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Strategies (both prophylactic and therapeutic) to reduce side effects of chemotherapy are reviewed. In particular, issues concerning proper patient information are discussed which should help to increase patient compliance. Chemotherapy, especially regimens with a curative intent, must normally be administered under the guidance of an oncologist. However, close cooperation with the general practitioner is essential in order to ensure high quality counselling and treatment of the outpatient.

Tumor markers can be used for screening, diagnosis, planning and monitoring of therapy, for early detection of relapse and for psychological reasons. Unfortunately none of the currently available tumor markers can be used for all these purposes. An ever increasing number of tumor markers can be determined; however, the advantage for the individual patient's management is less obvious. We therefore critically review the routine use of some tumor markers such as CEA, AFP, beta-HCG, LDH, CA-125, CA 19-9, prostate acid phosphatase, prostate specific antigen and CA 15-3. The use of tumor markers requires a sound knowledge of the biology of the marker, the neoplastic disease and the available treatment. When tumor markers do not add new information and have no diagnostic or therapeutic consequences, their use becomes an expensive medical nonsense!

This article outlines the historical development of anti-emetic therapies and reviews the pathophysiology and clinical aspects of cytostatic drug-induced vomiting. The methodology and the factors affecting the results of clinical trials with anti-emetics are discussed. Advances in knowledge of the role of 5-hydroxytryptamine in cytostatic drug-induced vomiting have improved current anti-emetic therapy with the development of 5-HT3 receptor antagonists such as granisetron. Early trials show granisetron to be a very effective anti-emetic and suggest useful advantages over the regimens currently considered to be standard therapy for prophylaxis and treatment of cytostatic drug-induced emesis.

O6-Alkylguanine-DNA alkyltransferase (ATase) activity and host cell reactivation (HCR) of 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC)-methylated viruses were compared in human melanoma cell lines that were sensitive or resistant to killing by the antitumor DNA-methylating agent MTIC. Enhanced HCR of adenovirus 5 (defined as the Mer+ phenotype) generally showed a semiquantitative correlation with the natural or induced resistance of the host cells to the toxic effects of MTIC and to the level of ATase activity. However, one MTIC-resistant cell line was found (MM170) which had a low level of ATase and intermediate HCR of adenovirus. The HCR of herpes simplex virus type 1 (HSV-1) was enhanced in the Mer+ cells that had natural resistance to MTIC compared with Mer- cells. On the other hand, HCR of HSV-1 in Mer+ cells with induced resistance to MTIC was similar to that in Mer- cells. Neither adenovirus 5 nor HSV-1 infection induced ATase activity in Mer- cells. This indicates that resistance to the toxic effects of methylating agents is not invariably associated with high levels of ATase activity in human melanoma cells. Furthermore, while induction of the Mer+ phenotype from Mer- cells was usually accompanied by the recovery of ATase activity, induced Mer+ cells had less proficient repair than natural Mer+ cells, as judged quantitatively by slightly lower cellular resistance and qualitatively by deficient HCR response for HSV-1. These results suggest that the Mer- and induced Mer+ cells lack an ATase-independent DNA repair mechanism. No differences in MTIC-induced DNA repair synthesis or strand breaks were found between the Mer-, natural Mer+, and induced Mer+ phenotypes. However, UV-induced DNA repair synthesis was higher in the natural Mer+ than in the Mer- or induced Mer+ cells, both of which had increased cellular sensitivity to the antimetabolites methotrexate and hydroxyurea. These differences may be related to the effects observed with MTIC. A wide range of ATase activities was found in human melanoma biopsy material.

Immunoscintigraphy was performed in 25 patients with malignant melanoma using a 99mTc labelled monoclonal antibody (225.28S). In four cases, imaging was repeated following treatment with recombinant gamma interferon. In 11 cases, tissue samples of metastatic lesions were investigated for the expression of melanoma associated antigens by immunohistochemical techniques. Overall, 59% of known lesions were detected by imaging. The highest rates of detection were in bone, liver and lymph nodes and the lowest in lung, stomach and bowel. Six lesions were detected which had not shown up on routine clinical and radiological examination. There was no evidence of enhanced or induced HMW-MAA expression following interferon treatment. This technique has been found to be useful in staging patients and has been free from side effects.

21 patients with hematological neoplasias (8 ALL, 4 AML, 4 NHL, 5 HD) were treated with high dose therapy and autologous bone marrow rescue (ABMT). At the time of ABMT 12 patients were in CR, 6 in PR and 3 in relapse. 66% of the patients were at high risk at the time of diagnosis. Before ABMT patients received an ablative regimen such as cyclophosphamide or ARA-C, VP-16, DNR and 12 Gy TBI in 6 fractions. In 9 patients the bone marrow was treated in vitro with monoclonal antibodies and complement. The hospital stay was a median 33 (24-57) days and isolation 19 (9-49) days. Complications were septicemia (7), herpes stomatitis (7), infections (6), fungal sepsis (1) and hemorrhagic cystitis (2). Late complications (up to 6 months after ABMT) were pneumococcal sepsis (1), cerebral toxoplasmosis (1) and herpes zoster (3). 10 of 19 evaluable patients are alive and relapse-free 1-33 months (median 10) after ABTM, and 3 of 10 more than 2 years later: 4 of 5 were transplanted in 1. CR, 4 of 6 in greater than or equal to 2. CR and 2 of 8 in PR. 4 patients are living in therapy sensitive relapse 2, 11, 11 and 39 months after ABMT in 2. CR or PR. 5 patients died 1-13 (median 3.5) months on relapse, 2 of 21 from septicemia. The morbidity of ABMT is comparable with conventional high dose chemotherapy. Relapse-free survival was significantly influenced by the remission status at ABMT. Long-term survivors can be expected even in patients with high risk hematological malignancies. However, only wider trials will serve to establish the efficacy of ABMT.

Kaposi's sarcoma is now the second most common AIDS-associated disease, Pneumocystis carinii pneumonia being the commonest. The clinical and radiological picture of bronchopulmonary Kaposi's sarcoma is often indistinguishable from that of nonspecific interstitial pneumonitis. Diagnosis of the sarcoma in the airways, and especially in the lung parenchyma, is difficult. The case of a patient with AIDS and bronchopulmonary Kaposi's sarcoma is presented and the diagnostic, therapeutic and prognostic problems are discussed.

In 38 patients with malignant melanoma 44 radioimmunoscintigraphies (RIS) with 99mTc labeled F(ab')2 fragments of an anti-melanoma monoclonal antibody (225.28S, Tecnemab-K, Sorin Biomedica) have been performed. No side effects have been observed even in the patients with repeated RIS. Overall 81% (35/43) of all lesions were detected by imaging and 9 lesions have been previously unknown. Sensitivity and specificity was highest for lymphnode metastases with 100% each. Poor imaging was observed in lung and mediastinal metastases (2/7) as well as small skin metastases. RIS has to be studied for its clinical value in staging of lymphnode metastases preoperatively in patients undergoing regional lymphnode dissection.

20 patients with advanced non-small cell lung cancer were treated with ifosfamide and mesna 1.5 g/m2 daily for 5 days; 10 received the drug by mouth and 10 i.v. Both schedules resulted in a reduction in the elimination half-life with an increased total and nonrenal clearance of ifosfamide over the 5-day period. Oral administration resulted in an unacceptably high incidence of encephalopathy(5/10) which was not seen in the i.v. group. In two patients this encephalopathy manifested itself as coma which lasted for 24 to 48 h but was fully reversible and in the other three cases as somnolence occurring for more than 50% of the patients' waking hours. Nadir blood counts and response rates were similar in both arms. The encephalopathy suggests that there are metabolic differences between the i.v. and oral routes and that a metabolite rather than the parent drug is responsible for this syndrome. In addition it was shown that the total and nonrenal clearance of the drug was significantly less when the drug was administered orally. None of the pharmacokinetic parameters either singly or in combination predicted for ifosfamide toxicity. No correlation between the creatinine clearance and ifosfamide renal clearance was demonstrated suggesting tubular reabsorption of the drug. In conclusion, ifosfamide cannot be given orally at the conventionally employed i.v. doses.

Epidermal growth factor receptor (EGF-R) expression was assessed in 63 lung tumour samples with a monoclonal antibody (EGF-R1) by indirect immunoperoxidase staining on cryostat sections. All 15 small cell lung cancer samples were negative whereas over 80% of the 48 non small lung cancer stained positively. In 30 bronchial biopsies two monoclonal antibodies against the cytoplasmic part of the EGF-R were evaluated. These antibodies showed weaker staining than EGF-R1. No additional or enhanced staining as compared with EGF-R1 was observed, suggesting a lack of enhanced expression of a truncated EGF-R analogous to the v-erb-B oncogene product. Monoclonal antibodies against the EGF-R may be helpful diagnostically in differentiating small cell from non small cell lung cancer and may also be important in elucidating biological differences in primary lung cancer.

The pharmacokinetics of ifosfamide (I) were determined in ten patients with bronchogenic carcinoma. In seven patients, doses of 1 and 2 g (I) were given both as a bolus orally and later intravenously and were well tolerated. A further three patients received 5 g (I) as a single oral dose but in two this produced reversible CNS toxicity and severe vomiting. The area under the curve (AUC, microgram . h . l-1) for the 1-g dose was the same following oral and i.v. treatment and this was also true for the 2-g doses. There was a proportionate increase in the AUC for the 5-g oral dose, indicating 100% bioavailability at all three dose levels. We conclude that doses up to 2 g by mouth represent a well-tolerated alternative route of administration.

For the first time in a clinical study oral Ifosfamide was used: 65 elderly or unfit patients with small cell lung cancer (SCLC) were treated as outpatients with fractionated oral Ifosfamide and Etoposide. Forty patients (62%) had extensive stage (ED) disease. The median age of the patients was 66 years. In the 60 patients evaluable for response the objective response rate was 90% with a complete response (CR) rate of 32% and a partial response (PR) rate of 58%. The overall median survival of all 65 patients was 11 months (13 months for LD, 9.5 months for ED). In those patients with LD achieving a CR or a PR radiotherapy was given to the mediastinum. No prophylactic cranial irradiation was given. There was a rapid improvement in the responding patients' performance status and symptoms generally with the first treatment cycle. Overall haematological toxicity was mild, with intravenous antibiotics only being required in 4% of the courses and with only one treatment-related death from septicaemia. A higher than expected rate of CNS toxicity was seen (30%). This was generally mild and always fully reversible and consisted mainly of forgetfulness, occasionally hallucinations, nightmares and somnolence. In only one case did encephalopathy necessitate early termination of treatment. This raises the question of whether Ifosfamide metabolism differs quantitatively or qualitatively when given by the oral route as opposed to the usual intravenous route. We conclude that this simple outpatient based treatment gives a high response rate with rapid improvement in symptoms.

Neurotoxicity is of increasing importance in the treatment of cancer patients. Since the dose-limiting hematological toxicity of most cytostatic drugs can now be overcome by modern supportive therapy, high-dose chemotherapy with curative intent can be used more often. Non-hematological toxicities such as neurotoxicity will therefore become dose-limiting with greater frequency, and to avoid disabling neurological side effects of chemotherapy the drug-induced neurological disturbances must be recognized before irreversible damage has occurred. The neurological side effects of the cytostatic drugs are reviewed.

In 407 patients with small-cell lung cancer (SCLC), 61 pretreatment variables were evaluated in a Cox multiple regression analysis to assess their prognostic value. All patients received short-term intensive regimens (cyclophosphamide, etoposide and methotrexate or ifosfamide and etoposide, both followed by thoracic irradiation if complete response was noted). Lactate dehydrogenase (p = 0.001), tumour stage (p = 0.0001), serum sodium (p = 0.0009), pretreatment Karnofsky performance score (p = 0.0121), alkaline phosphatase (p = 0.0186) and serum bicarbonate (p = 0.0321) were the important prognostic factors. Once these variables were taken into account no other variable provided additional prognostic information. A simple scoring system ("Manchester Score") using these variables was established and shows little loss of information compared to the Cox analysis. The score distinguishes 3 prognostic groups, the best of which contains all long-term survivors, whereas the bad prognostic group contains no patient surviving longer than one year. The scoring system may help to design new treatment strategies and may also facilitate the comparison of different studies.

IFN-gamma is an effective inducer of MHC class II antigen expression in cell lines of malignant melanoma. To investigate the possibility that IFN-gamma may increase MHC class I and II and melanoma tumour associated antigens in vivo, immunohistochemical analyses of biopsies from six patients with metastatic disease undergoing IFN-gamma treatment were performed. Before IFN-gamma treatment, the melanomas were class I positive and class II negative. After treatment, class I expression was neither enhanced nor class II expression induced in any tissue sample regardless of biopsy time or dose of IFN-gamma. TAA was similarly unchanged. However, in one of the six patients a primary cell line was established and IFN-gamma induced expression of MHC products. The possible reasons for lack of MHC induction are discussed, although qualitative changes in antigen expression cannot be excluded on the basis of qualitative immunocytochemical techniques alone.

A high performance liquid chromatography method is described for measuring Ifosfamide (I) in human serum. This involves solvent extraction, reverse phase HPLC and UV detection at 190 nm. Standard curves of peak height x detector sensitivity versus I concentration in serum were linear with a lower limit of detection of 100 ng/ml. Authentic 14C-labelled I cochromatographed with standard I and with I found in serum from treated patients. The concentration-time curves of I determined by both HPLC and gas chromatography were indistinguishable. We conclude that this method is suitable for determining I pharmacokinetics in biological specimens.

The use of chemotherapy will eventually be discussed in most patients with lung cancer, due to the systemic nature of the disease. In small cell lung cancer combination chemotherapy will achieve a response in the majority of patients and will lead to a five-fold increase in median survival. A small proportion of these patients will survive disease-free for a prolonged period of time and may be cured of their disease. In non-small cell lung cancer about one third of all patients will achieve an objective tumor response with the use of cisplatin-based combination chemotherapy. There is a small, but definite increase in median survival with the use of combination chemotherapy compared to best supportive care alone. Also in non-small cell lung cancer a small proportion of patients will survive after combination chemotherapy for a prolonged period of time. The use of cytotoxic treatment in lung cancer is associated with considerable toxicity so that optimal supportive care is mandatory.

The dose-limiting urotoxicity of the oxazaphosphorines (t1/2 = 4-15 h) is due to renal elimination of metabolites such as acrolein. The occurrence of hemorrhagic cystitis can be safely prevented by the concomitant use of i.v. or oral 2-mercaptoethanesulfonate sodium (DCI MESNA; Uromitexane). The bioavailability of oral MESNA is in the range of 20-50% and its unpleasant taste severely limits patient compliance. Due to the short half-life of MESNA (approx. 40 min) a regular fractionated or continuous administration is mandatory. In 6 healthy volunteers we have studied the pharmacokinetics of urinary MESNA elimination for the assessment of MESNA bioavailability after i.v. and s.c. drug administration. MESNA was given at doses of 400 mg for i.v. and s.c. bolus injections and 800 mg for continuous s.c. administration by a portable infusion pump. For the s.c. route an isotonic solution was prepared. The total amount of urinary thiols was assessed by the Ellman method (photometric reading at 412 nm). Total elimination of i.v. MESNA was 83.2 +/- 3.4% of the dose administered. The respective results for s.c. bolus and s.c. continuous drug administration were 81.9 +/- 3.4% and 79.4 +/- 3.6% of the dose. Continuous administration theoretically will provide optimal uroprotection from short term (hemorrhagic cystitis) and long term (bladder fibrosis and cancer) toxicity.

In 71 patients with malignant melanoma 85 radioimmunoscintigraphies (RIS) with 99mTc-radiolabeled F(ab')2 fragments of a murine monoclonal antibody have been performed. The antibody is specific for an epitope of the HMW-MAA glycoprotein complex which is present in 90% of melanoma tissue samples. Sensitivity for RIS was 79% (73 metastatic sites out of a total of 92). 20 previously unknown lesions were found and there were also 2 false positives. Conventional staging procedures alone revealed 78% of the metastatic sites (72 of 92). No side effects were observed. RIS was especially useful for detection of lymph node metastases not found by conventional methods and is therefore considered complementary to conventional preoperative staging procedures.