Response to multimodal treatment in advanced neuroblastomas. Factors associated with complete remission induction, and factors associated with prolonged survival.

The influence of patient and treatment variables upon the probabilities of response to chemotherapy in advanced neuroblastomas was investigated in 71 children with stages III-IV disease treated in Denmark between 1965-1980. The therapeutic regimens consisted of various combinations of chemotherapeutic agents with or without surgical excision of the primary tumour and irradiation. Complete response (CR) was achieved by 75% of patients in stage III, and another 17% showed partial response. In stage IV 60% responded, 19% with CR. Relationships between patient and treatment variables and the probability of being alive in CR 22 weeks after initiation of the treatment were examined by logistic regression analysis. The probability of CR was not related to age at diagnosis, the addition of an anthracycline to the chemotherapeutic regimens, or to irradiation. Factors related to the maintenance of CR could not be statistically examined due to the small number of complete responders at 22 weeks. Only age below 2 years seems, however, to have positive impact on the response duration. The influence of patient characteristics was further suggested by the result of secondary treatment attempts. 42% of the patients selected for secondary treatment responded, and 17% achieved CR. 1/25 (4%) had survived disease-free for more than 8 years. Factors related to the duration of survival were subsequently examined in the 71 children using Cox's regression analysis. Only children below 2 years of age at diagnosis had survived for more than 8 years. Resection of the tumour at diagnosis, irradiation and the addition of an anthracycline appear not to influence the length of survival in this patient population.

Radical cystectomy for residual of recurrent tumour after definitive radiotherapy (salvage cystectomy).

The results of salvage cystectomy for persistent or recurrent tumour following definite radiotherapy in 47 patients are reviewed. The calculated five-year survival rate was 25% for all stages, with a significantly better survival for the low pathological stages. Operative mortality was 12.8%. It was concluded that salvage cystectomy is a suitable supplement in the treatment of bladder cancer in spite of the considerable operative mortality and complication rate.

Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer: study of 27 cases in 500 patients.

Carcinoma in situ in the contralateral testis was diagnosed in 27 of 500 patients (5.4%) with unilateral testicular germ cell cancer. Eight of the 27 patients received intensive chemotherapy for spread of their initial testicular cancer. Follow up biopsy studies did not detect changes of carcinoma in situ in any of these patients, and none developed a contralateral testicular tumour (observation time 12-88 months). Of the remaining 19 patients with carcinoma in situ, seven developed contralateral testicular cancer. The estimated risk of developing invasive growth was 40% within three years and 50% within five years. None of the 473 patients without carcinoma in situ detected by screening biopsy developed contralateral testicular cancer (observation time 12-96 months). No serious complications arose from the biopsy procedures. All patients with unilateral testicular germ cell cancer should be offered biopsy of the contralateral testis.

The Copenhagen bladder cancer project II.

The aim of this study has been, on the basis of 746 cases of cancer of the bladder from The Copenhagen Bladder Cancer Project, to assess the prognosis in relation to the tumour classification employed. The following five-year survival rates were found: T1, 59.8 percent, T2, 39.0 percent, T3, 19.7 percent, T4, 5.7 percent. There are significant differences in survival between the different T categories. The survival rates were also calculated for the different histological grades, and significant differences were also found here. Both the T classification and the histological grading are, therefore, relevant prognostic criteria. Papillomatous tumours have the same survival, whether solitary or multiple, but solid tumours have a poorer prognosis than papillomatous tumours. Tumour size is likewise a significant prognostic criterion. Of special interest has been the results of radiotherapy related to the same parameters. Neither the T classification nor the histological grading can be used as prognostic criteria for patients in the present material who were treated by radiotherapy. The overall five-year survival for patients treated by radiotherapy was 22 percent. With the investigative parameters employed, it is not possible in advance to select the group of patients with radiosensitive tumours.

The Copenhagen bladder cancer project I.

A material of 746 consecutive patients with tumours of the bladder from three hospitals in Greater Copenhagen for the period 1968-1974 is presented. This is the result of The Copenhagen Bladder Cancer Project. Some of the aims of the project were to describe the manifestations of bladder cancer by means of a number of examination parameters. The material may be regarded as representative for the region. About 80 percent of the patients are men, and the mean age is 66 years, but higher for patients with deeply invasive tumours and tumours of low degree of differentiation. Haematuria was the presenting symptom in 84 percent of the patients, and only 3.4 percent had urinary tract infection as sole first symptom. The interval from first symptom to hospitalisation was an average of 7.6 months, but less for cases of deeply invasive tumours and tumours of low degree of differentiation. About 60 percent of all bladder tumours are evaluated as being without invasion of the bladder nusculature, and 59 percent of the tumours are of a high degree of differentiation (Grade 0+I+II). Squamous cell carcinomas are found in about three percent and adenocarcinomas in about one percent of the cases. Benign papillomas, corresponding to Grade 0 tumours, are found in only one percent of the cases. About 50 percent of all transitional cell tumours are both superficial and show a high degree of differentiation. Grade II tumours show invasive growth in at least 25 percent of the cases and Grade III tumours in at least 77 percent. The bladder tumours are papillomatous in 66 percent of the cases, and 24 percent of the patients have more than one tumour in the bladder. Intravenous urography showed a pathological condition in 70 percent of the patients.

Radiographic evaluation of pulmonary fibrosis following mantle field irradiation in Hodgkin's disease.

Sixty-nine patients given mantle field radiation therapy for Hodgkin's disease and considered relapse-free and possibly cured were re-examined for pulmonary fibrosis as observed on antero-posterior and lateral chest radiographs. A method is described for the systematic evaluation of these late stage changes, which are observed following irradiation, in a numerical form. The method gave reproducible results in this series, the correlation coefficient being 0.72/0.81 and 0.73 respectively for the intra-observer and the inter-observer variations. The method thus may facilitate comparison between different patient materials.

Central nervous system complications by malignant lymphomas: radiation schedule and treatment results.

During a 10-year period, 28 patients with spinal cord compression due to epidural malignant lymphoma and 47 patients with cerebral involvement of lymphoma were treated with radiation at our institution. Fifty-four percent of the patients with spinal cord compression had this complication at the time of initial presentation of the disease, whereas only 4% with cerebral involvement presented with CNS symptoms. Only one patient had primary lymphoma solely located in the brain. Characteristically, a majority of the patients with spinal cord compression complained of back pain several months before developing neurological symptoms. Because only one-third of the patients had positive spine roentgenograms at the time of spinal cord compression, a CT scan is suggested in patients with malignant lymphoma suffering from back pain in order to verify a paraspinal lymphoma. Thus spinal cord compression may be avoided by early diagnosis and treatment. Among the patients with spinal cord compression, Hodgkin's and non-Hodgkin's histology were equally represented, whereas only 6% had Hodgkin's lymphoma among the patients with cerebral involvement of lymphoma. The response to treatment defined as improvement in neurological deficit in the patients with spinal cord compression was approximately 90% in both the Hodgkin's and the non-Hodgkin's group. No difference in response was found among patients who had laminectomy compared to patients who did not. Patients receiving high dose, short-term treatment (5 Gy X 5-6) responded equally to patients receiving low dose, long-term treatment (2 Gy X 18-20). The median survival from initiation of radiation therapy in patients developing spinal cord compression or cerebral involvement during relapse was 30 months. In patients with spinal cord compression at initial presentation of the disease, median survival had not been reached after 5 years. Among patients with cerebral involvement 50% had improvement of neurological symptoms with no difference between patients receiving high dose, short-term and patients receiving low dose, long-term treatment. It is concluded that high dose, short-term irradiation is as effective as low dose treatment. Especially in patients with neurological complications at relapse, this treatment schedule is preferred because of the extremely short survival of these patients.

Therapeutic implications of mediastinal involvement in advanced Hodgkin's disease.

47 patients with advanced Hodgkin's disease (stage IIIB or IV) and mediastinal involvement, treated during the period 1969-78 and followed till death or from 36 to 126 months after initiation of therapy, were analysed. All 47 patients had received combination chemotherapy (MOPP or equivalent regimens). 20 had also received additional radiotherapy to mediastinum (and in some cases to other involved areas as well). The 2 treatment groups did not differ significantly with regard to the more important prognostic factors. Both in the case of stages IV and IIIB patients in the group treated with combination chemotherapy alone, remissions were significantly more often only partial, the frequency of relapse and of treatment failure was significantly higher, and relapse-free survival was significantly poorer than in the group treated with additional radiotherapy. Furthermore, survival from Hodgkin's disease and crude survival including all causes of death were significantly better for patients treated with combination chemotherapy plus mediastinal irradiation. Consequently, for patients with advanced Hodgkin's disease and mediastinal involvement a combined approach including radiotherapy as well as combination chemotherapy would seem advisable.

Spleen irradiation in chronic lymphocytic leukemia (CLL): palliation in patients unfit for splenectomy.

In 22 patients with CLL given 30 courses of spleen irradiation, 23 responses were observed (77%, 95% confidence limits, 58-90%). Response was defined as reduction in palpable spleen size accompanied by relief of symptoms (pain, abdominal discomfort, and sweating) or improvement in hypersequestration or hemolytic anemia. Reduction in leukocyte count alone was not regarded as response. All responses were partial. The median response duration was 1 year. Subsequently, three patients underwent splenectomy. The median survival from the beginning of spleen irradiation was 2.5 years (range: 1 month-greater than 5 years). Only six patients had minor side effects from the gastrointestinal tract. The hematologic effect was most pronounced on the white blood cell count, but also the platelet count was affected. It is concluded that spleen irradiation is a gentle and effective alternative in CLL patients suffering from splenomegaly (pain and hypersplenism), refractory to chemotherapy and glucocorticosteroids and unfit for splenectomy. Splenic irradiation may also be used with benefit preoperatively before splenectomy in patients with excessive splenomegaly and hypersplenism.

Testicular seminoma in Denmark 1976-1980. Results of treatment.

Over a five-year period the DATECA Study included 554 consecutive patients with seminoma, representing practically all cases in the country. The stage distribution was: stage I 424 patients, stage II 110 patients, and stage III 17 patients. Typical seminoma was registered in 515 patients, anaplastic seminoma in 26 patients, and spermatocytic seminoma in 13 patients. The treatment was post-operative irradiation except in a few very advanced cases who received chemotherapy. Three-year corrected survival was: stage I 99 per cent, stage II 89 per cent, and stage III 65 per cent. Anaplastic seminoma showed a significantly higher rate of metastatic spread than typical seminoma and the prognosis was worse. Treatment-related complications were few, but adjuvant bleomycin combined with irradiation of advanced seminoma resulted in 2 deaths from pneumonitis.

A randomized study of radiotherapy versus radiotherapy plus chemotherapy in stage I-II non-Hodgkin's lymphomas.

In a randomized, prospective trial from 1974-1978, 73 patients with non-Hodgkin's lymphomas in clinical Stage I or II were treated with extended field radiotherapy alone (RT) or RT plus adjuvant chemotherapy with vincristine, streptonigrin, cyclophosphamide and prednisone (RT + CT). With a median follow-up time of five years, 54% have relapsed in the RT group versus only 10% in the RT + CT group (P less than 0.01). There is no statistical difference in the overall survival yet, but 13/14 deaths in the RT group versus only 3/12 in the RT + CT group were due to progressive disease. Among patients with unfavorable histology, 13/22 in the RT group have died from disease progression against 3/34 in the RT + CT group (P less than 0.01). The results are in agreement with those from two other series published in detail. Based on these results we therefore recommend to use adjuvant CT with RT in all Stage I-II patients with unfavorable histology. Further observation is necessary before a conclusion can be drawn for the lymphoma patients with more favorable histology.

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.

Subtotal body irradiation with linear accelerator as preparation for marrow engraftment in aplastic anemia.

Two cases of multitransfused severe aplastic anemia were retransplanted with bone marrow from the same HLA compatible sibling donors after subtotal body irradiation (800 r). Only minor non hematologic toxicity was observed. No permanent take was seen in relation to this procedure. During the survival time of the patients (78-120 days) no signs of interstitial pneumonia were observed.

Coronary heart disease--a possible risk in megavoltage therapy?

A 21-year old man died of an extensive anteroseptal myocardial infarction 16 months after receiving megavoltage radiotherapy to a mantle field for Hodgkin's disease stage PS IA confined to the midcervical lymph nodes on the left side of the neck. Post mortem findings revealed severe atherosclerotic changes in the coronary arteries. This case and a review of the literature suggest that irradiation to the heart may induce or accelerate atherosclerosis of the epicardial vessels. This should be taken into consideration when starting prophylactic irradiation to the mantle field in patients with Hodgkin's disease stage IA without obvious involvement of the mediastinun. Histologic examination of the heart and coronary vessels should be performed in any fatal case after megavoltage therapy involving the heart.