Pirkko Sipilä

Pharmacology of antineoplastic agents in pregnancy

The use of antineoplastic agents in pregnant women poses obvious risks to both the patient and the developing fetus, particularly during organogenesis. While the use of antineoplastics during pregnancy is often unavoidable, the physician may limit the risks by having a clear knowledge of the pharmacology and teratogenic potential of individual agents. Specific physiologic changes in the pregnant patient, such as enhanced renal excretion of drugs, increased or decreased hepatic function, altered gastrointestinal absorption and enterohepatic circulation, altered plasma protein binding, an increase in plasma volume (50%), and creation of a fluid filled 3rd compartment (amniotic fluid) for water soluble drugs may all significantly influence the pharmacology of antineoplastic agents. These physiological changes may effect the pregnant patients ability to absorb orally administered drugs, metabolize drugs to either active or inactive metabolites, and eliminate cytotoxically active drugs. A resulting reduction in concentration x time (C x T) for drug exposure to the maternal system may reduce the efficacy of the antineoplastic agents, while an increase in C x T may expose the patient and her fetus to undue toxicity. The timing of drug administration to gestational age is also a critical factor for some drugs. While many drugs result in adverse effects on the fetus regardless of gestational age, others appear to pose less of a threat if administered beyond the first trimester. This review addresses the pharmacology, pharmacokinetics and the teratogenic potential of individual antineoplastic agents that are commonly used in pregnant patients. The aim of this review is to help the physician select, on a patient specific basis, antineoplastic agents that avoid at least some of the fetal risk involved while maintaining efficacy in the treatment of the patient.

Surgically staged high-risk endometrial cancer: Randomized study of adjuvant radiotherapy alone vs. sequential chemo-radiotherapy

OBJECTIVE Our purpose was to establish whether platinum-based chemotherapy combined with standard surgery and radiotherapy will improve overall and disease-free survival and lower the recurrence rate in patients with high-risk endometrial cancer. STUDY DESIGN A total of 156 patients with Stage IA-B Grade 3 (n=28), or Stage IC-IIIA Grade 1-3 (n=128) were postoperatively randomized to receive radiotherapy (56 Gy) only (Group A, n=72) or radiotherapy combined with three courses of cisplatin (50 mg/m(2)), epirubicin (60 mg/m(2)) and cyclophosphamide (500 mg/m(2)) (Group B, n=84). RESULTS The disease-specific overall five-year survival was in Group A 84.7% vs. 82.1% in Group B (p=0.148). The median disease-free survival in A was 18 (range 9-36) months and 25 (range 12-49) months in B (p=0.134), respectively. During a five-year follow-up 32 patients relapsed. Of the recurrences 5 were local and 20 distant, while 7 were combined. As calculated from the operation, the median time to recurrence was 15 (range 6-37) months in Group A, and 20 (range 8-60) months in Group B, respectively (p=0.170). Twenty-six patients died of the disease during the five-year follow-up, 11 in A and 15 in B. The patients succumbing in A lived a median 23 (range 15-44) months as compared to 37 (range 13-50) months in B (p=0.148). Chemotherapy was associated with an acceptable rate of acute toxicity. Less than 8% of the patients complained of Grade 3/4 nausea. The rate of Grade 3/4 leucopenia was at the highest at 16.6% during the third cycle but only 6.2% of the patients had Grade 3 infection. A total of 10 patients developed intestinal complications demanding surgery, 2 in Group A (2.7%) and 8 (9.5%) in Group B, respectively. CONCLUSION Adjuvant chemotherapy with cisplatin, epirubicin and cyclophosphamide failed to improve overall survival or lower the recurrence rate in patients operated on and radiated for high-risk endometrial carcinoma. Chemotherapy was associated with a low rate of acute toxicity but appeared to increase the risk of bowel complications.

The grand multipara--still an obstetrical challenge?

SummaryTo study whether grand multiparity (parity of 6 or more) still carries risk, we studied two birth cohorts in northern Finland: the first comprised 12231 births to 12068 mothers in 1966 and the second comprised 9478 births to 9362 mothers in 1985/86. The percentage of grand multipara decreased from 7.7 to 4.0. The grand multipara made fewer antenatal visits than the others. The proportion of grand multipara referred to maternity outpatient clinics of hospitals was smaller, but the mean number of visits was higher than of lower parity women. The mean number of admissions to hospital was similar in both groups but grand multipara stayed longer in hospital, smoked less (4.3% vs. 22.7%) and had a higher incidence of essential hypertension than women of lower parity. The grand multipara had fewer caesarean sections (7.5% vs. 14.1%) and vacuum extractions (0.5% vs. 5.1%) but more inductions of labour (33.1% vs. 23.%) than mothers of lower parity. The number of low birth weight (LBW) infants (<2500 grams), stillbirths and neonatal deaths (before 28 days) was significantly lower in 1985/86 than in 1966 in women of lower parity but there was no such change in grand multipara. However, the percentage of LBW infants was smaller among grand multipara than among women of lower parity in both cohorts (2.7% vs. 4.1%, NS). The stillbirth plus neonatal death rate in grand multipara was higher than in women of lower parity (1.9% vs. 0.9%,P<0.05) partly because of a higher incidence of major congenital anomalies.

Changes in prognosis of twin births over 20 years.

The study is based on two birth cohorts from the years 1966 and 1985-1986. Perinatal mortality of twins has fallen over 20 years from 9.2% to 3.1%. Improvement is particularly remarkable in neonatal mortality (less than 28 days) of preterm (less than 34 gestational weeks) twins, from 47.4% to 8.6%, whereas the incidence of stillbirths has not fallen greatly. The proportion of preterm births has not fallen significantly, 48.4% vs. 38.1%. Many factors, considered favourable to the course and outcome of pregnancy have improved simultaneously: women are taller, less overweight, and more educated; pregnancies are wanted and sick and maternity leave provisions have improved. The follow-up of twin pregnancies and deliveries has been centralized and is more effective. In particular, neonatal care is also better than 20 years ago. The prognosis of twins has improved in parallel with the singletons, but the perinatal mortality is still approximately four time and the incidence of prematurity ten times more than in singletons.

Changes in risk factors for unfavorable pregnancy outcome among singletons over twenty years

Objectives. To examine the change in the prevalence and relative effect of pre‐pregnancy risk factors for low birthweight and/or stillbirth and/or neonatal mortality over a period of twenty years.

Phase II evaluation of peroral carmofur, cyclophosphamide, and hexamethylmelamine as a second-line therapy in advanced epithelial ovarian carcinoma

A prospective phase II study was performed to evaluate the effect and tolerability of a peroral combination chemotherapy consisting of hexamethylmelamine, cyclophosphamide, and carmofur in patients with epithelial ovarian cancer previously heavily treated by cisplatin-based chemotherapy but no longer responding to it. Of the 27 patients 1 showed a clinical complete remission lasting 15+ months and 4 a partial remission of 6+ to 21 months. A further 7 patients had an unchanged situation of 4 to 13+ months. The median survival of the nonresponders was 3 months. The side effects were tolerable, mostly nausea and vomiting. Only 4 of 27 patients suffered from severe vomiting causing discontinuation of the therapy. The peroral ambulatory chemotherapy prolonged markedly the overall survival of about one-half of the patients with ovarian cancer who previously failed to respond to cisplatin-based chemotherapy.

Intracavitary irradiation of endometrial cancer of large uteri using a two-phase afterloading technique

A specific intracavitary two-phase technique was developed for irradiation of endometrial cancer located in uteri with a large uterine cavity. In this technique an insertion catheter (external diameter 9 mm) was used for the introduction and precise location of the treatment catheter (external diameter 6.4 mm). During the first phase of the therapy, one lateral half of the uterine body was irradiated. Thereafter the positions of the catheters were changed by 180 degrees, followed by irradiation of the other lateral half of the uterine body. Using a wax phantom and extirpated uteri as models, we observed that the dose distributions followed the uterine shape and the calculated doses in the radiographs. Clinical observations from 34 patients treated so far, and followed-up for periods of 3 months to 6 years, prove that this method yields similar results to those observed in previous studies employing the Heyman packing method or afterloading techniques with a one-source tandem in the intracavitary irradiation of endometrial cancer.

168 COMPUTER-BASED PERINATAL RISK PREDICTION IN A GEOGRAPHICALLY DEFINED PARTURIENT POPULATION. AN INTERVENTION STUDY

The risk of unfavourable perinatal events for a parturient population was predicted by a computer-based method and those at risk, 17.6 % of the total, were given recommendations for special care. The series consisted of the total parturient population in Northern Finland in 12 consecutive months in 1985 and 1986. Of the 96 antenatal clinics in the study area, a half were chosen as intervention clinics and the other half as control clinics matched in the number of deliveries in previous years, geographical location, urban or rural character and degree of development. The total number of deliveries in the intervention group was 3653 and that in the control group 4095. Those classified in the risk group and given recommendations for extra care, 642 mothers, had a significantly higher mean birth weight, a lower percentage of low birth weight infants and an almost significantly (p 0.070) lower percentage of pre-term deliveries than the mothers at similar risk in the control group without any such extra recommendations.

Intracavitary Irradiation of Endometrial Cancer of Large Uteri using a Two-Phase Afterloading Technique: The British Journal of Radiology, Volume 60, November 1987, 1093–1097

A specific intracavitary two-phase technique was developed for irradiation of endometrial cancer located in uteri with a large uterine cavity. In this technique an insertion catheter (external diameter 9 mm) was used for the introduction and precise location of the treatment catheter (external diameter 6.4 mm). During the first phase of the therapy, one lateral half of the uterine body was irradiated. Thereafter the positions of the catheters were changed by 180 degrees, followed by irradiation of the other lateral half of the uterine body. Using a wax phantom and extirpated uteri as models, we observed that the dose distributions followed the uterine shape and the calculated doses in the radiographs. Clinical observations from 34 patients treated so far, and followed-up for periods of 3 months to 6 years, prove that this method yields similar results to those observed in previous studies employing the Heyman packing method or afterloading techniques with a one-source tandem in the intracavitary irradiation of endometrial cancer.