small cell lung cancer. The patients received four courses of combination chemotherapy consisting of ifosfamide, carboplatin and etoposide, with higher doses of ifosfamide and carboplatin given in the first course, with routine growth factor support. Responding patients were then randomly assigned to one of three maintenance therapy arms. All patients with limited disease (LD) were given thoracic radiotherapy before maintenance therapy and those who had also achieved a complete response (CR) or minimal residual disease (MRD) received prophylactic cranial irradiation. In Arm 1 patients received IFN-alpha-2a, 6 MIU s.c. TIW for 4 weeks, followed by 3 MIU s.c. TIW, and 13-cis-retinoic acid 1 mg/kg/day p.o. BID daily. In Arm 2 patients received trophosphamide 100-150 mg/day p.o. BID. No maintenance treatment was given in Arm 3, the control group. Maintenance therapy was continued for 1 year. Eighty-five patients were treated according to the protocol. Twenty-one patients achieved CR, four achieved MRD and forty-two achieved partial responses to chemotherapy and radiotherapy. Sixty patients (71%) were randomly assigned for maintenance treatment. Median survival was 17.1 months in the IFN-alpha-retinoic acid arm, 12.4 months in the trophosphamide arm and 13.5 months in the control arm. One-year survival rates were 82, 56 and 55%, respectively. Duration of response was 6.5, 5.5 and 4.7 months, respectively. Time to progression was 8.6, 8.0 and 6.8 months, respectively The differences were not statistically significant. The IFN-alpha-retinoic acid maintenance treatment was well tolerated. Patients who received IFN-alpha-retinoid maintenance therapy lived longer after the onset of progressive disease. The treatment regime was effective, feasible and well tolerated.

Tumour response and radiation-induced lung injury in patients with recurrent small cell lung cancer treated with radiotherapy and concomitant interferon-α

The aim of this study was to determine whether either natural or recombinant interferon (IFN)-alpha can improve the response to radiotherapy (RT) in patients with small cell lung cancer (SCLC), and to assess the role of IFN in radiation-induced lung injury. All patients had previously participated in a randomised trial of chemotherapy alone or in combination with IFN-alpha in three arms (arm O: no IFN, arm I: natural IFN-alpha, arm II: recombinant IFN-alpha). Patients with locally progressive disease in the lungs following chemotherapy were treated with RT and they continued with their concomitant IFN-alpha. The RT dose was 50 Gy. Radiation-induced lung injury was assessed by lung function tests, computed tomography and bronchoalveolar lavage fluid (BALF) analysis which included cell findings, Interleukin (IL)-1 alpha/-1 beta expression by alveolar macrophages and surfactant components. Seventeen patients were entered in the study, 16 of whom were evaluable. Response rates in Arms O, I and II were 50, 67 and 50%, respectively. Median survival was 18.5, 7 and 23 months respectively, and 1-year survival was 67, 29 and 75% respectively. Long-term survival as assessed by 2- and 3-year survival rates was 29% in patients receiving natural IFN-alpha as compared to 17% in patients not receiving IFN (not statistically significant findings). Every patient had abnormal results when assessed for radiation-induced lung injury. No statistically significant difference was found in toxicity between the treatment arms. A high surfactant protein (SP)-A/phospholipid ratio and a high level of SP-A in BALF before RT was associated with a high degree of radiation-induced lung injury measured by lung function tests and computed tomography in all arms of the study. Thus, we could not show that the combination of IFN-alpha and RT induced more lung toxicity than RT alone as we did in our previous study. The role of high SP-A/phospholipid ratios and high SP-A levels in BALF before RT as predictors of the development of lung injury after RT needs to be determined in the future.

Review: Interferon Trials in Small Cell Lung Cancer at One Institution: A Comparison of Results Obtained Before and After Initiation of Systematic Treatment Trials Using IFN-α in Combination with Other Modalities

Chemotherapy became the primary treatment for small cell lung cancer (SCLC) in the early 1970s. The standard drug combinations were first vincristine, adriamycin, and cyclophosphamide (VAC) and then, from the early 1980s, etoposide-platinum combinations. Despite a good initial objective response, however, patients usually suffer a rapid relapse. Treatment development has, therefore, focused on ways to overcome drug resistance, and on the addition of cytokines to the chemotherapeutic arsenal. Interferon (IFN) was one of the first cytokines found to have anticancer effects, and it was introduced into the combined modality regimens used to treat SCLC in the early 1980s in an attempt to overcome the problem of early relapse. The role of IFN was investigated with the aim of establishing how best to combine it with other treatments for SCLC. In this paper, we review the impact of IFN on the outcome for 714 SCLC patients who were treated in randomized IFN trials at one institution over a period of 20 years and I...

Helicobacter pylori and gastrointestinal symptoms in diagnostics and adjuvant chemotherapy of colorectal cancer

5-Fluorouracil (5-FU)-based chemotherapy is the mainstay of adjuvant treatment for colorectal cancer (CRC). Few studies have explored Helicobacter pylori (H. pylori)-associated gastrointestinal symptoms in the diagnosis of CRC, and the association between H. pylori infection and gastrointestinal toxicity during adjuvant chemotherapy in CRC. Seventy-nine CRC patients were randomised in a prospective clinical trial to receive 5-FU and leucovorin administered as bolus injection (Mayo regimen) or continuous infusion (simplified de Gramont regimen). H. pylori antibodies were analysed at baseline, twice monthly during treatment and after treatment up to 12 months. Thirty-seven patients (47%) were H. pylori-seronegative at baseline. There was no significant association between baseline H. pylori seropositivity (n=42; 53%) and oro-gastrointestinal toxicity during chemotherapy. The median time from symptom onset of CRC to surgery was significantly longer in patients with H. pylori infection (median time, 6 vs. 5 months; P=0.012). Functional dyspeptic symptoms at presentation significantly delayed diagnosis (median time, 7.5 vs. 5 months; P=0.035), whereas anaemia, bowel symptoms, occlusion, blood in the stool, infection and hypolactasia did not. We conclude that there is no association between H. pylori status and gastrointestinal toxicity in CRC patients during chemotherapy. Dyspeptic symptoms and presence of H. pylori may delay the diagnosis of CRC. (www.controlled-trials.com/ISRCTN98405441).