Paul Berveiller

Taxanes for breast cancer during pregnancy: a systematic review

The co-occurrence of breast cancer and pregnancy is an important issue for the forthcoming years, given the trend for women to postpone childbearing [1]. Although the use of doxorubicinand epirubicin-based regimens appear quite safe in the second and third trimesters of pregnancy [2, 3], little is known on the safety of taxanes, with only 14 cases found in our literature review 2 years ago [1]. We aimed to collect updated data on the safety of taxanes in pregnant patients, and therefore carried out a systematic review of the English literature by search of Pubmed, Embase, and Web of Knowledge, using the search terms ‘paclitaxel AND pregnancy’, ‘docetaxel AND pregnancy’, and ‘taxanes AND pregnancy’. Only papers published in English from 1990 to 15 September 2009 were included. Twenty-three publications were identified [1, 4–12], describing 40 women and 42 neonates (two gemellar pregnancies). Paclitaxel was administered in 21 cases, docetaxel in 16 cases, and both drugs in 3 cases. Except for two cases [11, 13], taxanes were administered concomitantly or sequentially with other cytotoxic agents, mostly anthracyclines, cyclophosphamide, and platinum derivatives. Twenty-seven patients had breast cancer, 10 had ovarian cancer, and 3 had non-small-cell lung cancer. The 40 cases are summarized in Table 1. Docetaxel was administered during the first trimester

Chemotherapy for breast cancer during pregnancy: is epirubicin safe?

The co-occurrence of cancer and pregnancy is becoming more frequent, given the trend for women to postpone childbearing [1]. As a consequence, the collection of more information about the effects of anticancer agents during pregnancy is useful to improve the existing guidelines. The most frequent solid tumour observed in pregnant women is breast cancer [1]. Among the drugs potentially active in these patients, taxanes and vinorelbine display a favourable safety profile, whereas trastuzumab is associated with severe foetal toxicity [1].We and others have previously reported the feasibility of anthracyclines during the second and third trimesters of pregnancy [2, 3]. Recent international recommendations stated that anthracycline-based chemotherapy could be given to pregnant breast cancer patients during this period, with minimal risk to the developing foetus [3]. Although anthracyclines are a milestone of chemotherapy for breast cancer patients during pregnancy, only one prospective study was carried out in this setting [3] assessing the safety of a doxorubicin-based combination chemotherapy (FAC regimen). Hence, little is knownabout the safety of epirubicin, another anthracycline active in breast cancer, widely used in Europe. We aimed to collect data on the safety of epirubicin in pregnant patients and therefore carried out a systematic review of the English literature in order to evaluate its maternal and embryo–foetal toxicity. Data for this review were identified by search of PubMed, Embase and Web of Knowledge, together with references from relevant articles, using the search terms ‘epirubicin AND pregnancy’ and ‘anthracyclines AND pregnancy’. Only papers published in English from 1967 to 1 July 2008 were included. Redundant publications (describing the same cohort of patients) were identified and only the most recent data were analysed. A total of 13 publications [4–16] were identified, including three papers describing the same cohort of patients [4, 15, 16]. There were 48 cases of breast cancer, one case of nonHodgkin’s lymphoma and one case of acute leukaemia. The 50 cases are summarised in Table 1. Two of three administrations during the first trimester resulted in

Taxanes during pregnancy: probably safe, but still to be optimized.

in distribution volume may lead to decreased plasma exposure. Additionally, an increase in glomerular filtration could likely lead to increased excretion. Moreover, amniotic fluid may act as a third space for many drugs, as recently documented for dasatinib [5] . Finally, the decrease in albumin level observed during pregnancy may favor the transplacental transfer rate of many drugs, especially highly protein-bound molecules [6] . To date, little is known about the optimal dosing regimen for taxanes in pregnant patients because clinical pharmacokinetic studies are scarce [7, 8] . These data indicate that pregnant patients receiving paclitaxel had lower AUC and higher clearance compared to nonpregnant patients. Hence, this study suggested that conventional-dosing schedules may result in sub-optimal exposure. Besides, to date, no clinical data on docetaxel pharmacokinetics in pregnant women are available. Regarding the metabolism of taxanes, paclitaxel is mainly metabolized by cytochrome P450 (CYP) 2C8, and to a lesser extent by CYP3A4 [9] . On the other hand, docetaxel is mainly metabolized by CYP3A4. Importantly, CYP3A4 is a phase I enzyme with increasing activity (by 50–100%) during the third trimester of pregnancy [10] , putting pregnant patients at risk of sub-optimal exposure given the higher clearance. Breast and other gynecological cancers are increasingly prevalent in pregnant women. As far as chemotherapy is concerned, drug selection is critical in this setting, with the aim to efficiently treat the mother without harming the developing fetus. In the current issue of Oncology, Zagouri et al. [1] performed a systematic review regarding the use of taxanes in ovarian cancers occurring during pregnancy. This review suggests that taxanes (especially paclitaxel) might be used during the second and third trimesters of pregnancy in ovarian cancer patients with an acceptable safety profile. Moreover, data regarding the survival of mothers were reassuring as well. Similarly, regarding the use of taxanes in breast cancer patients during pregnancy, a previous systematic review seemed to confirm these reassuring data [2] . Hence, these results led international experts to conclude that taxanes may be safely used during pregnancy in breast cancer patients [3] . It is noteworthy that pregnancy leads to important physiological and metabolic changes that may alter or interfere with the pharmacokinetics and pharmacodynamics of anticancer drugs [4] . These changes could lead to suboptimal plasma concentrations, even if common doses of cytotoxic drugs are used. For instance, an increase Published online: August 16, 2012

The sentinel-node concept: a dramatic improvement in breast-cancer surgery

Until the late 1990s, axillary lymph-node dissection was considered the gold standard to assess lymph-node invasion in patients with breast cancer, although the procedure was associated with considerable morbidity. Roughly 50 years have passed since Gould and colleagues 1 investigated the idea of a possible sentinel lymph node (SLN), on the basis of Sappey’s works 2 regarding a specifi c centre in the lymphatic drainage of the breast. The SLN concept is based on the theory that tumour invasion of the fi rst node of the regional nodal basin reveals the tumour status of the entire basin. Hence, if the fi rst node is found to be metastasis-free, the rest of the regional nodal basin is also metastasis-free, and if the fi rst node is metastatic, radical lymph-node dissection is warranted. As a consequence, it seems possible to assess the complete nodal status with the excision of a unique node. The considerable morbidity associated with axillary lymph-node dissection 3 makes this less invasive approach more attractive. The SLN concept was fi rst described in parotid gland carcinoma, rather than breast cancer, by Gould and colleagues 1 in 1960. Their paper stressed the usefulness of radical neck dissection in patients with parotid tumours, given the high incidence of lymph-node invasion in malignant parotid tumours and the risk of false-negatives in pathological examination. Indeed, these latter considerations were illustrated by a case report of a primary tumour that appeared histologically benign until a biopsy of a macroscopically normal-appearing node revealed metastatic spread. The authors did not describe how this node was identifi ed during the surgical procedure. Gould and colleagues 1 also described 28 SLN biopsies of malignant or benign parotid tumours. The SLN was positive in three of eight patients with malignant tumours, who subsequently underwent radical neck dissection. Survival was similar in patients with or without radical lymph-node dissection. In 1977, Cabanas and co-workers 4 investigated the SLN concept in 46 cases of penile carcinoma. Instead of preoperative identifi cation of the SLN, they injected contrast media into the dorsal lymphatics of the penis, and found that the biopsy of the contrast-enhanced sentinel node could indicate the tumour status of the entire nodal basin. Reports of SLN biopsy in patients with breast cancer emerged in the 1990s, 5,6 along with the development of alternative methods for identifi cation of the SLN. These methods, including the use of radioactive tracers and patent blue dye, 7,8 were further investigated in cervical cancer, endometrial cancer, and melanoma. Nowadays, SLN biopsy is well accepted and recommended as a valuable alternative to axillary lymph-node dissection. 3,9 In patients with breast cancer, up to 70% of axillary lymph-node dissections can be avoided with SLN biopsy, which positively aff ects a patient’s quality of life—reducing postoperative pain, lymphoedema, paresthesia, and diminished arm mobility.

Drug selection and dosing in pregnant cancer patients: insights from clinical pharmacokinetics

The co-occurrence of cancer and pregnancy is a rare clinical situation (1/1000 pregnancies), with breast cancer being the most frequent solid tumour in pregnant patients [1]. Recent clinical data indicate that systemic treatment in breast cancer patients during the second and third trimesters of pregnancy should be as close as possible to that used in non-pregnant patients (level of evidence 2b) [2–4], with the exception of trastuzumab that exhibits renal toxicity for the foetus, due to major transplacental transfer [4, 5]. Clinical experience indicates a good tolerability of anthracyclines and taxanes during the second and third trimesters of pregnancy [6–9], but the known physiological variations in drugs pharmacokinetics during pregnancy [10] raise important questions regarding the optimal drug dosage in pregnant patients. Indeed, the favourable toxicity profile of these agents during the late trimesters of pregnancy questions whether pregnant patients could achieve suboptimal plasma concentrations compared with that observed in non-pregnant patients, resulting in decreased anti-tumour efficacy. Lessons from pharmacological literature in pregnant cancer patients could therefore be summarized as follows. Firstly, most anti-cancer agents are prescribed according to body surface area (BSA), resulting in large inter-patient variability even outside the pregnancy setting. In the context of pregnancy, no data are available to date to support the use of alternative dosing methods, and dosing based on BSA, using the actual patient’s weight, remains a standard [11]. On the other hand, the use of target-area under the curve (AUC)-based dosing for carboplatin (in platinum-sensitive diseases such as triple-negative breast cancer, lung cancer and gynaecological malignancies) cannot be recommended in pregnant patients [11]. Secondly, an increase in the activity of major enzymes involved in the metabolism of taxanes and anthracyclines (such as cytochrome p450 isoform CYP3A4) is observed during the late trimesters of pregnancy [12], potentially resulting in decreased drug exposure. In the present issue of Annals of Oncology, van Hasselt et al. [10] investigated the pharmacokinetics of doxorubicin, epirubicin, paclitaxel and docetaxel in pregnant and non-pregnant cancer patients. Whereas exposure to anthracyclines does not seem to be significantly influenced by pregnancy, exposure to taxanes was markedly decreased in pregnant patients. These data are in part supported by recent findings on doxorubicin pharmacokinetics in pregnant patients, pinpointing the lack of deleterious effects of pregnancy on doxorubicin AUC over 48 h [13]. As a consequence, current anthracyclines dosing methods should probably be remained unchanged, but clinicians should be aware of potential suboptimal exposure while using taxanes. Thirdly, although maternal drug exposure is a concern in terms of treatment efficacy, the transplacental transfer of anti-cancer agents is critical for fetal safety. Data on transplacental transfer rates indicate similar and reassuring data on doxorubicin, epirubicin and taxanes [14–16], still with major inter-patient variability, particularly marked with docetaxel [16]. Consequently, from the fetal safety point of view, paclitaxel should probably be preferred to docetaxel in the setting of pregnancy. Further studies on placental transporters and their influence on drug disposition are ongoing and will probably help handling taxanes in pregnant patients. To date, whether paclitaxel dose increases could result in (i) improved anti-tumour efficacy and (ii) different fetal toxicity remains largely unknown. Consequently, further clinico-pharmacological studies are needed before changing our practice on chemotherapy dosing during pregnancy. Although taxanes appear safe in the second and third trimesters of pregnancy, anthracycline-based chemotherapy should be preferred as initial treatment in breast cancer patients until concerns on paclitaxel exposure and efficacy are elucidated in pregnant patients. Collaborative studies such as those proposed by the European Society of Gynaecological Oncology Cancer in Pregnancy Taskforce (http://www.cancerinpregnancy.org/) are mandatory to improve knowledge and patients care in such a complex clinical setting.

Grossesse après cancer : pour qui et quand ?

Planning a pregnancy for patients with a history of cancer, including breast cancer, is a clinical situation that becomes more and more common. Several specific items are to be discussed: decrease of fertility after cancer treatment, fertility preservation options, impact of pregnancy on cancer recurrence risk and appropriate interval between cancer and pregnancy. Programming pregnancy after cancer is doable in a multidisciplinary setting, and begins at cancer diagnosis to anticipate the various specific pitfalls. Favor adequate oncologic care remains the leading rule.

Using Anti-Cancer Agents during the Post-Partum Period: Not that Simple

kinetic and pharmacodynamic changes during the first month following delivery. In the present issue of OnkOlOgie, Savvari et al. [8] report on a patient diagnosed with a Burkitt’s lymphoma with bilateral breast involvement. The diagnosis was made shortly after delivery, and the treatment was initiated during the next month. Despite disease-related liver dysfunction, the authors report a successful use of a multi-drug regimen, with adapted doses and omission of methotrexate. The diagnosis of breast malignancies during pregnancy is often difficult, and a delay in diagnosis is frequent [9]. For instance, in one series from the M.D. Anderson Cancer Center [10], the average delay in diagnosis in pregnant women was 8.2 months compared to 1.9 months in non-pregnant women. Burkitt’s lymphomas associated with pregnancy have a dismal prognosis, in particular when the diagnosis is made in early pregnancy, thereby making difficult the use of optimal dose-dense treatments [11]. Finally, the use of anti-cancer agents during the post-partum period (< 6 weeks after delivery) may be as challenging as their use during pregnancy. Although the fetal risk is by definition absent in this setting, the optimal maternal treatment should be tailored to the pharmacological properties of the drugs employed. Further studies in breast cancer patients receiving taxanes and anthracyclines in this period are on going, and may provide additional information in order to better handle anti-cancer agents in patients with pregnancy-associated malignancies.

Use of anticancer agents in gynecological oncology during pregnancy: a systematic review of maternal pharmacokinetics and transplacental transfer.

ABSTRACT Introduction: Cancer affects one in a thousand pregnant women and gynecological cancers are one of the most frequent malignancies. Chemotherapy remains the cornerstone treatment for gynecological cancer. Although all chemotherapeutic agents can cross the placental barrier, the extent of placental transfer varies considerably. Furthermore, the significant physiological variations observed in pregnant women may have an impact on pharmacokinetic parameters. Given the complexity of predicting placental transfer, in vivo and ex vivo studies are essential in this context. In view of the paucity of data on chemotherapy during pregnancy, the objective of the present study was to summarize all the available data on the transplacental transfer of anticancer drugs used to treat gynecological cancers. Areas covered: In order to evaluate the in vivo and ex vivo transplacental transfer of the anticancer drugs most frequently used in gynecological malignancies, we carried out a comprehensive review of the literature published from 1967 to 2015. Lastly, we summarized recent clinical guidelines on the treatment of gynecological cancers in pregnant patients. Expert opinion: The preclinical and scarce clinical data must now be extrapolated to define the maternofetal toxicity/efficacy profile and thus guide the physicians to choose anticancer drugs more efficiently in this complex situation.

Fertility-Sparing Approach in a Teenager with Uterine Tumor Diagnosed as a Sarcoma on Imaging

Background: Uterine tumors are extremely rare in teenage patients. Although magnetic resonance imaging (MRI) can help distinguish between leiomyoma and sarcoma, it may also seriously mislead the diagnosis. Case Report: An 18-year-old female patient presented with marked anemia, and a rapidly growing uterine tumor that strongly suggested uterine sarcoma on MRI. In order to avoid dispensable radical surgery, explorative laparotomy with tumor biopsy was performed after balancing risk/benefit ratio. Extemporaneous pathologic examination revealed a benign leiomyoma, and the patient subsequently underwent complete conservative myomectomy. Conclusion: Preserving fertility is an important issue in young patients with uterine tumors, and tumor biopsy may overcome MRI false positive results, as illustrated in this case. Conservative approach deserves further evaluation in this specific setting.

Placental perfusion: interest and limits

Department of Gynecology and Obstetrics, Centre Hospitalier Intercommunal de Poissy Saint Germain, Poissy, France, GIG-EA 7404, UFR des Sciences de la Santé Simone Veil, Université Versailles Saint Quentin en Yvelines, Montigny-le-Bretonneux, France, INSERM UMR-S 1139, Université Paris Descartes, Sorbonne Paris Cité, Paris, France, PremUp Foundation, Paris, France, and Department of Cytogenetic, Centre Hospitalier Intercommunal de Poissy Saint Germain, Poissy, France