The prevalence of burnout among oncology professionals: oncologists are at risk of developing burnout.

OBJECTIVE: International research shows that oncology staff suffers more from burnout than other healthcare professionals. Burnout is common among oncologists. The prevalence of emotional exhaustion, depersonalization, and low personal accomplishment appears to be significantly higher among physicians. Detecting burnout is highly relevant, because it affects the personal well-being and quality of life of the healthcare professional. A national study on the prevalence of burnout in oncology was never conducted in Flanders (Dutch-speaking part of Belgium). METHODS: The Cédric Hèle institute spread anonymous questionnaires among 923 healthcare workers in oncology (physicians, social workers, psychologists, nurses, and specialist-nurses) in Flanders. The questionnaire consisted of two parts. The first part contained questions concerning demographic and job features. The second part included the Dutch version of the Maslach Burnout Inventory. RESULTS: Five hundred and fifty subjects participated in the survey (response rate of 59.5%). Of the medical oncologists, 51.2% suffered from emotional exhaustion, 31.8% from depersonalization, and 6.8% from a lack of personal accomplishment. Multivariate analysis of variance suggested a significantly elevated level of emotional exhaustion and depersonalization in oncologists compared with other professionals. Logistic regression indicated that the following variables have predictive value on risk of burnout: gender, profession, and combining work in a university hospital with work in a private hospital. CONCLUSION: The CHi research showed a significantly increased level of burnout-components in professionals working in oncology, especially in medical oncologists. These results should have an impact on the daily clinic of oncology, and could be guidance for further research.

The 'Distress Barometer': validation of method of combining the Distress Thermometer with a rated complaint scale.

OBJECTIVE: Screening instruments may enhance the clinician's ability to detect elevated levels of distress in cancer patients, but these are often neither suitable nor effective for the routine of daily care for cancer patients. The newly developed Distress Barometer (DB) was intended to provide medical doctors with a convenient tool to interpret 'at single glance' the nature and the intensity of distress in ambulatory cancer patients. The DB, i.e. a combination of the Distress Thermometer (DT) and a new tool, the Colored Complaint Scale was developed to improve the specificity of distress screening without decreasing the sensitivity of the Distress Thermometer. METHODS: Distress was screened in a sample of 538 out-patients, using the Hospital Anxiety and Depression Scale (HADS) and the new Distress Barometer (DB). RESULTS: The results confirm the validity of the Dutch version of the DT against the HADS as standard measure. In addition, it was found that the overall accuracy of the new DB was higher, with a sensitivity of 0.79 and a specificity of 0.81. CONCLUSION: These results indicate that the Distress Barometer, which is convenient for both patients and doctors, can be used as an acceptable, brief and sufficiently accurate method for detecting distress in cancer patients.

Attitudes and knowledge about cancer pain in Flanders. The educational effect of workshops regarding pain and symptom control.

Despite international agreements and recommendations regarding cancer pain therapy, the effectiveness of pain treatment is still a major problem even in Western countries. Part of the problem is that physicians and nurses often lack knowledge of methods for the assessment and treatment of cancer pain and may have many rigid beliefs and attitudes. This study investigated the misconceptions of physicians and nurses that play a role in the undertreatment of pain in Flanders (Belgium). We approached 197 health care workers who participated in the pain and symptom control education sessions organized by the Federation Palliative Care Flanders, and asked them to complete a questionnaire both before and after the sessions. The impact of the education sessions on their knowledge and beliefs regarding the management of cancer pain was substantial. Methods of reaching the target groups that do not feel the need for further education are discussed.

The effect of pretreatment with docetaxel (taxotere; RP 56976) on irradiated subcutaneous MA 16/C murine tumors.

Docetaxel (taxotere; RP 56976) is twice as potent as taxol in the inhibition of microtubule depolymerisation and accumulates cells in their G2/M-phase, which is a highly sensitive phase of the cell cycle. The present study was designed to test the hypothesis that this property may lead to an enhanced effect of ionizing radiation on tumors. In a first experiment subcutaneous MA 16/C murine tumors, which are highly responsive to docetaxel, were treated intravenously with 45 mg/kg docetaxel and 6 hours later irradiated with 500 cGy (day 1). The pretreatment time of 6 hours resulted in a maximum mitotic index at the time of irradiation. On day 3 and 5, an additional 500 cGy was administered, without pretreatment with docetaxel. In a second experiment the radiation dose was given similarly, but pretreated with 15 mg/kg docetaxel. In both experiments, a prolonged increase of lifespan (%ILS) and a tumor growth delay (Td) was found among docetaxel treated mice and combinedly treated animals. Though a radiation dose of 1500 cGy on its own had no antitumoral effect on MA 16/C tumors, there was a marked tendency (but not statistically significant) to a better effect with the combined therapy in comparison with docetaxel alone (in experiment 1). Further studies with more radiosensitive tumors are warranted to determine the putative role of M-phase arrest on the radiosensitizing properties of docetaxel.

Phase I trial of erbulozole (R55104).

Erbulozole (R55 104) is a water soluble congener of the microtubule inhibitor tubulozole, which has proven to possess anti-invasive, antitumoral and radiosensitizing capacities. A dose-finding study was performed on respectively 9 patients (every three weeks; doses ranging from 20 mg/m2 to 100 mg/m2; maximum 2 cycles per patient) and 6 patients (weekly; doses ranging from 20 mg/m2 to 50 mg/m2; maximum 60 cycles per patient). At all dosages, hematological and biochemical toxicity was very limited. Seven patients complained of pain at the tumor site (grade I to III). Dose limiting toxicity appeared at respectively 100 mg/m2 (one administration every three weeks) and 50 mg/m2 (weekly administration). At this level, 2 patients displayed a dose-limiting Wernicke's encephalopathy-like syndrome. Other secondary effects were headache, fever, exacerbation of dyspnea and moderate nausea and vomiting.

5'-Nor-anhydrovinblastine (Navelbine) has an anti-invasive effect on MO4 mouse fibrosarcoma cells in vitro and in vivo.

5'-nor-anhydrovinblastine (Navelbine) is a hemisynthetic Vinca alkaloid for which a selectivity for mitotic microtubules has been demonstrated. In previous studies, we have demonstrated an anti-invasive effect of other Vinca alkaloids. Here the results of in vitro and in vivo assays concerning the effect of 5'-nor-anhydrovinblastine on growth and invasion of MO4 cells are presented. It is demonstrated that at cytostatic concentrations, 5'-nor-anhydrovinblastine also has an anti-invasive effect.

Levamisole plus 5-fluorouracil inhibits the growth of human colorectal xenografts in nude mice.

Fragments of human colorectal adenocarcinomas were inserted under the renal capsule of nude mice. The growth of these tumour grafts was significantly inhibited by the combination of 5-fluorouracil (5-FU) and levamisole. An alternating regimen of levamisole 2.5 mg/kg and 5-FU 20 mg/kg decreased the size of tumour implants by 33-59% and/or increased the number of macroscopically disappeared fragments in the combined group compared with ineffective monotherapy with saline, levamisole or 5-FU. This model could be valuable for investigating the mechanism of action of levamisole and to evaluate the effects of this adjuvant therapy in other oncological settings.

The effects of short-term treatment with levamisole on cytokines in volunteers and cancer-patients.

In search for clues to the potential immunomodulating mechanism of action of levamisole which might be used as monitoring parameters, we have determined a variety of cytokines in the peripheral blood of volunteers and carcinoma patients before and after a single or a 3-day-treatment with 150 mg/day. In cancer patients no changes could be detected 4 days after a 3-day-treatment course in the levels of TNF-alpha, IL-1beta, IL-2 or IL-6. In a placebo-controlled volunteer study the same treatment did not affect the levels of beta2-microglobulin, IL-1beta, IL-1alpha, IL-2 or IL-6. However, 24hr after the last treatment the concentration of neopterin was slightly but significantly increased and the concentration of soluble IL-2 receptors decreased. A single treatment failed to produce such an effect. It is suggested that the measurement of neopterin and soluble IL-2 receptors may provide useful information in future trials.

Erbulozole (P.I.N.N.) (R 55 104) encapsulated into cyclodextrins: has it a combined antitumoral and radioprotective potential?

The clinically applicable formulation of the microtubule inhibitor erbulozole (R 55 104), dissolved into an aqueous hydroxypropyl-beta-cyclodextrin solution (designated as R 55 104-CYCLO), exerts a similar effect on growth delay of subcutaneous MO4 fibrosarcomas in mice, with or without 10 Gy gamma-irradiation given locally to the tumors 2 h later, compared to R 55 104 in water. The drug concentration can be reduced from 80 mg/kg to 5 mg/kg without affecting the activity of this particular drug-radiation combination. Furthermore, 80 mg/kg R 55 104-CYCLO show a radioprotective effect when given 2 h before total body irradiation of non-tumor bearing mice. A radiation dose of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gy respectively was given resulting in a LD50(30) of 5.97 Gy for the irradiated mice and 7.65 Gy for the drug-radiation treated animals (Dose Effect Factor = 0.78). Therapeutic implications of both observations are discussed.

Antitumoral effects of R 75251 on the growth of transplantable R3327 prostatic adenocarcinoma in rats.

The antitumoral activity of a novel imidazole derivative, R 75,251, has been studied in the androgen-dependent R3327G Dunning prostate adenocarcinoma grafted subcutaneously in syngeneic rats. Dietary application resulting approximately in dose levels of 80, 120, and 160 mg/kg reduced tumor weight by 66, 81, and 79%, respectively. This effect was not significantly different from that measured after castration (-82%). In intact animals, however, serum testosterone levels were almost not affected by R 75,251 treatment while LH levels rose two- to threefold. In castrated rats a tenfold increase in LH was observed. Moreover, prostate and seminal vesicles weights decreased much less after R 75,251 treatment than after castration. In castrated animals, treatment with R 75,251 induced a slight, non-significant reduction in tumor weight (-36%) compared with castration alone. In castrated animals, tumor growth was restored by exogenous administration of testosterone. In such animals R 75,251 also significantly reduced tumor weight by 57%. Similar results were obtained with Dunning R3327G prostate adenocarcinoma grafted beneath the renal capsule in male syngeneic rats receiving twice daily orally by gavage a dose of 80 mg/kg of R 75,251. These data suggest that R 75,251 exerts an antitumoral effect independent of its inhibition of androgen biosynthesis.

Influence of the synthetic microtubule inhibitor erbulozole (P.I.N.N.) (R 55 104), a new tubulozole congener, and gamma irradiation on murine tumors in vivo.

Erbulozole (P.I.N.N.) (R 55 104) is a more water soluble congener of the synthetic microtubule inhibitor tubulozole (R 46 846) exhibiting a reversible antimicrotubular activity in vitro at a dose (1.56 x 10(-8) M) which is at least 10-fold lower. The compound also has an antiinvasive potential and shows antitumoral effects both in vitro and in vivo when administered appropriately. Eighty mg/kg R 55 104, given orally 6 h before or 3 h after radiotherapy, displays a prominent interactive effect with 10 Gy gamma irradiation in subcutaneous murine tumors which is similar to 160 mg/kg tubulozole administered 6 h before 10 Gy. The enhancing effect is also observed in a clinically relevant radiation dose fractionation schedule whereby eight fractions of 2 Gy each were pretreated 2 h before with 40 mg/kg R 55 104. Further study of this radiochemotherapeutic combination may lead to new clinical applications.

Interaction between the microtubule inhibitor tubulozole and gamma-irradiation in murine tumors in vivo.

The combined effect of the microtubule inhibitor tubulozole and gamma-irradiation has been investigated in vivo in subcutaneous MO4 fibrosarcomas and Lewis Lung carcinomas. A marked interactive effect on tumor growth was observed when 160 mg/kg tubulozole was orally administered before the tumors were treated with 10 Gy radiation. Dose dependency and optimal effect were obtained on tumor growth of MO4 tumor bearing animals when the drug treatment was given 6 hr prior to the irradiation. The optimal pretreatment time coincided with the time at which a peak mitotic index in the tumor tissue was observed. An enhancing effect is also noticed at other doses of radiation in MO4 tumors pretreated 6 hr before with 160 mg/kg tubulozole. The interactive effect is maintained in a clinically relevant dose fractionation schedule whereby 8 fractions of 2 Gy each were pretreated 6 hr before with 80 mg/kg tubulozole. Tubulozole-T, the stereo-isomer of tubulozole, neither exhibits any antimicrotubular action nor exerts an antitumoral effect on its own or in combination with gamma-irradiation. The possible mechanisms of interaction between tubulozole and gamma-irradiation in tumor tissue are discussed.

Numerical evaluation of the kidney invasion test.

We have implanted MO4 transformed mouse cells attached to a collagen matrix (artificial tumor) under the renal capsule of syngeneic mice. It was our purpose to evaluate whether or not the kidney invasion test (KIT) could be used for the determination in vivo of the invasive capacity of cultured cell populations. Invasion was expressed in terms of the proportion of the depth of the invasive part of the tumor to the total tumor thickness (invasion rate), both measured macroscopically after hemisection of the kidney. Macroscopic findings were confirmed by histology. For MO4 cells the invasion index changed in function of time after implantation. The relationship 'invasion index versus time after implantation' was demonstrated to be constant in 3 independent groups of mice. Therefore, we propose determination of the invasion rate versus time in the KIT as a method to compare the invasive capacity in vivo of different cell lines.

The kidney invasion test: its application to the Lewis lung carcinoma system.

Implantation of fragments from subcutaneously grown Lewis lung carcinoma 3LL under the renal capsule of syngeneic mice results in invasion of the kidney parenchyma. The synthetic microtubule inhibitor tubulozole blocks or decreases this malignant invasion in a dose-dependent manner. The inhibition of the invasion rate caused by tubulozole can be macroscopically quantified, and has been confirmed histologically.

Influence of the salmon mutant of Glossina morsitans morsitans on the susceptibility to infection with Trypanosoma congolense.

Four phenotypes of a sex-linked, maternally influenced semi-lethal eye color mutant of Glossina morsitans morsitans Westwood were fed on Trypanosoma congolense Broden infected guinea pigs. Infection rates were evaluated 25 days later by means of dissection. Procyclic as well as mature infections were significantly more common among females with salmon-colored eyes (sal/sal) than among heterozygous (+/sal, phenotypically wild-type) females. A tendency was found for more mature infections among sal/Y males than among wild-type males. Similarly, females tended to be more infected than males with both procyclic and mature infections. These results indicate that the genotype of the fly, exemplified by the allele salmon, might influence the development of T. congolense in G.m. morsitans. A possible explanation for this phenomenon is discussed.

The Kidney Invasion Test: an assay allowing macroscopic quantification of malignant invasion in vivo. Comparison between the microtubule inhibitor tubulozole and the podophyllotoxin congener etoposide (VP-16-213).

When MO4 tumor fragments were implanted under the renal capsule of syngeneic or allogeneic mice, invasion of the renal parenchyma was observed. Inhibition of invasion by the microtubule inhibitor tubulozole could be macroscopically quantified and compared with the invasion permissive drug etoposide (VP-16-213). These results have been histologically confirmed, and the use of this assay in vivo for the rapid macroscopical screening of compounds with potential anti-invasive properties is discussed.