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We reviewed 141 cases of paranasal sinus tumors treated at Karolinska Hospital from 1960 to 1980. Of these tumors, 100 were located in the maxillary sinus, 32 in the ethmoidal sinuses, 8 in both the ethmoidal and maxillary regions, and 1 in the sphenoidal sinus. The male-to-female ratio was 2.1 to 1. Squamous cell carcinoma and adenocarcinoma were the most frequent types of tumors (55% and 13%, respectively). Treatment included surgery, irradiation, or both. The 5-year survival rate was 34% for squamous cell carcinomas and 64% for adenocarcinomas. When compared to a previous material of patients treated at the same hospital from 1940 to 1950, the proportion of poorly differentiated squamous cell carcinomas had increased significantly. The age-adjusted incidence rate decreased from 1.2 to 0.4 for male patients and from 0.7 to 0.3 for female patients between 1960 and 1980. We conclude that the incidence of malignant paranasal sinus tumors has decreased, and that squamous cell tumors now seem to be generally less differentiated than they were 50 years ago.

This synthesis of the literature on radiotherapy for prostate cancer is based on 53 scientific articles, including 4 randomized studies, 3 prospective studies, and 44 retrospective studies. These studies involve 52 005 patients.The literature provides no apparent evidence to motivate radiotherapy, or any treatment, for highly differentiated TO tumors. Some findings suggest that radiotherapy or surgery may be indicated for poorly differentiated tumors. The literature however shows no differences in tumor effects between these two methods for treating TO tumors. Radiotherapy is milder and less mutilating.Conclusions cannot be drawn from the literature concerning whether surgery (radical prostatectomy) or external radiotherapy is preferable for Tl and T2 tumors. Most probably, some patients are more suitable for surgery, others for radiotherapy. More patients are, nevertheless, candidates for radiotherapy.The value of external radiotherapy for T3 tumors is documented.Radiotherapy is valuable as palliative treatment for T4 tumors.Radiotherapy may be valuable as localized, symptom-relieving treatment for generalized prostate cancer. Treatment given via a few high fractions saves patients' time, hospitalization, and resources.Concerning individualized treatment, the differentiation grade is important for the choice of treatment method, mainly in early, but even in late clinical stages. This may involve choosing between radiotherapy and endocrine therapy, or even choosing between radiotherapy and surgery. The value of external radiotherapy increases as the differentiation grade of the tumor decreases. It is essential to treat patients at facilities that have the diagnostic potential to establish the differentiation grade of tumors.The value of postoperative radiotherapy has not yet been demonstrated at any clinical stage of prostate cancer.Treatment results from interstitial brachytherapy alone appear to be clearly inferior to the results from other methods. The value of combining interstitial/external radiotherapy should be studied further.

This synthesis of the literature on radiotherapy for lung cancer is based on 80 scientific articles, including 2 metaanalyses, 29 randomized studies, 19 prospective studies, and 21 retrospective studies. These studies involve 28 172 patients.Basic treatment for limited-stage small cell lung cancer (SCLC), is chemotherapy. Addition of radiotherapy to the primary tumor and mediastinum reduces local recurrence, prolongs long-term survival, and is often indicated.Current, and future, studies can be expected to show successive improvements in results for SCLC by optimizing the combination of radiotherapy and chemotherapy. Should these treatments be given simultaneously or sequentially, and in which order? Which fractionation is best? Probably, no change in resource requirements for radiotherapy will be necessary, with the possible exception of changes in fractionation.Surgery constitutes primary treatment for nonsmall cell lung cancer (NSCLC) stages I and II. Radiotherapy may provide an alternative for patients who are inoperable for medical reasons.The value of radiotherapy following radical surgery for NSCLC remains to be shown. It is not indicated based on current knowledge.For NSCLC stage III, radiotherapy shrinks tumors and prolongs survival at 2 and 3 years. Whether it influences long-term survival after 5 years has not been shown. Considering the side effects of treatment, one must question whether limited improvements in survival motivate routine radiotherapy in these patients.Earlier attempts to add chemotherapy to radiotherapy to improve treatment results of NSCLC have not yielded convincing results. Several studies are currently on-going.Prophylactic cranial irradiation (PCI) greatly reduces the risk for brain metastases from SCLC. However, it has little influence on survival. Many treatment centers give PCI to SCLC patients who have achieved complete remission. This practice may be questioned since PCI is associated with serious complications. PCI is not indicated in patients with NSCLC.In SCLC, where the disease is extensive, only palliative radiotherapy is appropriate.Radiotherapy is an important treatment alternative in special palliative situations involving severe cough, severe bleeding, pain, pulmonary obstructions, and vena cava superior syndrome. In these situations, good results may be achieved with few fractions.

This report addresses the role of radiotherapy for treating solid tumors. It is based on a systematic and critical review of the scientific literature, covering close to 1 700 published studies, involving more than 700 000 patients. The report also compares current practice in radiotherapy with scientific evidence and estimates the cost of radiotherapy. The review of the literature shows there is a fairly solid basis for conclusions about appropriate practices in radiotherapy. There are about 650 studies available which are judged to be of high scientific quality, covering more than half a million patients. This article is a summary of the complete report, which appears as Supplement 6 and 7 of this issue. A third volume, 'Critical Issues in Radiotherapy' is available at SBU.

Abstract:  A group of 96 patients with advanced colorectal carcinoma were treated with the mouse (m) or chimeric (c) (mouse variable regions × human IgG1 constant regions) monoclonal antibody (mAb) 17-1A recognizing the tumour-associated antigen GA733-2. Eighty-two of the 83 patients treated with mmAb17-1A and 69% of the patients given cmAb17-1A (n = 13) developed anti-idiotypic antibodies (ab2). Auto-antibodies binding to tumour cells expressing GA733-2 were found in 7% of the patients. In a further 38 patients (40%) antitumour-cell antibodies, i.e. anti-anti-idiotypic antibodies (ab3), were induced by the mAb17-1A therapy. Patients with detectable ab3 after treatment had significantly higher ab2 levels than those not developing ab3. Addition of granulocyte/macrophage-colony-stimulating factor (GM-CSF) to mmAb17-1A significantly enhanced the induction of ab2 as well as induction of anti-anti-idiotypic antibodies (ab3), compared to mmAb17-1A alone. Patients with a high increase in antitumour-cell antibodies (ab3) induced by the therapy lived significantly longer than patients with no or a low level of induction of ab3 (P = 0.016). The results indicate that induction of an idiotypic network response might be an important effector mechanism in mAb therapy.

Abstract: Twenty-four patients were analyzed for the development of HAMA (human antimouse antibodies) after being treated with repeated doses (200–500 mg) of the mouse monoclonal antibody (MAb) 17-1A. All patients developed anti-17-1A IgG antibodies, and most of them also developed IgM antibodies. In only two patients could immune complexes be demonstrated. Allergic reactions were rare (1.9%). In an extended study, a further 19 patient were analyzed for an idiotypic response. Forty-one out of 43 patients developed antiidiotypic antibodies (ab2), and 20 of these also antianti-idiotypic antibodies (ab3). Ab3+ patients responded significantly better (p=0.01) and survived longer (p<0.001) compared to ab3− patients. In this study, we showed that MAb 17-1A could be repeatedly given on a safe basis. The development of high titers of HAMA did not cause significant clinical problems when further repeated infusions of MAb 17-1A were given. The development of an idiotypic response also indicate that the induction of HAMA might be beneficial and not harmful to the patient.

During the years 1958-1988, 808 522 individuals were registered in the Swedish national population-based cancer register with a total of 933 900 primary malignant tumors. Roughly 11% of the tumors reported to the Swedish Cancer Registry in 1988 were found in persons earlier registered for another primary malignancy. One hundred of the individuals registered with multiple primary malignant tumors were randomly selected for a study of the reliability of reporting of multiple malignancies. Medical records and - when necessary - histopathological slides and other relevant diagnostic material for each malignancy were collected and the diagnoses reevaluated. Three persons had to be excluded; thus 97 cases with 209 reported malignancies were analysed. Of these, 94% of the first, 98% of the second and 79% of the third malignancy were accepted. Twelve of the reported tumors were not accepted as malignant, five were benign or cancer in situ, five were incorrectly reported as new primaries and two were a second incorrect registration of a previously registered malignancy. All 97 persons had at least one malignant tumor, in 90% of the persons all reported diagnoses were accepted and 93% had multiple primary malignancies. The results of this quality control study indicate that suitable data are available in the Swedish Cancer Registry for investigations related to the occurrence of multiple primary malignancies in a large unselected population. The Swedish Cancer Registry, to which all newly diagnosed malignancies by law have to be reported, comprise today close to one million individuals with registered malignancies.

A group of 86 patients with advanced colorectal carcinoma were treated with the mouse (m) (IgG2A) or chimeric (c) monoclonal antibody (mAb) 17-1A. Prior to therapy, no patient had detectable levels of antibodies to mAb17-1A. All mmAb17-1A-treated patients (n=76) developed antibodies against both idiotypic and isotypic determinants. Addition of granulocyte/macrophage-colony-stimulating factor (GM-CSF) to mmAb17-1A significantly enhanced the induction of anti-idiotypic (ab2) as well as anti-isotypic antibodies. Of the mmAb17-1A-treated patients, 16 developed type I allergic reactions. These patients had significantly higher concentrations of anti-(mouse Ig) antibodies than patients without type I reactions. Of these 16 patients, 5 had received mmAb17-1A alone; they constituted 9% of this group (5/56). The remaining 11 patients had been given mmAb17-1A together with GM-CSF, and represented 55% of this treatment group (11/20). The difference was statistically significant (P<0.001). Of 10 patients, 9 (90%) treated with cmAb17-1A and GM-CSF developed ab2. The ab2 concentration in this patient group was significantly lower compared to those treated with mmAb-17A. Anti-(mouse Ig) antibodies caused clinical symptoms requiring therapeutic intervention in fewer than 10% of the patients treated with mmAb17-1A alone. With the addition of GM-CSF, the antibody concentration as well as the frequency of allergic side-effects calling for medical action increased significantly. Significantly more patients with a high ab2 concentration (at least 15µg/ml) 1 month after completion of mAb therapy responded to mAb treatment as compared to those with a low ab2 concentration (P<0.05). Moreover, patients with a high ab2 concentration (at least 15 µg/ml) had a median survival time of 15 months while those with a lower concentration survived for a median time of 9 months (P=0.01).

A therapeutic trial using repeated doses of a mouse monoclonal antibody against the tumor-associated antigen (TAA) CO17-1A in metastatic colorectal carcinomas was carried out. Metastatic lesions sampled by repeated thick needle (1.2 mm) biopsies during therapy were examined immunohistochemically for the presence of various TAAs, mouse IgG, complement, and infiltrating leukocytes. The CO17-1A was consistently expressed in all cases along the basement membrane of tumor glands and could only be demonstrated on cryostat sections whereas the TAAs GICA19-9, GA73-3, and Br55-2 were also visualized in B5-fixed paraffin-embedded biopsies. The CO17-1A and GA73-3 were predominantly present at the basal region in contrast to the GICA 19-9 and Br55-2 which were predominant at the luminal and the apical region of the tumor glands. Antigenic modulation was not seen either after 24–72 h or during prolonged treatment. In all cases the infused mouse IgG was detected, from 24 h after infusion up to 6–8 weeks, mainly along the basal region of tumor glands. In 13/14 posttreatment biopsies, complement factor C3 was found at the same sites as mouse IgG. In 6 out of 9 posttreatment biopsies an increase in mononuclear cells (monocytes, natural killer (NK) cells and/or T cells) was observed. Monocytes were close to the tumor cells whereas NK cells and T cells were predominantly scattered in the stroma.

More than 50% of the patients with large bowel cancer develop disseminated disease and invariably succumb. Adjuvant chemotherapy with 5-FU and levamisole have been shown to be more efficient than 5-FU alone or in combination with cytostatics. The combination of 5-FU, leukovorin and methotrexate induces prolonged survival with a good quality of life in metastatic colorectal cancer (CRC). During the last decade tumor immunotherapy has been an alternative facilitated by isolation and large scale production of cytokines and monoclonal antibodies. The mouse monoclonal antibody (MAb) 17-1A recognizes a tumor-associated antigen (TAA), present in high concentrations on the surface of gastrointestinal tumor cells. Injections of MAb 17-1A in patients with metastatic CRC induced generation of anti-idiotypic (ab2) in 90% and anti-anti-idiotypic (ab3) antibodies in 47% of the treated patients. The development of ab3correlated significantly with survival (mean 80 weeks) while ab3-patients survive only 38 weeks. One of 52 patients treated with MAb 17-1A is a complete remission after 66 months, 3 had minor regression and 6 had a stable disease (19% RR). Based onin vitrofindings showing increased antibody-dependent cellular cytotoxicity (ADCC) by the combination of granulocyte-macrophage colony stimulating factor (GM-CSF) and MAb 17-1A, 16 CRC patients have been treated with subcutaneously injections of GM-CSF for 10 days and intravenous infusions of MAb 17-1A at day 3. Two of 16 are in CR, 1 in MR and 3 in SD (37.5% RR). Minor side-effects were registered. A further development of immunotherapy of CRC might imply vaccination by injection of specific human anti-idiotypic antibodies (ab2) which mimics the nominal antigen, in order to induce a specific immunity.

CO17-1A/GA73-3/EpCam/KSA is a cellular adhesion molecule expressed on the majority of tumor cells in most patients with colorectal carcinoma. One of the first mouse monoclonal antibodies (MAbs) for therapeutic use was produced against this particular tumor associated antigen (MAb17-1A). MAb17-1A has served as a model for the development of antibody therapy. It exerts therapeutic effects through antibody dependent cellular cytotoxicity (ADCC), induction of an idiotypic network cascade and maybe also by complement activation. Addition of cytokines that augment these functions, mainly granulocyte macrophage-cerebrospinal fluid (GM-CSF), seemed to improve the clinical efficacy as well as chemotherapeutic agents (5-Fu). In advanced disease the clinical effect is, however, modest while the most beneficial clinical situation seems to be the adjuvant setting. Twenty years have passed since the EpCam antigen was identified as a target structure for immunotherapy, but still we do not know how to optimally use this target. The antigen might, however, be a rewarding structure to utilize for therapy. Preclinical and clinical trials are ongoing aimed at improving passive and active immunotherapy using CO17-1A/EpCam as a target antigen in colorectal carcinoma.

Granulocyte-macrophage colony-stimulating factor is by far the most widely used hematopoietic growth factor to augment immune responses. At present, the best secured effect is as an adjuvant cytokine for vaccination. Granulocyte-macrophage colony-stimulating factor can be delivered as gene-transduced tumor cells, as plasmid DNA, or as the soluble free granulocyte-macrophage colony-stimulating factor protein. Granulocyte-macrophage colony-stimulating factor must be present at the same site as the vaccine component. Granulocyte-macrophage colony-stimulating factor may also augment the effect of therapeutic monoclonal antibodies by enhancing various effector functions such as antibody-dependent cellular cytotoxicity and amplifying an idiotypic network response (ie, antitumor immunity). It may also be advantageous to combine granulocyte colony-stimulating factor with monoclonal antibodies (neutrophil and monocyte antibody-dependent cellular cytotoxicity) for tumor therapy. However, these growth factors might also induce immune suppression, which may hamper the contemplated effect of the growth factor. It is urgently warranted to better understand these dual effects on the immune system so that we can find optimal uses for the growth factors in various clinical settings.