Hans Strander

Interferon-α as the only adjuvant treatment in high-grade osteosarcoma: Long term results of the Karolinska Hospital series

This experience of single agent interferon-α treatment in high-grade osteosarcoma was based on observed anti-osteosarcoma activity in laboratory models and was started before introduction of aggressive combination chemotherapy. From 1971 to 1990, 89 consecutive patients with non-metastatic high-grade osteosarcoma received semi-purified, leukocyte interferon-α as adjuvant treatment. From 1971 to 1984, 70 patients were given a dose of 3 MIU daily for one month followed by 3 times weekly for an additional 17 months. For 19 patients treated from 1985 to 1990 the dose was increased to 3 MIU daily and the treatment duration extended to 3–5 years. All patients underwent surgery prior to interferon treatment. The toxicity was mainly constitutional and long-term toxicity was virtually absent. With a median follow-up of 12 years the observed 10-year metastases-free and sarcoma specific survival rates were 39% and 43%, respectively. Only one of seven survivors after relapse received chemotherapy. This work suggests activity of interferon-α as adjuvant treatment in high-grade osteosarcoma. The efficacy of interferon in combination with standard therapy should be explored in randomized trials.

Epstein-barr virus-specific serodiagnostic tests in carcinomas of the head and neck

Sera from 256 patients with cancers of the head and neck were examined for their profiles of IgG and IgA antibodies to Epstein‐Barr virus (EBV)‐specific, viral capsid antigen (VCA), the diffuse (D) and the restricted (R) components of the early antigen (EA) complex, and the EBV‐associated nuclear antigen (EBNA), in order to assess the value of these procedures in the routine diagnosis of poorly or undifferentiated nasopharyngeal carcinoma (NPC). In 13 NPC patients, the carcinoma had invaded cervical lymph nodes, and their sera revealed, in addition to high IgG anti‐VCA titers, elevated levels of IgA antibodies to VCA, of IgG antibodies to D, and most also had IgA anti‐D. Such profiles were seen in very few of the patients with carcinomas at other sites of the head and neck. They had not developed in four NPC patients whose tumors were limited to the postnasal space, and in three patients with other tumors at that site. Among 15 patients with cervical node metastases from occult primary tumors, 2 had EBV‐specific antibody profiles compatible with NPC, 1 was judged to have NPC on clinical grounds, and the other died of a pulmonary carcinoma, or possibly pulmonary metastases. In 4 of the remaining 13 patients with occult tumors, the primary site was found outside the nasopharynx, whereas it escaped detection in the other 9. These results lend further support to the usefulness of the EBV‐specific serology to clinicians in the diagnosis of NPC, especially in cases of lymph node invasion by undetected primary tumors. The data also emphasize the need of complementing the serology with the examination of biopsies for the presence of EBV deoxyribonucleic acid (DNA) or, more readily performed, EBNA‐positive carcinoma cells.

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).

Sequential methotrexate–5-fluorouracil treatment of squamous cell carcinoma of the head and neck

Thirty‐six patients with squamous cell carcinoma of the head and neck were treated with sequential methotrexate–5‐fluorouracil followed by leucovorin rescue. The frequency of objective tumor regression obtained was 64% (complete response + partial response) with 19% complete regression. In 20 not previously treated patients, the objective response rate was 70%. Approximately the same result was obtained for tumors of different anatomical sites of the head and neck. The degree of differentiation of the squamous cell carcinoma did not seem to be of prognostic importance for the initial tumor response. Toxicity was very mild and usually disappeared when the interval between the chemotherapy courses was prolonged from 1 to 2 weeks. Radiotherapy could be added sequentially to the treatment without measurable escalated toxicity.

Can historical controls be used in current clinical trials in osteosarcoma? Analysis of prognostic factors

Abstract A comparison with respect to possible prognostic factors has been made between a contemporary group of 44 patients with osteosarcoma in Sweden, who received treatment since 1971, and a historical group of 35 such patients treated prior to 1972. Only patients with no evidence of metastases on admission were included in the material. The case histories were reviewed by a team of pathologists and clinicians with experience of bone tumors, each case history was analyzed in detail and re-evaluated. The female/male ratio was lower, but not significantly so, for the contemporary group, 1:2.4, than for the historical group, 1:1.7. The mean age was similar in the two groups (18 and 17 years, resp.) Pain was the most common symptom in both groups, it was recorded in 86 and 100% in the contemporary and historical groups, respectively. Although the patients of the historical group generally presented more symptoms, the durations were similar in the two groups (3 months). The site patterns differed slightly, although not significantly so, in the two groups, there was a higher ratio of frequency of femoral and lower leg tumors for the historical group (54 and 32%, resp.) than for the contemporary group (36 and 45 %, resp.). The variability in tumor size was greater for the historical group, as was the tumor diameter (13 and 9 cm, resp.). The historical group had a greater proportion of osteoblastic tumors (83 and 63%, resp.) and these tended to be more malignant (Grade IV:80 and 68%, resp.). The study disclosed differences between the contemporary and the historical groups in respect to various factors that previous studies indicated might have a bearing on the prognosis in osteosarcoma. On the whole the prognosis would be expected to be less favorable for the historical group and there would seem to be a definite risk in using this group as a control group to the adjuvant interferon treated patients. Similar reviews of other non-randomized current clinical series would be a valuable aid in determining the efficacy of adjuvant therapy.

Adjuvant Interferon Treatment and the Late Development of Cerebral Metastases in a Patient with Osteosarcoma

A consecutive series of patients with osteocarcoma have been receiving adjuvant interferon therapy at the Karolinska Hospital in Stockholm. We report here a case of tibial chondroblastic Grade III osteosarcoma, a boy aged 17 years, who received interferon therapy for 15 months and survived more than 5 years. The first sign of tumour spread was multiple cerebral metaseases--an observation suggesting an antitumour effect of human leucocyte interferon on osteosarcoma.

Adjuvant interferon treatment in human osteosarcoma

The protocols of Rosen and collaborators have been used for several years in Scandinavia [1], with the exception of our institution, where adjuvant IFN has been utilized for 20 years [2]. The present report is an update of our IFN-treated osteosarcoma series conducted over the period 1971–1984; control patients representing a high-dose chemotherapy group and a nonadjuvant group are also presented.

Influence of human interferon-α therapy on cytotoxic functions of blood lymphocytes

SummaryVarious cytotoxic functions of blood lymphocytes were studied in 101 patients undergoing daily treatment with human interferon-α (IFN). Antibody-dependent cellular cytotoxicity and lectin-dependent cellular cytotoxicity were not altered to any major extent after 1 day or 1 week of IFN therapy. After 3 and 6 months of treatment a decrease in these functions was observed in most patients. Natural killer cell activity increased following the first injection of IFN and remained elevated during 1 year of IFN therapy.

IFN-Gamma Inhibits Osteosarcoma Xenografts in Nude Mice

Since 1981, we have transplanted fresh osteosarcoma tissue to nude mice and succeeded in establishing 13 osteosarcoma xenografts in serial passage. Studies on these human xenografts have not revealed any significant changes in tumor characteristics compared to the original tumor (1). The sensitivity of 11 xenografts to nIFN-alpha has been studied (2). All xenografts could be growth inhibited but the lowest growth inhibitory daily dose ranged from 1×105 IU for the most sensitive xenograft to 1×106 IU for the most insensitive. No IFN resistent tumors were found. The induced growth inhibition has mainly been attributed to a direct anti-tumor effect since human IFN does not effect mouse cells.

INTERFERON α TRIALS IN HUMAN TUMOR DISEASES11This work was supported by The Swedish Cancer Society and The Cancer Society of Stockholm.

ABSTRACT Interferon α (IFNα) can exert antitumor effects in some patients with tumors. Whether IFN therapy is superior to conventional treatment for any tumor disease is not yet known. Several randomized trials have been initiated to answer this question. Very little is known about the mechanism of the anti-tumor action of IFN in patients. Hopefully further studies will reveal the mechanism of action of IFNα in patients undergoing tumor regression.