Prognosis of patients treated for intracranial metastases with whole-brain irradiation.

Seventy-five patients with brain metastases from solid tumours were treated with whole-brain irradiation at our institution between 1990 and 1993. The primary cancers included 35 cases of lung cancer, 19 cases of breast cancer, nine cases of renal-cell cancer, six cases of melanoma and six cases of other primary sites. In each case the total dose to the whole brain was at least 25 gray (Gy). The primary site, age, performance status, number of brain metastases and the presence of extracranial disease were studied as prognostic factors for survival. The median survival for the whole population was 4 months (range 1-62 months). The patients with the brain as the only metastatic site had significantly better survival (P = 0.019) than those with both intracranial and extracranial metastatic sites. Poor performance status at the time of diagnosis of brain metastases was also related to short survival (P = 0.001). None of the other studied variables had prognostic significance. Four of the 75 patients with primary tumour sites in the breast (two patients) and the kidney (two patients) survived for more than 2 years. In general, patients with breast cancer had better survival than patients with other primary cancers. Our study confirms the generally poor prognosis of cancer with brain metastases, although individual patients may survive several years after whole-brain irradiation. Approximately two-thirds of the patients experienced a relief in symptoms allowing a reduction in the dose of corticosteroid medication, which clearly supports the use of whole-brain radiotherapy as a palliative treatment.

Quality of life after radiation therapy of cerebral low-grade gliomas of the adult: results of a randomised phase III trial on dose response (EORTC trial 22844). EORTC Radiotherapy Co-operative Group.

In 1985, the EORTC Radiotherapy Co-operative Group launched a randomised phase III study comparing high-dose (59.4 Gy in 6.5 weeks) versus low-dose (45 Gy in 5 weeks) radiotherapy with conventional techniques in patients diagnosed with low-grade cerebral glioma. The primary endpoint of the study was survival. No difference in survival was observed between the two treatment strategies. A quality of life (QoL) questionnaire consisting of 47 items assessing a range of physical, psychological, social, and symptom domains was included in the trial to measure the impact of treatment over time. Patients who received high-dose radiotherapy tended to report lower levels of functioning and more symptom burden following completion of radiotherapy. These group differences were statistically significant for fatigue/malaise and insomnia immediately after radiotherapy and in leisure time and emotional functioning at 7-15 months after randomisation. These findings suggest that for conventional radiotherapy for low-grade cerebral glioma, a schedule of 45 Gy in 5 weeks not only saves valuable resources, but also spares patients a prolonged treatment at no loss of clinical efficacy.

Tumor endothelium selectively supports binding of IL-2-propagated tumor-infiltrating lymphocytes.

Entrance of activated T cells into the tumor after adoptive transfer is a prerequisite for the efficacy of this form of immunotherapy. Because lymphocyte binding to vascular endothelium is the critical step in which lymphocyte extravasation into the tissue is controlled, we compared adhesion of tumor-infiltrating lymphocytes (TIL) to endothelial cells in tumors, peripheral lymph nodes, mucosa-associated lymphatic tissues, and inflamed synovium. Simultaneously, expression of the known homing-associated Ags both on TIL and tumor vasculature was analyzed. All TIL strongly expressed alpha 4-integrins, LFA-1 and CD44, whereas only a low level of L-selectin expression was detected. Tumor vasculature showed signs of activation in each patient on the basis of elevated levels of intercellular adhesion molecule-1, E-selectin, vascular cell adhesion molecule-1, and/or peripheral lymph node addressin (PNAd). TIL showed significantly enhanced binding to tumor vasculature in comparison with other endothelial specificities. Increased binding was not markedly due to up-regulation of the inflammation-induced endothelial cell adhesion molecules in tumors, because binding to inflamed synovium that expressed the same adhesion molecules was not enhanced. In summary, TIL show preferential binding to tumor vasculature and the binding is partially mediated by currently unknown mechanisms. In vitro analysis of endothelial cell binding properties may help to identify those TIL populations that will have the best potential to home back to tumor tissue after adoptive transfer.

Imaging of head and neck tumors with positron emission tomography and [11C]methionine.

PURPOSE: To evaluate the value of positron emission tomography and [11C]methionine in imaging of malignant tumors of the head and neck region. METHODS AND MATERIALS: Forty-seven tumors of the head and neck were investigated with 11C-labeled methionine and positron emission tomography before treatment. Because of the resolution limits of the positron emission tomography scanner, all tumors selected for the study were larger than 1 cm in diameter. RESULTS: Forty-two (91%) of the 46 malignant tumors were clearly visible in the positron emission tomography image (squamous cell carcinoma, n = 26; lymphoma, n = 9; adenocystic carcinoma, n = 2; lymphoepithelioma, n = 1; adenocarcinoma, n = 1; transitional cell carcinoma, n = 1; esthesioneuroblastoma, n = 1; plasmocytoma, n = 1), while three (7%) squamous cell carcinomas were visible, but less easy to detect due to physiological accumulation of the tracer in the area under observation. Only one (2%) squamous cell carcinoma could not be delineated from the positron emission tomography image, and there was no uptake of [11C]methionine in a benign pleomorphic adenoma. No correlation was found between the uptake of [11C]methionine and the histological grade in the subset of squamous cell carcinoma (n = 30). High physiological uptake of [11C]methionine was observed in the salivary glands and the bone marrow. CONCLUSIONS: Malignant head and neck tumors can be effectively imaged with positron emission tomography using [11C]methionine as the tracer.

Few surgical complications after 5,000 to 6,500 cGy pre-operative irradiation for carcinoma of the tongue.

Twenty-four patients with squamous cell carcinoma of the tongue were treated with 5,000 cGy to 6,500 cGy pre-operative irradiation. Surgery usually consisted of resection of the tongue, possibly the floor of mouth, and modified or radical neck dissection. Musculocutaneous flaps for reconstruction were used in three cases and a forearm flap in one case. Despite the high radiation dose, no major difficulties were encountered at surgery or during the convalescence period, except for one osteoradionecrosis of the mandible, which was successfully treated by microvascular osteomyocutaneous grafting. Residual carcinoma was seen on histological examination of the excised tissue in 9 out of 18 (50 per cent) patients who received > or = 6,000 cGy, and in 4 out of 6 (67 per cent) patients who received about 5,000 cGy tumour dose. The 2-year crude survival rate was 65 per cent. The data suggest that high dose pre-operative irradiation is feasible and does not compromise surgical treatment.

Interferon combined with irradiation in the treatment of operable head and neck carcinoma. A pilot study.

Twenty-two patients with operable head and neck cancer were randomized to receive natural leukocyte alpha interferon (IFN) and radiotherapy, or radiotherapy alone (control) before operation. IFN was administered at 6 MU i.m. daily for 4 weeks and thereafter 3 times per week for 2 months. IFN treatment was introduced simultaneously with radiotherapy (2 Gy daily, 5 fractions per week). The preoperative dose was 30-32 Gy. Tumor response and side-effects were registered. The patients underwent radical surgery 3 weeks after the preoperative irradiation, followed by postoperative irradiation with 22-32 Gy. After preoperative treatment there were one complete response and 4 partial responses among 10 patients receiving IFN and 2 partial responses among 12 patients treated with irradiation alone. No difference in survival was demonstrated between the 2 groups. In the histologic examination of the surgical samples malignant cells were found in 6 of the IFN patients and in 8 of the control patients. The IFN patients had considerably more pronounced mucosal radiation reactions than the controls. The accrual of patients to the study was discontinued due to the side-effects.

Resources and productivity in radiation oncology in Denmark, Finland, Iceland, Norway and Sweden during 1987.

Data concerning megavoltage equipment and use of megavoltage external beams in cancer management during 1987 in Denmark, Finland, Iceland, Norway, and Sweden were collected from all 37 centres serving a population of 23 million in these countries. Population per Linear Accelerator Equivalent (LAE) unit ranged from 0.30 million/LAE unit (Denmark) to 0.19 million/LAE unit (Sweden). The number of field treatments were 227,548 (Denmark), 259,917 (Finland), 10,426 (Iceland), 147,960 (Norway) and 490,126 (Sweden). The number of field treatments per million population per year ranged from 35,229 (Norway) to 58,438 (Sweden). The number of field treatments per LAE unit/year ranged from 13,192 (Denmark) to 9,546 (Norway). The fraction of cancer patients receiving megavoltage radiotherapy in 1987 out of all newly diagnosed cancer patients during 1987 was 24% in Denmark, 37% in Iceland, 25% in Norway, and 34% in Finland and Sweden. We conclude that Denmark and Norway probably did not provide adequate levels of radiotherapy for their cancer patients during 1987.

Recombinant interferon-alpha 2a and vinblastine in advanced renal cell cancer: a clinical phase I-II study.

Twenty patients with metastatic renal cell cancer were treated with a combination of recombinant interferon-alpha 2a (Roferon-A), 18 MU intramuscularly three times weekly and vinblastine 0.1 mg/kg intravenously once every 3 weeks. Three patients experienced a complete response (CR) (15%) and three a partial response (PR) (15%). The response duration was 3, 13, and 15 months in the CR group, and PRs lasted 11, 13, and 14 months. Constitutional symptoms like fever, anorexia, and fatigue were the most common side effects. One patient had reversible hepatitis, which was probably unrelated to antineoplastic therapy. Dose modifications had to be made in seven patients due to leukopenia or thrombocytopenia. No very serious side effects were noticed. In view of what has been reported previously, the overall response rate (30%) of this regimen is good and tolerance of the treatment is acceptable.

Treatment of advanced breast cancer with 20 mg toremifene, a phase II study. Preliminary communication.

Fourteen postmenopausal women with estrogen-receptor positive advanced breast cancer and no prior cytostatic treatment received 20 mg toremifene daily as a single dose after a loading dose (120----60----60 mg) for the first 3 days. All were evaluable and had undergone at least 6 weeks' treatment. Results were: no complete remissions (CR), 3 partial remissions (PR), 8 no change (NC) and 3 cases of progressive disease (PD). Three patients had mild side effects: nausea, insomnia, sweating and arm pain.

Safety and efficacy of toremifene in breast cancer patients. A phase II study.

46 postmenopausal women with estrogen receptor positive breast cancer entered a phase II study with a novel antiestrogen, toremifene. Patients had either recurrent or primarily inoperable advanced disease. No prior or concurrent cytostatic or hormonal treatment was allowed. Eight patients (17%) achieved complete response (CR), 17 (37%) partial response (PR) and 13 (28%) had stabilization of their disease at least for three months. The mean durations of responses were 52 +, 53 + and 27 + weeks, respectively, with 5 patients in CR, 6 in PR and 1 with no change (NC) still continuing the treatment. No significant differences could be seen in response rates according to the concentration of estrogen receptors or presence of progesteron receptors in this group of patients. Toxicity was not a problem, in general, the treatment was well tolerated. Two side effects (sweating and vertigo) were classified as severe and one patient after achieving PR interrupted the treatment because of tremor.

Radiation-induced morphological changes and radiocurability in squamous cell carcinoma of the head and neck region. A preliminary report.

Tissue samples taken from 22 patients before and during radical irradiation of squamous cell carcinomas in the head and neck region were studied by light and electron microscopy. The changes in keratinization pattern at the ultrastructural level seemed to be correlated with the outcome of the radiotherapy. The irradiation induced several cellular changes, of which nuclear atypia was the most prominent. This atypia was considered to be mainly due to cell death rather than to an aggressive nature of the tumor, because the number of mitoses decreased at the same time. The tumor invasion pattern remained unchanged. The keratinization pattern remained almost unchanged at the light microscopical level, but a slight increase of intracellular filaments and desmosomes was found in the electron microscopic study. The amount of intercellular filaments increased in three patients out of four with complete remission (CR), but in no case with tumor dissemination (n = 3) during radiotherapy. In patients with local persistent tumor or a local recurrence (LP + LR) (n = 15) the filaments either increased, decreased or remained unchanged. The number of desmosomes either increased or remained unchanged in three of four CR patients, in 13 of 15 LP + LR patients and in only one of three patients with tumor dissemination. They decreased in two patients with tumor dissemination, but only in one case with CR and in 2 cases with LP + LR. It is suggested that changes in cytoskeleton and desmosomes might be important in anchorage of tumor cells locally and might have value for prediction of the tumor response to radiotherapy. Further studies on larger materials are, however, needed before more definite conclusions can be drawn.

Is it possible to predict the outcome of radiation therapy of head and neck cancer?

Methods for predicting the outcome of radiation treatment are discussed. The correlation of tumour decrease during irradiation with recurrence-free survival is poor. A reliable method for predicting the long-term result of radiation therapy is urgently needed. Methods using flow cytometry, electron microscopy and positron emission tomography with short-lived radiopharmaceuticals are under investigation.

Vincristine, doxorubicin and cyclophosphamide with and without etoposide in limited small cell lung cancer.

A total of 80 patients with limited disease of small cell lung cancer were randomized to receive either vincristine 1 mg/m2 (max. 2 mg), doxorubicin 50 mg/m2 and cyclophosphamide 750 mg/m2 (VAC) i.v. on day 1, or the same drugs and etoposide 80 mg/m2 i.v. daily for 3 days (VACE) every 3 weeks for nine courses. Chest irradiation was given in both regimens after the second course. The response rate was 84% for VAC (41% complete responses) and 75% for VACE (46% complete responses). The median survival time was 10 months with VAC regimen, and 14 months with VACE (difference statistically not significant). The median duration of remission was 8 months with VAC and 14 months with VACE (p = 0.03), and the median survival for complete or partial responders was 12 months and 20 months respectively (p = 0.006). Myelosuppression was significantly greater in the VACE group, and there was one treatment related death in the group receiving VACE. In this study the addition of etoposide to VAC improved the duration of response, but did not lead to longer survival of patients with limited disease of small cell lung cancer.

Ultrastructural effects of irradiation on squamous cell carcinoma of the head and neck.

Tissue samples taken before and during the radical irradiation of the squamous cell carcinoma of the head and neck region were studied by light and electron microscopic examination. Radiation-induced cellular changes of which nuclear atypia was most pronounced. The tumor invasion pattern remained unchanged but the number of mitoses decreased. The lymphocytic infiltration increased at the beginning of the therapy (from 10-30 Gy) but decreased at the end of radiotherapy. The amount of neutrofils and the keratinization pattern remained almost unchanged at the light microscopic level, but intracellular filaments and desmosomes slightly increased in electron microscopic study. The changes in nuclear morphologic features pointing in a more undifferentiated direction are considered to be due to cell damage rather than to the more aggressive behavior of the tumor cells. This is in agreement with the decrease of mitoses which is due to radiation-induced arrest of tumor cells to the G2 phase. These changes might be related to the disappearance of tumors during irradiation. The leukocyte compartment seen in the samples might take part in the destruction of the tumor cells and in the removal of the cell debris.

Radiation-induced changes of fibroblasts in the squamous cell carcinoma of the head and neck.

The regrowth of mesenchymal tissue (stroma) surrounding the malignant epithelium is an important step in tissue remodelling during and after irradiation. The radiation-induced fibroblastic changes were studied on tissue samples taken before, during and after the radical irradiation of the squamous cell carcinoma of the head and neck. Elongated fibroblasts with large amount of rough endoplasmic reticulum were seen around the tumor epithelium before radiation. The fibrosis increased during irradiation and at the same time the shape of the fibroblasts changed so that they became more triangular and nuclear structures became more prominent together with hyperchromasia. The amount of cell organelles declined although there was a large amount collagen present. Epithelial cells invaded through the basal lamina. In most samples the basal lamina could not be seen at all and the tumor cells were dispersed between stromal elements. On the other hand there were close contacts between epithelial and mesenchymal cells throughout the study in places where the basal lamina was broken, which might indicate epithelio-mesenchymal interaction. Also the connective tissue formed by fibroblasts and collagen might be part of the radiation induced healing and destruction of the tumor cells.

Combined interferon and vinblastine treatment of advanced melanoma: evaluation of the treatment results and the effects of the treatment on immunological functions.

Thirteen patients with metastatic malignant melanoma received interferon alpha-2a (Roferon-A) and vinblastine. The interferon dosage was increased from 3 x 10(6) IU to 9 x 10(6) IU daily in 10 weeks and thereafter 9 x 10(6) IU was administered three times weekly intramuscularly. Vinblastine (0.075-0.15 mg/kg) was given every third week intravenously. One of the ten evaluable patients had partial remission (PR) (11%) for 10 months. The diseases was stabilized (NC) in three patients (30%) for 3, 6 and 9 months. Progression (PD) occurred in six patients. The treatment time varied from 5 weeks to 44 weeks. The median survival time from the beginning of this combination treatment was 5 months. The most common side-effects were fever, fatigue, loss of taste, weight loss and neutropenia. The mitogen response to phytohemagglutinin and purified protein derivative of tuberculin decreased in all patients. The response to concanavalin A decreased less and began to increase again in the patients with PR and NC. The natural killer cell activity in PD patients decreased more than in the patients with PR and NC. The ratio of T4/T8-positive cells was restored in PR + NC patients but rose in PD patients indicating a difference in the immunomodulatory effect of the combination or of the advanced disease itself on T-cell function in PD patients. This combination of daily interferon and vinblastine did not prove to be effective in melanoma. The depression of immunological functions, which was more marked in patients with PD, might indicate that vinblastine in this combination counteracts the immunostimulatory effect of interferon.

A flow cytometric analysis of 23 carcinoid tumors.

Twenty-three carcinoid tumors were investigated from paraffin-embedded tissue with flow cytometry (FCM) in order to correlate the DNA ploidy with clinical variables. DNA aneuploidy was found in ten tumors (45%) and one tumor was classified as tetraploid. Diurnal urinary excretion of 5-hydroxy indolic acetic acid (5-HIAA) was known to be elevated in seven of eight diploid tumors and in four of seven aneuploid carcinoids with distant metastases. Six (55%) of the diploid tumors had not given rise to metastases at the time of diagnosis, compared with three (30%) of the aneuploid tumors. Six of seven patients with an aneuploid tumor and three of five patients with a diploid tumor, observed for at least 10 years, died of the disease. It was concluded that, unlike in earlier studies with static DNA cytometry, DNA aneuploidy is common in human carcinoid tumors and may occur in tumors secreting biogenic amines.