癌症治療與生兒育女

<<鄧豪偉醫師 編譯 2016/3/31>>

前言:
大(結)腸直腸癌，是最常見的惡性腫瘤之一，初步診斷為第II-III期病友中 (超過50％)，約6-12％的患者是年輕成年人(生育年紀)。隨著大(結)腸直腸癌在年輕成人的增加發病率和接受治療形成治癒後，在過去的幾十年裡，產生許多治療後的生育問題。
由於許多癌症治療會損害的生育力，處於生育年齡患者，在癌症的治療過程中，常必須面對和考慮重要和複雜的現在和將來的生育能力問題，因此，治療前。應該諮詢他們的癌症醫療團隊有關癌症治療可能對他們生育及孩子的影響，使他們可以進行適當的選擇。

只要你還想生育:
首先，最重要的是"提出你的問題(需求)"，
病人可以問他們的腫瘤科團隊醫生(包括婦產生殖內分泌醫師)。

 

舉例常見問題如下:
1.會不會造成女性改變月經狀況?
2.治療會不會造成不孕 ?
3.如果順利有小孩，其先天基因會不會受影響。
4.如何保留生育能力(在開始治療前)？
5.將來有哪些可用的選項來幫忙我在未來生育？
6.停止治療後，多久才能嘗試生育？( 等多久才是不復發? 所以常建議2-5年後才考慮懷孕； 懷孕改變免疫會復發嗎?)

這些問題常須依疾病別，治療方式，個別討論，但還是有個大致方向:

 

簡單說，
1.只要你還有想生育的想法，那就會診"婦產生殖內分泌醫師":
2.存精子(數天 準備)
3. 存卵子(2-4周 準備)
4. 將來再想辦法形成受精卵，再想辦法著床，生育。

 

下面是較細部的問題:

1.開刀直腸是否吊高卵巢? (是為了不要接受電療直接影響，但還是常無法避開間接電療對卵巢影响?)
2.電療腦部: 影響腦部賀爾蒙控制生育賀爾蒙。
3.電療下腹部: 影響卵巢(生育賀爾蒙)，子宮功能，(因為成年女性生殖細胞的變化受生育4.賀爾蒙調控，如果荷爾蒙的作用失調，使卵子無法順利排出，生殖機能就會受影響，所以成年女性化療後的不孕常是導因於荷爾蒙失調無法排卵所致，而不是卵子直接受到傷害)。
5.化學治療:影響月經(生育賀爾蒙)，精子DNA(形成_alkylating agents affect sperm production)，卵子發展，子宮功能...。
6.標靶治療: 影響很難評估!
7.懷孕期接觸治療，好像在短期(2-3年)小孩評估中，影響小孩不大。(Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy September 29, 2015, at NEJM.org.)

 

<<藥物說明>>
1.大部分化學治療會傷害卵子影響生育:
影響較大者(舉例)(most likely to cause egg damage and infertility)
Busulfan, Carboplatin, Carmustine (BCNU), Chlorambucil, Cisplatin, Cyclophosphamide (Cytoxan®), Dacarbazine, Doxorubicin (Adriamycin®), Ifosfamide, Lomustine (CCNU), Mechlorethamine, Melphalan, Procarbazine, Temozolomide
影響較小者(舉例)
5-fluorouracil (5-FU),Bleomycin, Cytarabine, Dactinomycin, Daunorubicin, Fludarabine, Gemcitabine, Idarubicin, Methotrexate, Vinblastine, Vincristine

2.標靶治療(很多新校要等資料): 舉例
癌思停 (avastin, bevacizumab) 使卵巢失能
基立克（Gleevec）  使胎兒缺陷

 

個論
<<Irinotecan>>
Embryofetal Toxicity(有畸胎風險)
Irinotecan hydrochloride injection can cause fetal harm when administered to a pregnant woman. Irinotecan was embryotoxic in rats .....Irinotecan was embryotoxic and resulted in decreased learning ability and female fetal body weight in surviving pups; the drug was teratogenic at lower exposures (approximately 0.025 times the AUC in humans at the 125 mg/m2 dose). There are no adequate and well-controlled studies of Irinotecan in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Irinotecan hydrochloride injection.
Impairment of Fertility(可能影響生育)

No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of Irinotecan in doses of up to 6 mg/kg/day to rats and rabbits; however, atrophy of male reproductive organs was observed after multiple daily Irinotecan doses both in rodents at 20 mg/kg and in dogs at 0.4 mg/kg. ........

 

<<Oxaliplatin>>
Pregnancy Category D(有畸胎風險)
Based on direct interaction with DNA, Oxaliplatin may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Oxaliplatin in pregnant women. Reproductive toxicity studies in rats demonstrated adverse effects on fertility and embryo-fetal development at maternal doses that were below the recommended human dose based on body surface area. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant and use effective contraception while receiving treatment with Oxaliplatin.
Pregnant rats were administered Oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days 1 to 5 (pre-implantation), 6 to 10, or 11 to16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6 to 10 and 11 to16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6 to10. Administration of Oxaliplatin to male and female rats prior to mating resulted in 97% post-implantation loss in animals that received approximately one-seventh the recommended human dose based on the body surface area.
Impairment of Fertility(可能影響生育)

In a fertility study, male rats were given Oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of Oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight). Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered Oxaliplatin at 0.75 mg/kg/day × 5 days every 28 days for three cycles. A no effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose on a body surface area basis.

 

<<爾必得舒 Cetuximab>>
Pregnancy Category C(!有畸胎風險)
There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Impairment of Fertility(?可能影響生育)
Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

 

FDA Pregnancy Categories
Category A: Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). Example drugs or substances: levothyroxine, folic acid, magnesium sulfate, liothyronine
Category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. Example drugs: metformin, hydrochlorothiazide, cyclobenzaprine, amoxicillin, pantoprazole
Category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Example drugs: tramadol, gabapentin, amlodipine, trazodone, prednisone
Category D There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Example drugs: lisinopril, alprazolam, losartan, clonazepam, lorazepam
Category X Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. Example drugs: atorvastatin, simvastatin, warfarin, methotrexate, finasteride

Category N FDA has not classified the drug.

references

http://www.cancer.org/