Patient preference for oral or intravenous chemotherapy: a randomised cross-over trial comparing capecitabine and Nordic fluorouracil/leucovorin in patients with colorectal cancer.

Until recently, fluorouracil (F) and leucovorin (L) had been considered the standard therapy for patients with colorectal cancer. However, several studies have shown that oral therapy with UFT/L or capecitabine is as effective as intravenous (i.v.) therapy and in addition it is claimed that patients prefer oral to i.v. therapy as long as efficacy is not compromised. In a previous crossover study by Borner et al., it was shown that 26 out of 31 patients preferred oral therapy with UFT/L to i.v. FL (Mayo regimen) [Borner M, Schöffski P, de Wit R, et al. Patient preferences and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 2002;38:349-58]. The objective of the present study was to investigate patient preference between i.v. FL and oral capecitabine using the design described by Borner. The Nordic FL schedule is a bolus regimen with efficacy comparable to other i.v. regimens and at the same time a very tolerable and easy administered regimen. We randomised 60 patients with colorectal cancer (53 patients received adjuvant therapy and seven patients received palliative therapy) to start therapy with either oral capecitabine or Nordic bolus FL. After 6 weeks of therapy (two courses of capecitabine or three courses of Nordic FL) patients were crossed over to the other regimen. After having completed 12 weeks of therapy the patients (49 evaluable patients) were asked to choose one of the regimens for a further 12 weeks of therapy. Patients had more side-effect when treated with capecitabine and a total of 30 out of 49 (61%) preferred the Nordic FL regimen and 19 (39%) preferred capecitabine. We conclude that patients prefer the regimen with less toxicity and that it is of minor importance whether the medication is administrated orally at home or i.v. at the hospital.

Dual modulation of UFT with leucovorin and hydroxyurea in metastatic colorectal cancer.

The aim of the study was to investigate the possibility of dual modulation of UFT with leucovorin and hydroxyurea in a phase II trial of metastatic colorectal cancer. A total of 77 patients with measurable disease were included. UFT (300 mg/m2) was given with a fixed dose of 1-leucovorin (22.5 mg daily) and hydroxyurea (0.5 g daily) for 28 days followed by a 7 days' rest period. Treatment continued until progression or unacceptable toxicity. Sixty-three patients were evaluable for response. One patient (1.6%) had a complete remission and 13 (20.6%) a partial response for an overall response rate of 22.2%. The treatment was well tolerated. No significant bone marrow depression occurred. Grade 2 gastrointestinal toxicity was recorded in 28.5% of the patients, and grade 3 in 12.9%. The median time to progression was 6.8 months and the median crude survival was 11 months. In conclusion, hydroxyurea did not appear to increase either the response rate or the toxicity. Phase III trials along the same line cannot be recommended.

Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group.

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.

Clonal dominance between subpopulations of mixed small cell lung cancer xenografts implanted ectopically in nude mice.

Clonal evolution of neoplastic cells during solid tumour growth leads to the emergence of new tumour cell subpopulations with diverging phenotypic characteristics which may alter the behaviour of a malignant disease. Cellular interaction was studied in mixed xenografts in nude mice and during in vitro growth of two sets of small cell lung cancer (SCLC) subpopulations (54A, 54B and NYH, NYH2). The tumour cell lines differed in cellular DNA content enabling flow cytometric DNA analysis (FCM) to be used to monitor changes in the fractional composition of the mixed cell populations. The progeny clone 54B was found to dominate the parent 54A clone when grown as mixed subcutaneous xenografts in nude mice, whereas no dominance was exerted during in vitro growth. The in vivo dominance could not be explained by differences in growth kinetics between the two tumour cell lines, and the interaction was not dependent on 54B being in excess in mixed tumours. The dominance was dependent on close in vivo contact as no remote effect on the growth of 54A was found when the dominating 54B cells were growing in the opposite flank of tumour-bearing mice. Irradiation inactivated 54B cells were unable to exert the dominating effect, indicating that the interaction required viable and proliferating cells. Clonal dominance was not found in mixed NYH-NYH2 tumours indicating that the dominance mechanism(s) may not always be operational between subpopulations in heterogeneous tumours. Recognition of interaction between tumour cell populations may result in a better understanding of the behaviour of heterogeneous human malignancies.

Low-dose chemotherapy delays relapse of a dominated and resistant sub-population in a heterogeneous human SCLC xenograft in nude mice.

We investigated the influence of cellular heterogeneity on the response to low-dose BCNU chemotherapy of an artificially mixed human small-cell lung cancer (SCLC) xenograft in nude mice containing a BCNU-sensitive and dominating sub-population and a BCNU-resistant and undetectable (dominated) sub-population. The cell lines differed in DNA content, making them distinguishable by DNA flow cytometry (FCM). After 3 weeks of tumor growth, the mice were stratified according to tumor size and randomized to 2 different low-dose treatments with BCNU or no treatment. After a further 3 to 4 weeks, a high-dose treatment (LD10) was given to both groups of treated tumors. Changes in the relative proportions of and cell lines in the tumors were measured by FCM on fine-needle tumor aspirates. At the time of low-dose treatment, all the tumors were totally dominated by the sensitive cells. A temporary response was seen after low-dose treatment. After the high-dose treatment, a similar short response was seen. In the non-treated group, the sensitive cells continued to dominate. At the time of tumor regrowth after the low-dose treatment, most of the tumors continued to be dominated by the sensitive population. At the time of progression after the response to the high-dose treatment, the resistant cell line was the predominant population. If compared with a single high-dose BCNU treatment, the response of tumors treated with a low dose was superior, indicating that the presence of a dominating and slower growing sub-population influenced the outcome of the treatment.

Interaction between three subpopulations of Ehrlich carcinoma in mixed solid tumours in nude mice: evidence of contact domination.

Clonal interaction between three subpopulations of Ehrlich carcinoma were studied during growth as mixed solid tumours and as ascites tumours in immune-incompetent nude NMRI mice. The tumour cell lines differed in DNA content as determined by DNA flow cytometry (FCM). Tumour growth was evaluated by tumour growth curves including calculation of tumour volume doubling times, tumour weight on day 14, cell cycle times (per cent labelled mitoses) and cell cycle distributions (FCM). Two subpopulations (E1.15 and E1.95) showed nearly identical growth characteristics during both solid and ascites tumour growth. The third subpopulation (E1.80) grew more slowly. FCM on fine-needle tumour aspirates was used to determine the relative proportions of the cell populations in mixed solid tumours in which E1.95 showed a growth-dominating effect on E1.15. No such effect was demonstrated during single-cell tumour growth in ascitic fluid in which the cells had no intimate contact. Ascitic fluid from E1.95-bearing animals or radiation-killed E1.95 cells had no effect on the growth of E1.15, and no remote effect was seen when the two cell lines were growing in opposite flanks. This indicates that only viable E1.95 cells in close in vivo contact were able to induce growth inhibition of the E1.15 subpopulation. Both the E1.95 and the E1.15 cells dominated the E1.80 cells, but in these cases cell kinetic differences may have played a role as the E1.95 and the E1.15 lines grew faster than the E1.80. The E1.80 cell line had no dominating effect on the E1.15 or E1.95. It is concluded that non-immunologically mediated cellular dominance in heterogeneous tumours may contribute to the evolution of these tumours and may be involved in fundamental tumour biological phenomena.

A dominated and resistant subpopulation causes regrowth after response to 1,3-bis(2-chloroethyl)-1-nitrosourea treatment of a heterogeneous small cell lung cancer xenograft in nude mice.

In order to address the question of the influence of a primarily chemoresistant tumor cell subpopulation on the progression of a heterogeneous tumor after cytotoxic therapy, in vitro established human small cell lung cancer cell lines of a 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-sensitive (592) and a resistant (NYH) tumor were used to produce mixed solid tumors in nude mice. Mixtures of 592/NYH (9:1 and 1:1) were inoculated s.c. After 3-4 weeks of tumor growth, the mice were stratified according to tumor size and randomized to treatment with BCNU 40 mg/kg i.p. (10% of lethal dose) or no treatment. Tumor growth curves were used to calculate the effect of the treatment, and changes in the relative proportions of 592 and NYH in the mixed tumors were monitored by flow cytometric DNA analysis by which the two cell lines were distinguishable due to differences in DNA content. A significant response was demonstrated in the 9:1 mixed tumors in which only 592 cells were detectable at the start of the treatment. The response was short and less pronounced compared with tumors containing only 592. In the regrowing tumors after treatment, only NYH was detected. In untreated 9:1 mixed control tumors, only 592 cells were detectable throughout the entire observation period. It is substantiated that the 592 cells were able to inhibit the growth of the NYH cells completely when grown together in 9:1 mixed tumors. This was not the case in the 1:1 mixed tumors. The 1:1 mixed tumors did not respond to BCNU, although 592 was eradicated. These results indicate that resistant and undetectable (dominated) subpopulations in heterogeneous tumors may be responsible for relapse and that the fractional size and the growth characteristics of the resistant subpopulation may determine the magnitude of the clinical response to cytotoxic treatment.

In vitro and in vivo evaluation of the indoloquinone EO-9 (NSC 382 459) against human small cell carcinoma of the lung.

As the indoloquinone EO-9 has previously shown activity in several tumor model systems it was evaluated against four human small cell lung cancer cell lines by the clonogenic assay. In two cell lines (Nyh and Tol), exponential dose-response curves were achieved with both 1 h and continuous exposure, whereas no cell kill was obtained in the other two cell lines (69 and 592) when tested with 1 h incubation up to 0.25 microgram/ml. When the cells were exposed to drug in vitro, flow cytometric DNA analysis showed perturbations in the cell cycle distribution of the most sensitive cell line (Tol) at a lower EO-9 concentration than in the less sensitive cel line (592). This in vitro predicted difference in EO-9 sensitivity between two of the cell lines (592 and Tol) was confirmed when the cell lines were heterotransplanted to nude mice.

Interactions between three subpopulations of Ehrlich ascites tumor and a P388 murine leukemia in mixed solid tumors in immune competent mice.

Cellular interactions between three subpopulations of Ehrlich ascites tumor and between these and the P388 murine leukemia were studied during growth of solid tumors obtained by mixtures of the cells in immune competent N/D mice. An immunogenic Ehrlich cell line (E1.15) induced an immunologically based growth inhibition of the two other Ehrlich cell lines (E1.80 and E1.95) which themselves were non-immunogenic. E1.15 was, however, unable to induce an immunological response against the P388 cell line. It is therefore suggested that when in close contact, immunologically induced cellular responses imposed by an immunogenic cell line on other cell lines require genetic and thereby close immunogenic resemblance between the cell lines. Another type of interaction was found between the E1.95 cell line and the P388 line which showed nearly identical growth characteristics as determined by tumor weight day 14, tumor growth curves, cell cycle times (per cent labelled mitoses) and cell cycle distributions (flow cytometric DNA analysis). After 2 weeks of growth of mixed P388/E1.95 tumors, flow cytometric DNA analysis on fine-needle tumor aspirates showed nearly total dominance of P388. This type of interaction required close cellular contact of viable cells, and no cellular immune response was elicited by the host animals. A third finding was that a faster growing Ehrlich cell line E1.95 dominated the tumors when inoculated in mixture with a slower growing subpopulation E1.80. This could be explained on the basis of the cell kinetic differences between these two cell lines.

High-dose ketoconazole to untreated stage D prostate cancer.

Eleven previously untreated patients with stage D prostate cancer were treated with ketoconazole in a dosage of 400 mg p.o. every 8 h. s-Testosterone was used as a measure of antiandrogen effect. Nine patients had a reduction in s-testosterone to castrate levels (less than 2.9 nmol/l) within 3 days. In the remaining two patients, dose escalation of ketoconazole to 400 mg every 6 h did not lead to sufficient reduction in s-testosterone. Two patients had a complete response and four patients had a partial response of 6/11. Additionally, two patients had bone pain relief without normalization of acid phosphatase. Side-effects and adverse reactions were prominent, causing discontinuation of the treatment in nine patients. It is concluded that high-dose ketoconazole is effective in disseminated prostate cancer, but the high frequency of side-effects makes it less attractive than conventional hormone manipulations like castration or estrogens.

Interaction among two subpopulations of Ehrlich ascites tumor in vivo: evidence of a contact mediated immune response.

Clonal interaction among two subpopulations of Ehrlich ascites carcinoma was studied during in vivo growth in immune competent N/D mice in which the cell lines had been propagated for several years as ascites tumors. A growth inhibitory interaction by a subcutaneously slow growing subpopulation (E1.15) on a fast growing subpopulation (E1.95) was demonstrated only when the cells had contact during solid tumor growth. The effect was dependent on the relative proportion of the suppressing cell line. An identical effect was exerted by radiation killed inhibitor cells. The inhibition was only transient. If the tumor cell lines were grown intraperitoneally as ascites tumors without cellular contact, no interaction was found using flow cytometric DNA analysis to determine alterations in the relative proportions of the cell lines. Ascites from the inhibitor cell line E1.15 had no inhibitory effect on E1.95. Pre-immunization with radiation killed E1.15 cells or simultaneous growth of E1.15 in the opposite flank did not affect the growth of E1.95 significantly. A mononuclear cell infiltrate was found to surround the subcutaneously growing E1.15 tumors in immune competent N/D mice. This was not the case in T-lymphocyte deficient athymic nude mice in which E1.15 grew without delay subcutaneously. It is suggested that the E1.15 cell line was able to elicit a T-lymphocyte immune response only when grown subcutaneously, and that the close contact between E1.15 and E1.95 in mixed tumors would induce a non-specific growth inhibition of E1.95 cells which themselves were not able to induce a T-lymphocyte response.

Chemotherapy for adenocarcinoma of the lung (WHO III): A randomized study of vindesine versus lomustine, cyclophosphamide, and methotrexate versus all four drugs.

Two hundred seventy-nine patients with previously untreated nonresectable adenocarcinoma of the lung (ACL) entered a prospective randomized trial, comparing vindesine (VDS) to a combination of lomustine (CCNU), cyclophosphamide (CTX), and methotrexate (MTX), and to a regimen including all four drugs. Response assessment was possible in 218 patients, while 259 were evaluable for survival. Response rates were similar (22%, 23%, and 27%, respectively) as were median durations of response (15 weeks overall) and survival (29 weeks overall). Patients with dose-limiting toxicity had significantly higher response rate and longer survival than patients without toxicity. The major toxicity was peripheral neuropathy with VDS treatment and myelosuppression with the other two regimens. The VDS single-agent activity in ACL was confirmed, but addition of VDS to the three-drug regimen did not increase activity. Future studies of VDS in combination with other active agents, and comparison to a matched control group on supportive care, are indicated.

Prostate cancer: evaluation of response to treatment, response criteria, and the need for standardization of the reporting of results.

Response criteria and the reporting of results in clinical trials on drug therapy of stage D prostate cancer were evaluated by examination of studies listed in the Index Medicus 1980-1984. During this 5-year period, 70 studies (51 phase II and 16 phase III) were listed, comprising 3184 evaluable patients. Among 346 patients reported as having evaluable disease according to the WHO criteria, 198 had well-defined evaluable disease. A variety of response criteria were used, the NPCP criteria being the most frequent. Only three studies included solely patients with evaluable disease according to the WHO criteria. Reporting of results was often inadequate. The value of the most frequently used response parameters such as acid phosphatase, bone scan, per-rectal ultrasound, CT scan, bone pain and performance status is discussed. A system to standardise the reporting of results is proposed.

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.

Carcinoembryonic antigen (CEA) and alkaline phosphatase in progressive colorectal cancer with special reference to patient survival.

The prognostic value of serial CEA tests was evaluated in 175 consecutive patients with progressive colorectal cancer who subsequently died of their disease. The upper normal plasma CEA limit was determined to be 8 ng/ml from serial CEA determinations in 31 patients radically operated on for colorectal cancer and observed in median 40 months without evidence of recurrence. A CEA value of greater than 8 ng/ml was highly suggestive of residual disease or recurrence, even when no clinical evidence was present. Approximately 90% of the patients dying from colorectal cancer showed an increase in CEA to greater than 8 ng/ml during the course of the disease. In 63% of the patients CEA increase preceded clinical progression or relapse, with a median time period of 4 months. Sixty-eight per cent of the patients had rising CEA values over an extended time period of many months, 14% had a preterminal increase, 13% had constantly normal and 5% constantly elevated CEA. As 6/9 patients developed a drop in CEA in relation to initiation of chemotherapy without clinical response, it is concluded that CEA is not a reliable indicator of clinical response to chemotherapy. Patients with liver metastases had higher CEA and alkaline phosphatase levels than patients with only localized disease. However, no good statistical correlation between CEA and serum alkaline phosphatase was found in patients with liver metastases (coefficient of correlation r = 0.35). An increase in CEA from normal to above 8 ng/ml predicted a decrease in survival time of median 60% counted from the time of diagnosis. The numerical CEA value was predictive of shortening of survival only when greater than 3000 ng/ml. Such high values were observed only in a minority of the patients (12%). Greater than 1000 U/l (27% of the patients) alkaline phosphatase predicted an extremely poor prognosis, with a median survival of 1 month (range 0.5-4 months). It is concluded that a rise in CEA to greater than 8 ng/ml indicates with high degree of certainty relapse or disease progression in colorectal cancer patients. CEA is not a reliable indicator of clinical response to chemotherapy, and an increase in the CEA level is of little prognostic value concerning survival. Alkaline phosphatase seems to be a more valuable predictor of a worsening of prognosis.

Lung abscess in small cell carcinoma of the lung during chemotherapy and corticosteroids: an analysis of 276 consecutive patients.

Two hundred and seventy-six consecutive patients with small cell carcinoma of the lung (SCCL) treated with combination chemotherapy and in 79 cases with "high-dose" steroids (greater than 40 mg of prednisone per day) were reviewed for the presence of lung abscess. This was diagnosed in 17 patients, in 4 (1.5%) at the time of their malignant diagnosis and 13 (4.9%) during chemotherapy. Five of 79 patients receiving "high-dose" glucocorticoid therapy and 8 of 184 patients not receiving steroids developed lung abscess (no statistical difference, P greater than 0.05). "High-dose" steroids do not facilitate the development of lung abscess. Eleven patients presented with a lung abscess within a month of initiation of chemotherapy. Median survival of these patients was 182 days and not significantly different from a median survival of 224 days (P greater than 0.05) observed in 31 compatible patients without lung abscess. Lung abscess per se in patients with SCCL should not prevent the use of intensive combination chemotherapy and "high-dose" steroid therapy.