Adjuvant chemotherapy with doxorubicin in high-grade soft tissue sarcoma: a randomized trial of the Scandinavian Sarcoma Group.

From January 1981 to February 1986, a total of 240 patients with primary, malignancy-grade III or IV soft tissue sarcoma were entered into an adjuvant chemotherapy multicenter trial conducted by the Scandinavian Sarcoma Group (SSG). Of these patients, 181 were evaluable. The tumor was located in the extremities in 155 patients. After radical surgery (wide and compartmental) the patients were randomized to treatment with single-agent doxorubicin 60 mg/m2 administered as an intravenous (IV) bolus once a month for 9 months (group 1, n = 77) or to control (group 2, n = 77). If the surgical procedure was marginal, the patients initially received postoperative radiotherapy, followed by doxorubicin (group 3, n = 16) or control (group 4, n = 11). The control groups did not receive any adjuvant chemotherapy. Adjuvant therapy was initiated within 6 weeks of surgery (group 1) or within 10 weeks of surgery for patients receiving postoperative radiotherapy (group 3). With a median follow-up of 40 months, there was no significant difference between the four treatment groups in overall survival (group 1, 75%; group 2, 70%; group 3, 69%; group 4, 73%), disease-free survival (group 1, 62%; group 2, 56%; group 3, 62%; group 4, 64%), or local tumor control (group 1, 92%; group 2, 92%; group 3, 87%; group 4, 90%). The conclusions were the same whether the total group or evaluable patients only were included in the analysis. The local recurrence rate for patients undergoing radical surgery was 8% and for patients undergoing marginal surgery followed by radiotherapy was 12%. This study indicates that the use of single-agent doxorubicin as postoperative adjuvant chemotherapy has no significant clinical benefit in patients with high-grade soft tissue sarcoma.

[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.

[Thoraco-scapular amputation in sarcomas of the shoulder girdle]. / Intertorakoskapulaer amputation ved sarkomer i skulderbaeltet.

A total of 121 patients with sarcomas localized to the shoulder girdle were referred to the Sarcoma Centre in Arhus. Of these, 17 (14%) underwent interscapulothoracic amputation. At the time of treatment, the average age was 51 years (17-82 years). Eleven of these patients had sarcomas of bone and six had soft tissue sarcomas. Late diagnosis or previous surgical interventions contributed to the indication for the mutilating procedure. At the time of referral, six of the 11 cases of bone sarcomas were complicated by a pathological fracture and all six soft tissue sarcomas had been submitted to incisional biopsy or non-radical treatment. The soft tissue sarcomas were usually large with an average maximum diameter of 10 cm (4-15 cm). Postoperative recovery was uncomplicated in all cases. Local recurrence occurred in three patients (18%). Eight patients (47%) developed metastases and died from the tumour on an average of 32 months (7-94 months) after operation. Two patients died from other causes without tumour. Seven patients (41%) were tumourfree and alive for an average of 69 months (21-128 months) after operation. Only three of these seven patients wore their shoulder-arm prosthesis regularly while the remainder preferred to be either without a prosthesis or to use a lightweight shoulder prosthesis. None of the seven patients still experienced phantom pain necessitating analgetics. All of the patients were self-reliant in everyday life and the five patients who had been occupationally active until the time of operation had returned to work. The prognosis after interscapulothoracic amputation depends upon the primary malignant disease.(ABSTRACT TRUNCATED AT 250 WORDS)

[Radiation induced sarcoma of the shoulder girdle]. / Stråleinducerede sarkomer i skulderbaeltet.

A well-known complication after irradiation of tissue is development of postradiation sarcomas, and the shoulder girdle is in this connexion a frequent location, because it relatively often is exposured to x-rays. During the period 1956 to 1989 121 patients with sarcomas located to the shoulder girdle were referred to the Sarcoma centre in Arhus. Of these, six were postradiation sarcomas. The indication for the initial irradiation was in two cases cancer of the breast, in one malignant lymfogranulomatosis, in one a metastasis from malignant melanoma and finally two cases of peritendinitis humeroscapularis. In average 15 years (7-26 years) elapsed from irradiation to the diagnosis of the sarcomas. There were four bone sarcomas, two located in the clavicles and 2 in the humeri. Of these, three were osteogenic sarcomas and one a malignant fibrous histiocytoma. There were two soft tissue sarcomas, both located subcutaneously with involvement of deep fascia and muscle. Both tumors were extraskeletal osteogenic sarcomas. Three patients died of tumor on an average after 11 months. Two died without tumor from other causes, and one patient is alive without tumor 11 years after the treatment. If a patients presents with pain at the side of prior radiation, the diagnosis postradiation sarcoma must be considered and the patient referred to the Sarcoma centre. Radiation therapy should not be used in patients with benign lesions.

[Synovial sarcoma]. / Sarcoma synoviale.

During the period 1962-1984, 26 cases of synovial sarcoma were seen in the center for bone and soft tissue tumours in Arhus, Denmark. None of the tumours were located in direct relation to bursa or joint cavities and the majority of the patients were initially operated in other hospitals and subsequently referred to the centre. Twenty-three patients were operable. Local excision was the primary treatment in 17 patients and amputation in six patients. Fourteen had local recurrence after an average of 12 months. At the status in June 1987, 14 patients had died of the disease, one survived with metastases to the lungs 30 months after the initial operation, one showed no evidence of disease after approximately three years, six patients were alive and without evidence of disease after at least five years. Five and ten-year survival rates for operable cases were 42% and 31%, respectively.

[Merkel cell carcinoma]. / Merkel-cellekarcinom.

Eight patients with Merkel cell carcinoma are reported to document their response to surgery and/or radiotherapy. Four patients who initially underwent surgery without postoperative radiation therapy all had local recurrence. Two patients were treated with postoperative radiation therapy and two were treated with radiation therapy without excision of the tumour. None of these four patients had local recurrence. Five patients developed regional recurrence. Recurrence was seen in one patient in the irradiated field. Metastatic disease was not seen in any case. These results combined with a review of the literature suggest that radiation therapy postoperatively to both the surgical bed and the draining lymph nodes may improve local regional tumour control.

Radiotherapy versus combined modality treatment of stage I and II Hodgkin's disease.

In a multicenter study in which data from all Hodgkin's disease patients in Denmark have been registered since 1971, all patients with supradiaphragmatic stage I and II disease (as confirmed by staging laparotomy) were randomized to receive either radiotherapy (RT) to supradiaphragmatic and infradiaphragmatic lymph node regions (total nodal irradiation) or RT to a mantle field followed by six cycles of MOPP combination chemotherapy (CT) (RT plus CT). Interim results up to July 1980, when 261 patients had entered the study, showed 28 failures among 128 patients in the total nodal irradiation group and four failures among 133 patients in the RT plus CT group (P less than 0.05). Stage II, nodular sclerosing or mixed cellular histology, and gross hilar/mediastinal involvement defined subsets of patients in the RT group with a relatively high relapse frequency. Salvage treatment of the relapsed patients has so far been good and there is as yet no difference in overall survival. However, longer observation time is needed before the cure rate can be evaluated with certainty. Two patients treated with RT alone and one treated with RT plus CT developed acute myeloid leukemia.

Experiences from the National Danish Hodgkin's Study Group (LYGRA) with respect to diagnosis, classification and treatment of Hodgkin's disease.

From September 1971 to April 1983, 1200 patients with newly diagnosed Hodgkin's disease were admitted to the centres which had founded LYGRA (the Danish Hodgkin's Study Group), to undergo uniform staging procedures and treatment. Present problems concerning staging, treatment, and complications, such as the risk of pneumococcal infection following splenectomy, the loss of fertility, and the risk of secondary malignancies, in particular leukaemia, are discussed.

Treatment of glomus tumours. A retrospective survey.

A retrospective survey of symptomatology, treatment and course of disease in 45 patients with glomus tumours treated between 1959 and 1986 at the Radium Centre and ENT Department of the Aarhus University Hospital is presented. Nine patients were treated surgically, 7 had surgery and irradiation combined, and 25 patients were treated solely with radiation therapy. Six patients developed recurrence of tumours. Two patients died of tumour, one of them with pulmonary metastases.

Tumor burden as the most important prognostic factor in early stage Hodgkin's disease. Relations to other prognostic factors and implications for choice of treatment.

Two hundred ninety patients with Hodgkin's disease pathologic stage (PS) I or II were treated in the prospective randomized trial of the Danish National Hodgkin Study (see Appendix) with radiotherapy +/- adjuvant combination chemotherapy. The initial tumor burden of each patient was assessed, combining tumor size of each involved region and number of regions involved. Multivariate analyses of prognostic factors including treatment, tumor burden, histologic subtype, pathologic stage, number of involved regions, mediastinal size, systemic symptoms, erythrocyte sedimentation rate (ESR), sex, and age were carried out. With regard to disease-free survival tumor burden was by far the most important prognostic factor for patients treated with adjuvant chemotherapy as well as for patients treated with radiotherapy alone. With regard to survival from Hodgkin's disease only tumor burden and age were independently significant. A combination of tumor burden, histologic subtype, and sex singled out patients with a high relapse rate both after radiotherapy only, and after radiotherapy plus chemotherapy. This combination also singled out patients destined to die from Hodgkin's disease more accurately than other prognostic factors.

Histopathological grading of soft tissue tumours. Prognostic significance in a prospective study of 278 consecutive cases.

A consecutive 10-year series of 278 soft tissue sarcomas was prospectively graded, using a system based on the number of mitoses and taking into account parameters such as cellularity, anaplasia, necrosis, and histogenetic type and subtype of tumour. Prognostic factors in relation to metastasis-free survival were studied by uni- and multivariate analysis. Fifty-seven (20.5 per cent) were low-grade tumours, 43 (15.5 per cent) were intermediate, and 178 (64 per cent) were high grade. High-grade tumours were divided into two groups; 80 (29 per cent) grade 3A (= 5-20 mitoses per 10 high power fields (HPF)) and 78 grade 3B (28 per cent) (= more than 20 mitoses/10 HPF); 10 HPF corresponds to 2.5 mm2. Twenty (7.2 per cent) high-grade tumours could not be further subdivided. Grading was found to be the prognostic factor associated with the strongest predictive value. Five-year survival in low-grade and intermediate tumours (95 and 86 percent, respectively) differed significantly (P less than 0.0001) from high grade (50 per cent) and (p = 0.0018) between grade 3A (64 per cent) and grade 3B (41 per cent). Other prognostic indicators of importance in high-grade tumours were age, local recurrence at presentation (primary operation outside the Centre), and localization (superficial vs. deep).

Tumour burden in early stage Hodgkin's disease: the single most important prognostic factor for outcome after radiotherapy.

One hundred and forty-two patients with Hodgkin's disease PS I or II were treated with total or subtotal nodal irradiation as part of a prospective randomized trial in the Danish National Hodgkin Study during the period 1971-83. They were followed till death or--at the time of this analysis--from 15 to 146 months after initiation of therapy. The initial tumour burden of each patient was assessed, combining tumour size of each involved region and number of regions involved. Tumour burden thus assessed proved to be the single most important prognostic factor with regard to disease free survival. Other known prognostic factors such as number of involved regions, mediastinal size, pathological stage, systemic symptoms, and ESR were related to tumour burden and lost their prognostic significance in a multivariate analysis. The only other factors of independent significance were histologic subtype and, to a lesser extent, sex. Combining tumour burden and histologic subtype made it possible to single out a group of patients with a very poor disease free survival. These patients also had a poorer survival from Hodgkin's disease and thus clearly candidates for additional initial treatment.

A prospective study of circulating immune complexes in patients with breast cancer.

Levels of circulating immune complex (cIC) and complement split product C3d were studied in 86 patients with breast cancer (BC), 22 patients with benign breast disease (BD), and 72 age- and sex-matched blood-bank donors (NC), using solid-phase Clq-protein A RIA, Clq-anti-IgG RIA, anti-C3d anti-IgG RIA, and polyclonal IgM-rheumatoid factor ELISA for clC detection. No significant differences in cIC and C3d levels were found between the groups. The incidence of raised cIC levels varied from 4.9 to 8.2% in the BC group and from 4.5 to 22.7% in the BD group in comparison with 2.9 to 3.0% in the NC group. Using the solid-phase polyclonal IgM-rheumatoid factor ELISA we found that the cIC levels of patients with stage-III cancer were significantly higher than those of patients with stage-I or stage-II cancer. However, the other tests showed no relationship to tumor burden. Likewise, an effect of mastectomy on the cIC levels was also only detectable by one of the assays, i.e., the post-mastectomy levels of cIC as measured by the solid-phase anti-C3d anti-IgG RIA were significantly lower than the pre-mastectomy levels. Serial analyses of cIC and C3d levels were performed pre-operatively, one month post-operatively and every 3 months during the first year after mastectomy in 46 of the patients. During a I-year observation period, 7 patients developed metastatic disease. The occurrence of metastatic disease was not, however, preceded by characteristic changes in serially determined cIC and C3d levels.

Tumor cell concentration and tumor burden in relation to histopathologic subtype and other prognostic factors in early stage Hodgkin's disease. The Danish National Hodgkin Study Group.

Prognostic factors were examined by multivariate analysis after a recent follow-up of the 300 patients with Hodgkin's disease pathologic stage (PS) I or II treated with radiotherapy +/- adjuvant combination chemotherapy in the prospective randomized trial of the Danish National Hodgkin Study. Initial biopsy material was classified according to the Rye histopathologic classification, the grading and subclassification proposed by the British National Lymphoma Investigation (BNLI), and tumor cell concentration in sections. Tumor cell concentration as a prognostic factor turned out to be better than the other classifications. However, if macroscopic tumor burden was taken into account both tumor cell concentration and the other histopathologic classification systems lost their prognostic significance. Significantly, however, a combination of macroscopic tumor burden and tumor cell concentration, yielding an estimate of the total tumor cell burden, was even better than the macroscopic tumor burden as a prognostic factor. In conclusion, a simple tumor cell concentration count seems to be the most useful form of histopathologic subtyping for prognostic purposes in early stage Hodgkin's disease.

Radiotherapy versus radiotherapy plus chemotherapy in stages I and II Hodgkin's disease. A prospective, randomized study by the Danish National Hodgkin Study Group, LYGRA.

In a multi-centre study in which data from all Danish Hodgkin patients have been registered since 1971, all patients in supradiaphragmatic stages I or II, as confirmed by staging laparotomy, were randomized to either radiotherapy (RT) to supra- and infradiaphragmatic lymph node regions (total nodal irradiation, TNI), or RT to a mantle field followed by 6 cycles of MOPP combination chemotherapy (RT+CT). Interim results up to July 1979, when 237 patients had entered the study, showed a treatment failure rate of 19/117 in the TNI group and 4/120 in the RT+CT group (P less than 0.05). 19 of the 23 relapsing patients were under the age of 40, and 14 in the TNI group and 3 in the RT+CT group belonged to stage II. 13 patients had nodular sclerosis, 9 had mixed cellularity and 1 had lymphocytic predominance histology. 12 of 19 relapsing patients in the TNI group had hilar or mediastinal involvement as against 51 of the 117 patients in the entire group. Most of the TNI failures could be retreated, and as yet there is no difference in the overall survival.