Tyrosine kinase inhibition in renal cell carcinoma and gastrointestinal stromal tumours: case reports.

BACKGROUND: Sunitinib malate is approved multinationally for the treatment of metastatic renal cell carcinoma (mRCC) and advanced imatinib-refractory gastrointestinal stromal tumour (GIST). Greater exposure to sunitinib is associated with improved efficacy. Therefore, minimising the impact of adverse events (AEs) on patient quality of life is important to enable patients to achieve optimal exposure to sunitinib and maximum clinical benefit. DESIGN: This report describes four patient cases in which sunitinib was utilised for the management of advanced malignancies: two cases describe mRCC patients who received first-line sunitinib and two cases describe the use of targeted therapies, including sunitinib, in patients with advanced GIST. RESULTS: In all four cases, effective AE management enabled patients to receive long-term therapy with sunitinib and achieve sustained clinical benefit. The two mRCC cases show prolonged responses and manageable AEs with sunitinib. The two GIST cases demonstrate that patients with imatinib-refractory GIST with KIT exon 9 mutations, including elderly patients, can achieve sustained responses to sunitinib. CONCLUSIONS: These case studies support the long-term efficacy and safety of sunitinib in the management of mRCC and imatinib-refractory GIST and demonstrate how AE management can be used to optimise patient responses.

Impact of therapy and androgen receptor polymorphism on sperm concentration in men treated for testicular germ cell cancer: a longitudinal study.

BACKGROUND: Testicular cancer (TC) patients have a high survival rate, and the question of post-therapy recovery of sperm production and its dependence on genetic predisposition is of major interest. METHODS: Ejaculates were obtained from 112 TC patients at one or more of the following time points: post-orchidectomy, or 6, 12, 24, 36 and 60 months post-therapy. The lengths of the androgen receptor (AR) function modulating CAG and GGN repeats in leukocyte DNA were also analysed. RESULTS: No significant decrease in sperm concentration was seen in men who received 1-2 cycles of adjuvant chemotherapy (ACT). Radiotherapy (RT) or more than two cycles of chemotherapy (HCT) caused an initial decline in sperm concentration, which returned to pre-treatment levels 2-5 years after therapy. In the HCT group, sperm concentration 12-24 months post-treatment (T(12-24)) was inversely correlated with CAG length (rho = -0.72, P = 0.03). The type of treatment, but not the concentration at T(0), was an independent predictor of sperm concentration at T(6) (P < 0.0005) and T(12-24) (P = 0.004). CONCLUSION: ACT did not induce a significant decline in sperm concentration. After HCT and RT, a significant reduction of sperm concentration was observed, recovering to pre-treatment levels 2-5 years post-treatment. In HCT-treated patients, the AR CAG length influenced the recovery of spermatogenesis.

Palliative radiation with a radiolabeled diphosphonate (rhenium-186 etidronate) in patients with hormone-refractory disseminated prostate carcinoma.

MATERIAL AND METHODS: The present study investigates the safety and efficacy of 2590 MBq rhenium-186 (186Re) etidronate (i.e. twice the activity normally used) administered intravenously in 15 patients with disseminated prostatic carcinoma and bone pain. RESULTS: Pain relief was observed in 11 of 14 evaluable patients (79%), 4 of whom became completely free from pain. Five of the responding patients also noted an improvement in daily activity and two found it possible to reduce or discontinue morphine medication. Pain relief occurred within one week in four patients, and within two weeks in eight of the responding patients. The mean duration of pain relief after the first course of 186Re-etidronate was 6 weeks (range 4-10). The toxicity was mild (< or = grade 2), transient, and restricted to hematological toxicity. CONCLUSIONS: 186Re-etidronate provided rapid pain-relief and had mild toxicity in most patients with disseminated hormone-refractory prostatic carcinoma, but doubling the activity did not markedly improve the efficacy.

Risk-adapted treatment of clinical stage 1 non-seminoma testis cancer.

250 patients with clinical stage 1 non-seminomatous germ cell tumours of the testis (NSGCT 1) were included into a prospective multicentre protocol during 1990-1994 and treated according to three risk strata: patients without tumour cell invasion of vascular structures in the testis (VASC-) and elevated serum AFP levels (AFP+) at orchiectomy were considered low risk (LR) and only observed closely. VASC- and AFP- or VASC+ and AFP+ patients were presumed intermediate risk (IR) and pathologically staged (PS) by retroperitoneal lymph node dissection (RPLND). VASC+ and AFP-patients were regarded as high risk (HR) and received adjuvant chemotherapy (PEB x 3). At a median observation time of 40 (7-68) months, all patients were alive and without evidence of active germ cell cancer. The actuarial relapse rate in the 106 LR patients was 22%, and 70% (14/20) had elevated serum tumour markers at relapse. One of 32 (3%) HR patients relapsed with a resectable retroperitoneal mature teratoma despite adjuvant chemotherapy. Only 14% of the 99 IR patients who underwent RPLND had PS2 disease, and the actuarial relapse rate in 85 PS1 patients was 18%. This multicentre study demonstrated that excellent therapeutic outcome is possible when 18 comparatively small urological and oncological centres follow a strict and formal cancer care programme. The useful prognostic effect of VASC was once again verified. Pathological staging by RPLND in NSGCT1 is, in our opinion, not necessary, with presumed low-risk patients offered surveillance and high-risk patients offered adjuvant chemotherapy.

Familial testicular cancer in Norway and southern Sweden.

Information about occurrence of testicular cancer (TC) in relatives of TC patients has been collected using questionnaires from 797 out of 922 consecutive Norwegian and 178 out of 237 Swedish patients with TC seen at the Norwegian Radium Hospital and the University Hospital Lund in Sweden during 1981-91. Fifty-one Norwegian and five Swedish patients had a relative with confirmed TC. Thus, 51/922 (5.5%) of the Norwegian and 5/237 (2.1%) of the Swedish patients treated during the time interval investigated were considered to have familial TC. Thirty-two of the patients had an affected first-degree relative. Expected numbers of cancers in the relatives were computed from data in the Norwegian and Swedish Cancer Registries. Standardised incidence ratios (SIRs) were taken as observed numbers of TC/expected numbers of TC in the relatives. The SIR for brothers was 10.2 (95% confidence interval 6.22-15.77). SIR for fathers was 4.3 (1.6-9.3) and for sons 5.7 (0.7-23.2). The point estimate for the risk to brothers in the Norwegian part of the sample to develop TC by the age of 60 was 4.1% (95% CI 1.7-6.6%). This study indicates that genetic factors may be of greater importance in TC than previously assumed. Patients with familial testicular cancer had bilateral tumours more often than sporadic cases (9.8% bilaterality in familial vs 2.8% in sporadic cases, P=0.02). For patients with seminoma age of onset was lower in familial than in sporadic cases (32.9 vs 37.6 years, P=0.06). In father-son pairs, there was a statistically significant earlier age of diagnosis in the generation of sons (28.8 years vs 44.9 years, P=0.04). The prevalence of undescended testis (UDT) did not seem to be higher in familial than in sporadic TC (8.2% in familial TC and 13.3% in sporadic cases). This may indicate that different factors are of importance for the development of familial TC and UDT.

Risk of cancer in relatives of testicular cancer patients.

The incidence of cancer at sites other than the testis has been investigated in the families of 797 Norwegian and 178 Swedish patients diagnosed with testicular cancer during 1981-91. In the families of the Norwegian patients, the total number of cancers in the relatives was significantly lower than the expected number derived from national incidence rates [observed number of cancers 250, expected number of cancers 281.92, standardised incidence ratio (SIR) 0.89, 95% confidence interval (CI) 0.78-1.00]. This finding can be accounted for almost entirely by the finding of fewer than expected prostate and gastrointestinal cancers in the parents of cases. The other common cancers were found at slightly lower than or near the expected levels in the relatives. In the Swedish cohort, which accounts for less than 20% of cases, the observed number of cancers was very close to the expected number. Fourteen fathers of cases had prostate cancer compared with 27.57 prostate cancers expected, giving a SIR of 0.51 (P=0.006). Mothers had more lung cancers (ten cases observed, SIR=2.11, P=0.04) and cancers of the endometrium than expected (13 cases observed, SIR=1.73, P=0.09). These findings may be interpreted as support for theories proposing hormonal dysfunction as causing testicular cancer. Fifty-four gastrointestinal cancers were observed in the parents compared with 68.48 expected (SIR=0.78, P=0.082). Furthermore, testicular cancer was not found to be associated with the known dominantly inherited cancer syndromes [Familial breast (-ovarian) cancer, hereditary no-polyposis colon cancer]. However, one patient belonged to a Li-Fraumeni family, raising the possibility that testicular cancer may be an infrequent component of this rare cancer syndrome. This study supports the hypothesis that families of testicular cancer patients are not prone to cancer.

Morbidity of pelvic lymphadenectomy, radical retropubic prostatectomy and external radiotherapy in patients with localised prostatic cancer.

Staging pelvic lymphadenectomy (PLND) was performed in 210 prostatic cancer patients (mean age 67 years, clinical stage T0-T3 M0). A radical retropubic prostatectomy was subsequently performed in 54 men, ten of whom also received postoperative radiotherapy due to positive surgical margins. Ninety-eight patients were treated with external beam radiation alone (70 Gy in 35 fractions) and the remaining 58 received endocrine therapy. The complications of PLND alone (156 patients), consisted of wound infection in eight patients, hematoma or lymphocele in seven, venous thrombosis in three, and cardiac infarction in one patient. Early side-effects of radiotherapy included mild to moderate proctitis and/or cystitis in 57 patients. One year after completion of therapy, 48 of the irradiated men had proctitis, but only six had severe symptoms. Four patients developed radiation cystitis and two urethral stricture. Following prostatectomy (54 patients), two patients died in pulmonary embolism and another one developed a deep venous thrombosis. Hematoma occurred in five patients. Of the 42 surviving patients who did not receive postoperative radiotherapy, eight developed anastomotic strictures and four had severe stress incontinence. Only five were fully potent one year after surgery. Eight of the ten patients receiving radiotherapy after prostatectomy developed side-effects from the intestine and/or the urinary bladder. Two of them became totally incontinent. One developed a severe hemorrhagic cystitis necessitating urinary diversion. All ten were impotent after treatment.

Cyclooxygenase inhibitors - invitro and invivo effects on antitumor alkylating-agents in the emt-6 murine mammary-carcinoma.

The nonsteroidal antiinflammatory drugs that inhibit cyclooxygenase block the formation of prostanoids in vivo. These agents may be useful as modulators of cytotoxic anticancer therapies. EMT-6 mouse mammary carcinoma cells growing in culture were exposed for 1 h or 24 h to eleven different nonsteroidal antiinflammatory agents or acetaminophen. None of these drugs was very cytotoxic. A concentration of 50muM of the nonsteroidal antiinflammatory drugs or acetaminophen was chosen for modulator combination studies with the antitumor alkylating agents CDDP, L-PAM, BCNU and 4-HC in cell culture. Several of the modulators protected the EMT-6 cells from the cytotoxicity of the antitumor alkylating agents; however, diflunisal, sulindac, indomethacin, acetaminophen and in some cases ibuprofen and tolmetin were positive modulators of the antitumor alkylating agents under the cell culture conditions tested. EMT-6 tumor cell survival studies and bone marrow CFU-GM survival studies were carried out with seven of the modulators and various doses of cyclophosphamide. Tolmetin, ibuprofen, sulindac, piroxicam and diflunisal in combination with cyclophosphamide produced increased tumor cell killing compared with cyclophosphamide alone without marked changes in toxicity to the bone marrow derived CFU-GM. In EMT-6 tumor growth delay experiments, none of the six modulators tested affected the growth of the tumors; however, tolmetin, ibuprofen, diflunisal and sulindac increased the tumor growth delay obtained with standard dose-schedules of cyclophosphamide or CDDP. When minocycline, a collagenase inhibitor, was added to treatment regimens including diflunisal or sulindac and either cyclophosphamide, CDDP or L-PAM further increases in tumor growth delay were obtained especially when L-PAM was the cytotoxic therapeutic agent. The number of lung metastases and the percentage lung metastases with diameters >3 mm were reduced by treatment with the modulator combinations alone and further reduced with the addition of the antitumor alkylating agents. These results indicate that agents which inhibit signaling pathways among tumor cells and between tumor cells and normal cells can be useful additions to cytotoxic therapies.

Early clinical stages (CS1, CS1Mk+ and CS2A) of non-seminomatous testis cancer. Value of pre- and post-orchiectomy serum tumor marker information in prediction of retroperitoneal lymph node metastases. Swedish-Norwegian Testicular Cancer Project (SWENOTECA).

During a 5-year period (1981-86) 588 consecutive patients with nonseminatous germ cell tumors of the testis were included into a prospective Swedish-Norwegian multicenter study (SWENOTECA) and clinically staged according to the Royal Marsden system. A total of 370 patients (63%) had early clinical stages (CS) of disease; 295 (50%) had CS1, 32 (5%) had CS1Mk+ (CS1 with pathological serum tumor marker patterns after orchiectomy) and 43 (7%) had CS2A disease. Pathological staging with retroperitoneal lymph node dissection (RPLND) of the retroperitoneum was performed in 345 (93%) of the early CS patients and 128 (37%) had pathological stage 2 (PS2) disease; 27% of the CS1, 100% of the CS1Mk+ and 66% of the CS2A patients. The overall clinical staging accuracy was 75%. All the 40 patients with pathological serum AFP and/or HCG patterns before RPLND had PS2 disease, compared to 81/282 (29%) of patients with normal marker patterns. The PS2 patients with pathological marker patterns had significantly more and larger retroperitoneal metastases than those with normal AFP and HCG values. Elevated pre-orchiectomy AFP level indicated significantly reduced risk of PS2 disease in CS1 patients, but this effect became non-significant if the CS1Mk+ and CS2A cases were included into univariate or multivariate analyses. We suggest that the 'good risk' effect of pre-orchiectomy AFP elevation for CS1 cases may be caused by a selection mechanism during the clinical staging process.

Influence of human leukocyte interferon (HuIFN-alpha/Le/) and cimetidine on the proliferation of cultured melanoma cells in vitro.

We have previously demonstrated the therapeutic efficacy of combined treatment with partially purified leukocyte interferon and cimetidine in patients with metastatic malignant melanoma. To study possible effector mechanisms behind this anti-tumor activity, the antiproliferative effect in vitro on two human melanoma cell lines by the two substances used singly or in combination was investigated. Both cell lines demonstrated a dose-dependent sensitivity to interferon. Over a concentration range of 10(-4) to 10(-7) M cimetidine did not exert an anti-proliferative effect, nor did it enhance the effect of interferon. Only at higher concentrations did cimetidine suppress the growth of one of the lines. These results suggest that the observed clinical effect is not mediated by an augmentation of a direct growth inhibitory effect of interferon by cimetidine.

Immune functions in melanoma patients during treatment with interferon [HuIFN-alpha (Le)] alone or in combination with cimetidine.

While leukocyte interferon was found therapeutically ineffective in a series of 20 patients with metastatic malignant melanoma, subsequent combination treatment with interferon and cimetidine induced 5 complete and 1 partial tumour remissions. Prior to interferon therapy initiation, regressor patients demonstrated a significantly greater ability to mediate antibody-dependent cellular cytotoxicity than progressor patients and also tended to have higher natural killer-cell activity. These differences were more pronounced following in vitro exposure of effector cells to interferon alone or in combination with cimetidine. During therapy the differences decreased to statistically nonsignificant levels. The number of immunoglobulin producing cells and lymphocyte proliferative responses to Con A were found to increase in both patient groups after interferon therapy initiation; but this augmentation vanished gradually upon combined treatment with cimetidine. A gradual decrease of the number of T lymphocytes and granulocytes was also recorded. None of the demonstrated alterations in the activities of circulating lymphocytes appears to be a relevant correlate to the efficacy of combined therapy compared to interferon alone.

Influence in vitro on NK and K cell activities by cimetidine and indomethacin with and without simultaneous exposure to interferon.

The histamine-2 receptor antagonist cimetidine (10(-5)M) and the prostaglandin synthesis inhibitor indomethacin (10(-8)M) augmented natural killer cell activity in the majority of healthy controls and patients with advanced melanoma and in a lower frequency of patients with colorectal carcinoma. Antibody-dependent cellular cytotoxicity was increased in most melanoma patients but in a lower proportion of patients with colorectal cancer. Compared with the effect of interferon the augmentation of NK- and K-cell activities was small in most patients. Cimetidine was also demonstrated to bring about a further increase in the interferon-induced NK activation of peripheral blood mononuclear cells from a majority of healthy donors and patients with melanoma. Furthermore, cimetidine augmented the interferon-induced K-cell activation of peripheral blood mononuclear cells from most patients with melanoma and colorectal cancer.

Recombinant leukocyte A interferon as single agent therapy or in combination with cimetidine in patients with advanced colo-rectal carcinoma. A phase II investigation.

Recombinant leukocyte A interferon used as single agent therapy (7.5 X 10(6) units/m2 three times weekly intramuscularly) showed very limited clinical efficacy in patients with advanced colo-rectal carcinoma. No objective tumour regressions were documented in 15 evaluable patients, although three patients demonstrated a stable disease status after 12 weeks of treatment. Neither were any objective tumour regressions registered in 13 patients during subsequent combined therapy with Recombinant Leukocyte A Interferon and cimetidine (1 000 mg/day orally). Two of the 3 patients maintained their stable disease status. No change in natural killer (NK) cell activity or in antibody dependent cellular cytotoxicity (ADCC) of peripheral blood mononuclear cells was seen during the two treatment periods.

Feasibility of extracorporeal on-line large-scale plasma adsorptions on protein A-sepharose columns in cancer patients.

The feasibility of extracorporeal adsorption of 1.5-3 L plasma on protein A-Sepharose was investigated in six patients with advanced cancer. Anticoagulation with heparin was associated with respiratory distress syndrome in two patients, most likely caused by complement activation as indicated by a transient leukopenia during plasma reinfusion and appearance of C3 degradation products in the extracorporeal circulation. Addition of citrate abolished the respiratory symptoms, C3 degradation, and leukopenia, and no adverse reactions were observed. No objective tumor regression was observed in any of the patients. Three patients progressed during therapy. In one of these, multifocal central tumor necrosis was observed as a possible, although unproven, therapeutic effect. Increased natural killer and/or killer cell activities were recorded in three patients and increased complement-dependent serum cytotoxicity in one patient. The level of circulating immune complexes decreased significantly (18-28%) in three patients studied. It is concluded that extracorporeal plasma adsorption on protein A-Sepharose is feasible when citrate is added to the extracorporeal system, but its therapeutic efficacy is uncertain.

Complete remission in a patient with acute myelogenous leukemia treated with leukocyte alpha-interferon and cimetidine.

A 76-year-old woman with acute myelogenous leukemia with approximately 65% myeloblasts on bone marrow examination was treated daily with a combination of 4 megaU of leukocyte interferon IM and 1,000 mg cimetidine PO. During therapy there was a gradual decrease of bone marrow myeloblasts down to 9% and a normalization of peripheral white blood cells. The treatment was discontinued after 6 weeks because of increasing fatigue and anorexia. The general condition improved greatly during the following weeks and the patient entered complete remission, which has continued for 6 months so far. In the course of therapy there was a gradual appearance of antibodies showing a selective binding capacity to autochthonous leukemic cells with no tendency to increased binding to remission cells. The aim of this report is to stimulate a further evaluation of this form of therapy in additional AML patients whenever this might be justified as an alternative to conventional chemotherapy.

Metastatic malignant melanoma: regression induced by combined treatment with interferon [HuIFN-alpha(Le)] and cimetidine.

With the aim of potentiating the anti-tumour effect of interferon in metastatic malignant melanoma by concomitant inhibition of suppressor T cells, oral cimetidine (histamine-2 receptor antagonist) medication was added to interferon (HuIFN-alpha(Le] therapy in a series of 20 patients. While no objective tumour responses were recorded with interferon treatment alone administered intramuscularly or intratumorally, six patients had objective tumour regressions on subsequent combined therapy. Five out of eight patients with metastases confined to skin and subcutaneous tissue had complete tumour regressions while one patient with skin and lung metastases achieved an extensive partial regression of the skin tumour and a complete roentgenological regression of the lung metastasis. Three additional patients attained a stable disease status for prolonged periods of time. Histopathological examinations confirmed disappearance and/or degeneration of melanoma cells and demonstrated a marked lymphocyte infiltration in tumour sites of the patients with objective tumour regression.

En-bloc irradiation of unresectable bronchogenic carcinomas and their regional lymphatics.

Patients with unresectable or inoperable bronchial carcinoma were treated with en-bloc irradiation of the tumour and the mediastinal lymph nodes to a total target absorbed dose of 40 Gy in 20 fractions. The first 52 patients were treated in one series and the last 45 patients in two series (split-course). Radiation adverse effects were only mild. The two regimens gave the same palliative results. The median survival was the same for the 2 groups (8 months). Most patients died in disseminated disease.

Staging laparotomy with splenectomy in Hodgkin's disease.

The series includes 91 patients with Hodgkin's disease who underwent a staging laparotomy with splenectomy during the years 1971-1976, in 82% of them as part of the initial evaluation before therapy. Positive abdominal lymph nodes were found in 29% of the patients, a positive spleen in 37%, and a positive liver in 10%. Follow-up of patients who lacked abdominal involvement at laparotomy indicate that sampling error was only of marginal importance. Evaluation of the therapeutic implications of the operation indicated that 41% of the patients benefited from the procedure; 31% by changing stage and 10% by changing radiation therapy port. Five patients had minor surgical complications. The mortality rate was nil.