Chemotherapy in soft tissue sarcoma. The Scandinavian Sarcoma Group experience.

The Scandinavian Sarcoma Group (SSG) started its first chemotherapy study in soft tissue sarcoma (STS) in 1981 (SSG I). This study evaluated single agent doxorubicin given adjuvant in a prospective randomized trial in patients with high-grade STS. Neither overall survival nor disease-free survival was improved. Combination chemotherapy was hereafter studied in a phase II study (1991-1994) combining ifosfamide and continuous infusion etoposide with growth factor support (SSG X). The response rate in previously untreated patients was high (42%), but complete remissions were few. Analysis made on patients operated after chemotherapy indicated improved survival in this subgroup. Meta-analyses of adjuvant chemotherapy for localised resectable STS in adults, including the SSG I trial, has indicated improved disease-free survival and a trend towards improved overall survival. Presently, SSG is testing whether such a benefit can be found for adjuvant ifosfamide and doxorubicin treatment given after primary surgery in selected patients with high-grade STS and other well defined unfavourable prognostic factors (SSG XIII).

Outcome of ipsilateral treatment for patients with metastases to neck nodes of unknown origin.

It is not uncommon for head and neck cancer patients to present with neck node metastases. Standard treatment for patients in whom no primary tumor is found include surgery and radiotherapy but there is still controversy about the type and extent of treatment. A retrospective review was carried out on 51 consecutive patients with cervical lymph node metastases of unknown origin, treated between 1980 and 1994 at Radiumhemmet, Karolinska Hospital. All patients received radiotherapy to the ipsilateral neck and the corresponding mucosa and surgery was performed in 55% of cases. The 5-year overall survival rate was 41%. A primary tumor was later found in 6 cases (12%). Two cases of cancer were detected after 5 years and classified as 'second primaries'. Results from this small retrospective material have to be interpreted with caution but indicate that limited, ipsilateral radiotherapy to mucosa and lymph nodes combined with surgery, when possible, may be justified.

GM-CSF at relatively high topic concentrations can significantly enhance the healing of surgically induced chronic wounds after radiotherapy.

Combinations of radiotherapy and surgery are often used in local cancer treatments. Preoperative radiotherapy may delay wound healing after surgery. Chronic wounds are debilitating conditions that require frequent medical attention. Two patients suffering from chronic and slowly healing wounds post-surgery and preoperative radiotherapy are described. A significant acceleration of the healing by local injections with GM-CSF was demonstrated.

Radiation therapy in the management of brain metastases from breast cancer.

A retrospective analysis of 99 patients treated at Radiumhemmet, Karolinska Hospital 1979-1990 with palliative radiotherapy for brain metastases from breast cancer was performed. A relief of symptoms was obtained in 45% of patients. Median time from diagnosis of breast cancer until CNS metastases was 33 months. Median survival time with CNS metastases after diagnosis was 5 months. Prognostic indicators for survival were studied. Patients operated for a singular brain metastasis and irradiated postoperatively had a mean survival of 21 months while patients with multiple brain metastases and meningeal spread displayed a short median survival. Extracranial disease status influenced prognosis significantly. Radiation dose (CRE) did not correlate with survival.

Shrinkage of desmoid tumor with interferon alfa treatment: a case report.

We report on a case with desmoid tumor sucessfully treated with low-dose interferon alfa. A desmoid tumor was diagnosed in August 1998 in the right shoulder area of a 23-year-old woman. Surgery would probably have permanently impaired muscle function in her shoulder and arm. Therefore, interferon alfa treatment (0.9 million units twice daily subcutaneously) was started in November 1998 (time = 0). The tumor volume based on magnetic resonance imaging (MRI) was initially 16 cm3. The size of the tumor decreased gradually during 12 months of treatment, and in November 1999 (time = 12 months) MRI showed no clear tumor demarcation. This treatment modality may be considered as an alternative to mutilating surgery in patients with desmoid tumor.

Prognostic impact of complete remission after preoperative irradiation of tonsillar carcinoma: a retrospective analysis of the radiumhemmet data, 1980-1995.

PURPOSE: This retrospective study was done to determine the outcome of patients with tonsillar carcinoma treated at Radiumhemmet, Karolinska Hospital, between January 1980 and December 1995 with radiotherapy alone or in combination with surgery. In addition the importance of tumor remission for patient survival was analyzed. METHODS AND MATERIALS: The analysis is based on 167 previously untreated patients with biopsy-proven, invasive tonsillar squamous cell carcinoma of the tonsillar region. All patients were consecutively admitted to the Department of General Oncology, Radiumhemmet, and treated with curative intent. The median follow-up time was 20 months. The median target dose was 64 Gy, delivered in fractions of 2 Gy 5 times weekly. Twenty-eight percent of the patients underwent surgery of the primary site and/or neck dissection after radiotherapy (RT). RESULTS: The overall local control rate for the whole patient group after radiotherapy was 79%. Probability of survival after 5 years for patients responding with complete remission (CR) was 43% and for patients with incomplete response (non-CR) 9%, (p<0.0001). The survival in the non-CR group treated with combination therapy was 20 months longer than in patients receiving radiotherapy alone (p<0.0001). There was no statistically significant difference in prediction of long-term survival when the patient population was stratified according to tumor differentiation grade, age, sex, nodal status, or treatment time. CONCLUSION: The strongest clinical predictor of survival was the degree of tumor remission after RT. For the non-CR group receiving combination treatment including surgery there was a survival benefit as compared to patients treated with RT alone (p<0.0001) although there were few long-term survivors in this patient group.

Chemotherapy in soft tissue sarcoma. The Scandinavian Sarcoma Group experience.

The first chemotherapy study of soft tissue sarcoma (STS) by the Scandinavian Sarcoma Group was started in 1981 (SSG I). It evaluated the single agent adjuvant doxorubicin in a randomized setting in patients with high-grade STS. No improvement was noted in the overall survival or disease-free survival rate. More intense chemotherapy was thereafter (1991-1994) evaluated in a phase 2 study, introducing ifosfamide and a continuous infusion of etoposide with growth factor (SSG X). The response rate of previously untreated patients was high (42%), but complete remissions were few. Analysis of patients undergoing surgery after preoperative chemotherapy suggested an increased survival. A recent meta-analysis of adjuvant chemotherapy for localized resectable STS in adults, including the SSG I trial, indicated a better disease-free survival and possibly improved overall survival (Thierny et al. 1997). At present, we are studying whether such a benefit can be shown in patients with high-risk prognostic criteria by giving adjuvant ifosfamide and doxorubicin treatment after primary surgery (SSG XIII). In the latter SSG study, started on July 1, 1998, the adjuvant therapy is evaluated in a phase 2 study in selected patients with high-grade STS and other unfavorable prognostic factors.

Economic evaluation of gemcitabine single agent therapy compared with standard treatment in stage IIIB and IV non-small cell lung cancer.

Chemotherapy treatment of patients with advanced non-small cell lung cancer (NSCLC) has been characterised by low cure rates, serious side effects, and expensive inpatient care. The aim of the present report was to perform an economic evaluation of gemcitabine monotherapy compared with standard chemotherapy treatment for NSCLC stages IIIB and IV. Standard chemotherapy treatment was identified as cisplatin/etoposide and ifosfamide/etoposide. Effectiveness expressed as survival and tumour response rates was assumed to be broadly equivalent for the alternatives. A cost-minimisation analysis was therefore performed. Total costs per patient per first treatment cycle of chemotherapy for the alternatives cisplatin/etoposide, ifosfamide/etoposide and gemcitabine were Skr 15,131, Skr 25,226, and Skr 13,266, respectively. The results are sensitive to whether chemotherapy could be given in inpatient or in outpatient care. Monotherapy with gemcitabine outpatient treatment in patients with stage IIIB and IV NSCLC was found to be a cost saving alternative when compared with currently used inpatient combination regimens. The treatment alternative with gemcitabine appears to be associated with higher costs for drugs and outpatient care, but lower costs for inpatient care and treatment of adverse events.

Acupuncture treatment of patients with radiation-induced xerostomia.

Xerostomia is a common and usually irreversible side effects in patients receiving radiation therapy (> 50 Gy) for head and neck cancer. Of 38 patients with radiation-induced xerostomia, 20 in the experimental group were treated with classical acupuncture and 18 patients in the control group received superficial acupuncture as placebo. Within both groups the patients showed significantly increased salivary flow rates after the acupuncture treatment. In the experimental group 68% and in the control group 50% of the patients had increased salivary flow rates at the end of the observation period. Among those patients who had had all their salivary glands irradiated, 50% in both groups showed increased salivary flow rates (> 20%) by the end of the observation period of 1 year. The study indicates that among the patients who had increased salivary flow rates already after the first 12 acupuncture sessions, the majority had high probability of continual improvement after the completion of acupuncture treatment. The improved salivary flow rates usually persisted during the observation year. The changes observed in the control group were somewhat smaller and appeared after a longer latency phase. Significant differences for salivary flow rates could be observed only within each group, and there were no statistically significant differences between the groups. There were no differences in the improvement of salivary flow rates between those patients who were irradiated within a year before the acupuncture treatment and those who had received radiation therapy several years earlier. The results indicate that acupuncture might be a useful method for the treatment of radiation-induced xerostomia, and that superficial acupuncture should preferably not be used as placebo acupuncture.

Long-term adjuvant interferon treatment of human osteosarcoma. A pilot study.

During the period from 1971 to 1990 all osteosarcoma patients referred to the Karolinska Hospital without signs of metastases received human leukocyte interferon (IFN) as adjuvant treatment. Patients referred between 1985 and 1990 were given more intensive human leukocyte IFN treatment, i.e. a standard dose of 3 MU s.c. daily for 3-5 years. These 19 patients, all followed for 5 years, were included in a pilot study which entailed patients with central localization where radical surgery was not feasible. Metastases developed in 9 patients, of whom 3 had local recurrences. Sixty-three percent are free of disease at 5 years. Side-effects were negligible and long-term toxicity practically non-existent. It is suggested that a randomized multicenter IFN trial should be instituted on patients with poor prognosis receiving chemotherapy and/or that IFN treatment should be combined with other therapeutic modalities--irradiation, chemotherapy or anti-angiogenic substances--in osteosarcoma.

Proliferating cell nuclear antigen (PCNA) expression and nuclear DNA content in predicting recurrence after radiotherapy of early glottic cancer.

Proliferating cell nuclear antigen (PCNA) is a DNA replication protein maximally elevated in late G1 and S phases of the cell cycle. By using monoclonal antibodies, the expression of PCNA can be quantified and the rate of tumour cell proliferation estimated. The degree of DNA aberration in a tumour cell population reflects its genetic instability and has been implicated as a prognostic factor in an increasing number of solid tumours. The nuclear DNA content can be assessed by densitometric image cytometry DNA analysis. Both PCNA and DNA analysis can be performed on histological sections from paraffin embedded biopsies. In search of efficient and reproducible methods to identify early glottic cancers with increased risk for recurrence after radiotherapy, the PCNA expression as well as the DNA content of the diagnostic biopsies from 28 T1N0M0 glottic cancers were assessed. The group of tumours which recurred locally after radiotherapy displayed lower PCNA expression and higher DNA aberration than the group of tumours which were cured. Moreover, a combination of both parameters improved the possibility to discriminate the two groups. For T1 glottic cancer displaying high grade of genetic instability or low grade of proliferation, treatment regimes other than radiotherapy and closer follow-ups could be considered.

Interaction of melphalan and dexamethasone in a human myeloma cell line.

The effects of a combination of melphalan and dexamethasone on cell growth, cell cycle flow, cell loss and DNA cross-links were studied on a myeloma cell line (RPMI 8226). At low concentrations melphalan reduced the cell growth by prolonging the S and G2 stages. Steroid sensitivity of the cell line was characterized by dose-dependent inhibition of cell growth after exposure of up to 1 micron dexamethasone with no cell loss found even at 10-fold saturation concentration. Dexamethasone induced prolongation of all cell cycle phases without any preferences. In combined treatment with melphalan and dexamethasone, inhibition of cell growth was found after 24 h followed by cell loss after 48 h. This cell loss was obtained with concentrations of the drugs which by themselves are only growth inhibitory. Calculation of cell flow showed that cell loss is a delayed process occurring after the cells have left the G1 phase. By alkaline elution it was found that dexamethasone treatment caused an increase in melphalan-induced DNA interstrand crosslinks.

Cell cycle arrest and DNA damage after melphalan treatment of the human myeloma cell line RPMI 8226.

Exposure of a myeloma cell line (RPMI 8226) to a 30-minute pulse of melphalan (1-phenylalanine-mustard) resulted in a cell cycle progression delay characteristic for DNA cross-linking agents. Reduction of outflow of cells from late S- and G2-phases was more pronounced as compared to that from G1-phase. The consequence is a progressive accumulation of cells in late S- and G2-phases. At restoration of outflow of cells from late S- and G2-phases, complete removal of DNA interstrand cross-links, as measured by DNA alkaline elution, was noted. At this time less than 50% of maximum DNA-protein cross-links were removed. Further we found no correlation between restored outflow of cells from the G2-phase and removal of DNA-protein cross-links during the follow-up time of 72 h. No DNA double strand breaks as measured by DNA neutral elution were formed during the observation period. The data suggest that removal of DNA interstrand cross-links seems prerequisite for the outflow of cells from G2 after melphalan treatment.

Efficacy of peptide bound m-L-sarcolysin (peptichemio) on melphalan resistant human myeloma cells in vitro.

Peptichemio (PTC) is a mixture of six synthetic oligopeptides, each containing the alkylating agent m-di(2-chloroethyl)amino-phenylalanine. Freshly obtained myeloma cell infiltrated human bone marrow specimens were in parallel exposed to melphalan and PTC. The cytotoxic effect of the drugs on the myeloma cells of each specimen was measured by the differential staining culture method (DISC). PTC displayed higher cytotoxicity to the myeloma cells as compared to melphalan in all 12 cases analysed. The increase of the cytotoxic effect of PTC compared to melphalan varied between different cases. In melphalan resistant cases the cytotoxic effect of PTC as compared to melphalan was clearly significant (P = 0.001).

Interphase cell death as related to the cell cycle of melphalan-treated human myeloma cells.

The effect of melphalan on cell loss, cell growth and cell-cycle traverse was studied on the human myeloma cell line RPMI 8226. Melphalan treatment resulted in arrest of cells in late S- and G2-phases in a population of unsynchronized cells. At high concentrations of melphalan (e.g. 40 microM), cell loss was noticed during the first cell cycle after melphalan treatment in addition to the aforementioned arrest of cells in late S and G2. The cell loss after melphalan treatment was further analysed in cells enriched for G1-phase. Cell death in this population of cells occurred between 24 and 48 hr after treatment as the cells were in S and moving over to G2.

Oral dosage of melphalan and response to treatment in multiple myeloma.

Forty-nine consecutive patients with multiple myeloma were analysed for treatment response in relation to dose of orally administered melphalan (induction therapy). All patients were given at least six courses of melphalan-prednisone. Treatment response, defined as a reduction of the myeloma protein of greater than 50%, was seen in 26 patients while 23 were non-responders. When treatment response was related to the dosage of melphalan given by mg/kg of body weight, the numbers of responding and non-responding patients were similar in the group of patients without dose reduction as well as in that with dose reduction. Drug-induced suppression of white blood cell and platelet count was similar in the responding as well as in the non-responding group indicating that the reason for non-response is not simply explained by deficient drug absorption. When the cumulative dose of melphalan given during the induction therapy was analysed, however, a positive correlation (r = 0.47, P less than 0.001) was seen between the cumulative dose and the degree of response. Thus, the cumulative dose of melphalan given during induction therapy seems to be of importance for the response, but other factors as intrinsic differences in cell sensitivity may also explain the individual responsiveness.

Radiation therapy in early glottic cancer. Analysis of 177 consecutive cases.

Early vocal cord carcinomas (TiS or T1) in a consecutive series of 177 patients treated by primary radiotherapy over a 10-year period 1970-79 at the Department of General Oncology, Radiumhemmet, Karolinska Sjukhuset, were analysed regarding treatment results. In 137 cases the tumours were invasive (T1N0M0) and in 40 cases carcinoma of in situ type (TiS). Patient were treated with cobalt 60 gamma irradiation in fractions of 2 Gy up to a total dose of 64 Gy delivered as split course (CRE=17.8). Minimum follow-up time was 5 years. Tumour recurred in 21 cases (12%). All but 4 patients were rescued by subsequent surgery, giving 98% total survival. Treatment failures after primary radiotherapy were analysed in detail. Failures could not be attributed to treatment irregularities. No difference in pretreatment tumour size was detected when cured patients were compared with patients who relapsed. Biological factors that cause a relative radioresistance are considered to be the main reason for radiotherapy failures in early glottic cancer.

Interferon exerts a cytotoxic effect on primary human myeloma cells.

A dye exclusion method was used for testing the sensitivity of primary human myeloma and normal bone-marrow cells to interferon (IFN). Following 4 days of incubation with 5000 units/ml of natural (n) IFN-alpha, there was a greater than 90% decrease in the number of viable myeloma cells in cultures from some patients, whereas myeloma cells from other patients showed intermediate or no sensitivity to IFN. The number of viable non-malignant bone-marrow cells (from the same patients) following a 4-day exposure to nIFN-alpha (5000 units/ml) decreased by 10-60%. Exposure of malignant and non-malignant bone-marrow cells to natural beta- and recombinant alpha- and gamma-IFN, also induced a decrease in the number of viable cells. The decreased number of viable myeloma cells could be observed already after 1 day of exposure to IFN-alpha in vitro. To test whether inhibition of proliferation could account for the observed effects, proliferation, as measured by [3H]thymidine uptake, was studied in some experiments. Only approx. 1-2% of the myeloma cells were labeled with [3H]thymidine during the 4 days of culture in vitro, whereas the proportion of labeled non-malignant cells was approx. 40%. Thus, the IFN-induced reduction of cell number in normal bone-marrow cells could possibly be attributed to a cell multiplication inhibitory effect of IFN, whereas the effect observed in myeloma cells cannot be attributed to cell multiplication inhibition. To test the possibility that the reduction in the number of myeloma cells could be attributed to the activity of autologous cytotoxic T-cells, NK-cells or macrophages, these cells were depleted in some experiments. Depletion of these cells did not, however, influence the IFN-induced decrease in the number of viable myeloma cells. We thus conclude that IFN can reduce the number of viable tumor cells by a cytotoxic effect, unrelated to cell multiplication inhibition.