- Email: [email protected]
Neoadjuvant chemotherapy in cervical cancer in pregnancy
Accepted Manuscript Neoadjuvant Chemotherapy In Cervical Cancer In Pregnancy Associate Professor Arunachalam Ilancheran, MBBS, M MED, FRCOG, MD, FAMS
PII:
S1521-6934(15)00190-X
DOI:
10.1016/j.bpobgyn.2015.10.008
Reference:
YBEOG 1555
To appear in:
Best Practice & Research Clinical Obstetrics & Gynaecology
Received Date: 29 July 2015 Accepted Date: 9 October 2015
Please cite this article as: Ilancheran A, Neoadjuvant Chemotherapy In Cervical Cancer In Pregnancy, Best Practice & Research Clinical Obstetrics & Gynaecology (2015), doi: 10.1016/ j.bpobgyn.2015.10.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Associate Professor Arunachalam Ilancheran
Division of Gynecologic Oncology Department of Obstetrics & Gynaecology National University Hospital
TE D
Singapore
M AN U
MBBS, M MED, FRCOG, MD, FAMS
Email: [email protected]
AC C
EP
Tel: (65) 67724274 Fax: (65) 67794753
Conflicts of Interest: (None)
SC
Neoadjuvant Chemotherapy In Cervical Cancer In Pregnancy
RI PT
ACCEPTED MANUSCRIPT
RI PT
ACCEPTED MANUSCRIPT
Abstract
M AN U
SC
Cervical cancer is the most common gynecological cancer encountered in pregnancy. The standard treatment of early cervical cancer is usually surgical removal of the cervix(in selected cases) or more commonly, the uterus. However, when cervical cancer occurs in pregnancy, definitive surgical treatment often needs to be postponed so that the fetus reaches maturity. Neoadjuvant chemotherapy (NACT) is an innovative way of managing these patients. It helps in controlling the disease and at the same time help delay the timing of delivery in these patients. This paper will review the history of NACT and review the literature. Practice points and agenda for further research will be presented.
Cervical cancer in pregnancy Neoadjuvant chemotherapy
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EP
Fertility preservation
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Key words
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Neoadjuvant chemotherapy in cervical cancer in pregnancy.
RI PT
Introduction The standard of care in the treatment of cervical cancer is surgery in early stages and chemoradiation in the more advanced stages. Surgery may involve only the removal of the cervix, in cases where fertility preservation is important, or a hysterectomy when this is not a consideration. With chemoradiation, fertility preservation is not possible currently.
M AN U
SC
When cervical cancer is diagnosed in pregnancy, it presents a complex situation for the patient and her physician. It needs a multidisciplinary approach that involves the gynecologic oncologist, radiation oncologist, medical oncologist, the obstetrician, pathologist and most importantly, the patient. Her concerns for the health of the unborn fetus, herself and future fertility will all have a great impact on the final mode of treatment. The same considerations present a very difficult situation for the treating physician. Among these, the most difficult is the need for fertility preservation. Fertility preservation is usually considered only in early stage (stages 1 & 2A) cervical cancer in pregnancy.
Chemotherapy in pregnancy
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Neoadjuvant chemotherapy (NACT) is an innovative way of managing cervical cancer in pregnancy. It helps in controlling the disease and at the same time may help delay the timing of delivery in patients whose fetus hasn’t reached state of viability. It may also help in reducing tumour size which can help in performing fertility sparing procedures like trachelectomy. This review will highlight the types of drugs used in NACT, their effects on the fetus and the mother and the efficacy of NACT in treating cervical cancer in pregnancy by reviewing the published literature.
1
EP
Chemotherapy had been used in pregnancy since early 1950’s . The first clinical experience with
AC C
chemotherapy during pregnancy was reported by Aviles et al in 1988 2. They treated women with hematological malignancies during pregnancy where any delay in treatment would have been fatal to the mother and child. The biggest fear of using any chemotherapy is the potential teratogenic effects of these agents and the risk of miscarriage. The teratogenicity of any drug depends on the timing of exposure, the dose, and the degree to which the drug crosses the placenta. The most vulnerable period 3
appears to be the period of organogenesis, weeks 2-8 after conception . First trimester use of chemotherapy may result in spontaneous abortion, fetal death and fetal malformations. When the drugs are given in the second and third trimester, there is increased risk of intrauterine growth restriction and low birth weight. However, long term studies have shown no significant effect on learning disabilities or any hematological or immunological abnormalities. In a prospective study of 70 children who were exposed to chemotherapy in utero, the general health, cognitive development and 4
cardiac outcome levels were comparable to the general population (median follow-up: 22 months) . On the other hand, it is well known that prematurity is associated with impaired cognitive function and it
ACCEPTED MANUSCRIPT
should be avoided whenever possible. The decision to use chemotherapy during pregnancy must balance the risk to the fetus versus prolonging maternal survival.
SC
RI PT
Many different types of chemotherapy agents have been used in pregnancy, depending on the malignancy being treated. In this article, we will confine ourselves to the agents that have been used to treat cervical cancer in pregnancy. These mainly include cisplatin, vincristine, and bleomycin . More recently there have been reports of use of carboplatin and paclitaxel in these patients. The most widely used drug of these has been cisplatin. Whilst the side effects of cisplatin in the non-pregnant patients are well documented, the effects of cisplatin on the fetus has not been well studied. Most reports on use of cisplatin in pregnancy have either been small, retrospective studies or individual case reports. The pharmacokinetics of drugs in pregnancy is not very well understood. During pregnancy, many changes occur in the physiology, such as absorption, distribution and metabolism. These alterations are more pronounced during the third trimester of pregnancy which may alter the efficacy and toxicity of 5
the chemotherapeutic agents . Knowledge about the transplacental passage of chemotherapy agents in the humans is very limited. Also the metabolism of platinum in pregnant patients may be different from
M AN U
6
TE D
the non-pregnant women. In the first study of its kind, Marnitz et al measured cisplatin concentrations in 7 patients presenting with cervical cancer in pregnancy. Synchronous samples from maternal blood, umbilical cord blood and amniotic fluid were taken. All patients had delivered healthy babies. The cisplatin concentrations in the umbilical cord and amniotic fluid were 31-65 and 13-42% of the maternal blood respectively. The authors concluded that there was a significantly lower level of cisplatin in the umbilical cord blood and amniotic fluid compared to maternal blood and that these findings give additional security to use neoadjuvant cisplatin chemotherapy in pregnancy. However, they emphasized that long term oncologic and pediatric followup is essential to confirm the safety of this practice. In animal studies, it has been found that that less than 2% of maternal plasma levels of taxanes are found in the fetal plasma and in the case of carboplatin, fetal plasma concentrations reach up to 60% of 7
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EP
maternal levels .
NACT in cervical cancer
In 1999, concurrent chemotherapy was accepted as the standard of care in the treatment of high-risk early stage and locally advanced cervical cancer, after the publication of 5 randomized trials which 8-12 showed the superiority of this treatment over conventional radiotherapy alone . In a systematic 13
review and meta-analysis of 19 randomized trials, Green et al besides confirming the superiority of chemoradiation over radiation alone, also stated that the most striking finding in their meta-analysis was the highly significant reduction in the incidence of distant metastasis in the chemoradiotherapy group.
ACCEPTED MANUSCRIPT
The rationale for the use of neoadjuvant chemotherapy for locally advanced cervical carcinoma is 14
based on the following observations :
RI PT
1. Tumor size is an important factor determining radiation responsiveness. Primary chemotherapy may lead to a tumor bulk reduction and thus improve local control by irradiation or surgical resection. 2. Neoadjuvant chemotherapy may control micrometastases in distant sites as well as in regional lymph nodes, early in the course of the disease.
SC
3. Tumor vascularization and bone marrow reserve are compromised by irradiation. Therefore, better response rate to up-front, more aggressive chemotherapy may be tolerated and a better vascularity promotes a higher concentration of drug delivery to the tumor bed before pelvic irradiation. 15-17
.
M AN U
More recently, NACT has been used in fertility sparing surgery in cervical cancer
NACT in pregnancy
TE D
Treatment of cervical cancer in pregnancy depends on the stage of the disease, the gestational age at diagnosis, the patient’s desire to maintain the pregnancy and the histology. When fetal viability has not been attained, delaying delivery raises concern about progression of the disease. The use of NACT in these circumstances is an attractive option that allows the pregnancy to progress to viability and, at the same time, possibly, keeping in check the progression of the tumour. 18
The guidelines from an International Consensus Meeting on Gynecological Cancers in Pregnancy , have recommended NACT under the following circumstances:
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1. In node negative stage 1B1, less than 2 cm, treated during second trimester of pregnancy in patients wishing to preserve pregnancy. 2. In Stage 1B1 (2-4 cm), NACT can be used either in node negative patients as before or be given primarily before nodal assessment by lymphadenectomy. 3. In stages 1B2-2B, NACT is used till maturity and delivery.
The guidelines recommend that the chemotherapy regime should be cisplatin based. The addition of paclitaxel may increase the response rates. The combination of carboplatin and paclitaxel may be less toxic to the patient. In a review of the English literature up to early 2015, we found reports of 39 cases of cervical cancer in pregnancy that have been treated with NACT. (Table 1)
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Table 1 Neoadjuvant chemotherapy in cervical cancer during pregnancy Stage Chemotherapy/cycles Response to Treatment Followup Status chemotherapy (mths) at last visit Giacolone IB1 Cisplatin CR CS RH 12 NED 19 PLND 1996 PALND Caluwaerts IB1 Cisplatin PR CS RH 10 NED 20 PLND 2006 PALND de Lima 1B1 Cisplatin, Vincristine PR CS, RH, 24 NED 21 PLND, adj 2013 CT Chun IB1 Cisplatin, PR CS RH 49 DOD 22 Paclitaxel PLND 2010 PALND Kong et al 1B1 Cisplatin, Paclitaxel PR CS, RH, 104, 24 NED 23 (n=2) PLND, Adj 2014 CT Favero IB1 Cisplatin NA NA 12,10,5 NED=3 24 (n=5) NA=2 2010 Fruscio IB1 Cisplatin PR=3, SD=1 CS RH 41-65 NED=4 25 (n=4) 2012 Smyth IB2 Adriamycin, PR CS NA NED Cyclophosphamide 201026 Tewari IB2 Cisplatin, PR CS RH 24 NED 27 Vincristine PLND 1998 Karam IB2 Cisplatin NR CS RH 14 NED 28 PLND 2007 PALND Chun IB2 Cisplatin PR Cs RH 60 NED 22 Paclitaxel PLND 2010 PALND Rabaiotti IB2 Cisplatin SD CS 24 DOD 29 XRT 2010 30 IB2 Cisplatin SD CS RH x 2 52 DOD Lai 1997 (n=2) Vincristine PR 59 DOD Bleomycin 31 IB2 Cisplatin PR CS, XRT 21 NED Li 2011 (n=2) Paclitaxel CS 13 x2 Fruscio IB2 Cisplatin, Vincristine SD CS RH XRT 21 NED 25 (n=5) Cisplatin PR CS RH 13 NED 2012
Baby
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Author
Well
Well
Well
Well
Well
NA Well Well Well Well
Well
Well NA
Well x 2 Well x 5
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Cisplatin, Paclitaxel
Peculis 32 2015 Tewari 27 1998 Bader 33 2007 Chun 22 2010
IB2
Cisplatin, Adriamycin
CR
IIA
Cisplatin Vincristine Cisplatin Vincristine Carboplatin Paclitaxel
PR
Marana 34 2001
IIB
Cisplatin Bleomycin
Declined treatment after delivery PR
IIA IIA
PR PR
27 153 113 35
DOD NED NED NED
Well
20
NED
Well
5
DOD
Well
80
NED
Well
48
AWD
Well
13
DOD
Well
RI PT
1B2
CS RH CS RH CS RH XRT CS, RH, PLND, Adj CT CS RH PLND CS RH PLND CS RH PLND CS RH PLND PALND CS
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Kong et al 201423
PR PR SD PR
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Cisplatin Cisplatin,Paclitaxel
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Palaia IIB Cisplatin RH PLND 10 NED Well 35 Paclitaxel 2007 Boyd IIB Cisplatin NA XRT 15 NED Well 36 2009 Benhaim IIIB Vincristine PD CT XRT 10 DOD Well 37 2008 Seamon IIIB Cisplatin PR XRT 48 NED Well 38 Vincristine 2009 (CR=Complete Response; PR=Partial Response; SD=Stable Disease; CS=Cesarean section; RH=Radical hysterectomy; RHND=Radical Hysterectomy; PLND=Pelvic Lymph Node Dissection; PALND=Para Aortic Lymph Node Dissection; XRT=External Radiotherapy; Adj CT=Adjuvant chemotherapy; NED=No Evidence of Disease; DOD=Died Of Disease)
Conclusion
Though no randomized trials exist, the available information suggests that NACT is an attractive and viable option in the management of cervical cancer in pregnancy. The vast majority of the patients had response to the chemotherapy allowing prolongation of the pregnancy. The most common drug used was cisplatin although the duration of therapy varied among the authors. Fetal well-being was not compromised in any of the cases reported. This last observation is an important one in counseling mothers going for NACT; for often the worry uppermost in their mind is the teratogenic effects on the unborn child.
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Practice Points.
RI PT
. Cervical cancer is the most frequently encountered gynecological malignancy in pregnancy. . The patient MUST be managed by a multidisciplinary team comprising the obstetrician, gynecologic oncologist, medical oncologist, radiation oncologist and social worker. . It is safe to continue the pregnancy, until it reaches maturity, in the presence of cervical cancer.
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. Cisplatin is a safe drug to use in pregnancy in the neoadjuvant setting.
Research agenda
. To evaluate the role of other drugs like carboplatin, which is less toxic to mother, in neoadjuvant setting.
References
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. To explore the role of fertility preserving surgery after NACT in pregnancy.
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1. Thiersch JB, Therapeutic abortions with a folic acid antagonist, 4-aminopteroylglutamic acid (4amino P.G.A) administered by the oral route. AJOG, 63:1298-304, 1952. 2. Aviles A, Niz J. Long-term followup of children born to mothers with acute leukemia during pregnancy. Med Pediatr Oncol 1988; 16:3-6. 3. Williams S, Schilsky RL. Antineoplastic drugs administered during pregnancy. Sem Oncol 2000; 27:618:22. 4. *Amant F, Van Calsteren K, Halaska MJ et al. Long term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: An observational study. Lancet Oncol 2012; 13:256-64. 5. *Amant F, Han SN, Gziri NM et al. Chemotherapy during pregnancy. Curr Opin Oncol 2012; 24:580-6. 6. Marnitz S, Kohler C, Oppelt P etal. Cisplatin application in pregnancy: first in vivo analysis of 7 patients. Oncology 2010; 79(1-2):72-7. 7. Van Calsteren K, Verbesselt R, Devilieger R et al. Transplacental transfer of paclitaxel, docetaxel, carboplatin and trastuzumab in a baboon model. Int J Gynecol Cancer 2010; 20:1456-64. 8. Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC Jr, et al:Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy
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14. 15.
16. 17.
18. 19.
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in stage IIB-IVA carcinoma of the cervix with negative paraaortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999; 17: 1339–1348. Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 340: 1137–1143. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al: Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999; 340: 1144–1153. Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL 3rd, et al: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999; 340:1154–1161. Peters WA 3rd, Liu PY, Barrett RJ 2nd, Stock RJ, Monk BJ, Berek JS, et al: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000; 18:1606–1613. Green JA, Kirwan JM, Tiernwy JK et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and metaanalysis. Lancet 2001; 358:781-96. Edelmann, David Z.; Anteby, Shaoul O. Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer--Where Does It Stand?: A Review. Obstet Gynecol Surv 1996; 51:305-313. Robova H, Halaska MJ, Pluta M et al. Oncological and pregnancy outcomes after high-dose density neoadjuvant chemotherapy and fertility sparing surgery in cervical cancer. Gynecol Oncol 2014; 135:213-6. Kobayashi Y, Akiyama F, Hasumi K. A case of successful pregnancy after treatment of invasive cervical cancer with systemic chemotherapy and conization. Gynecol Oncol 2006; 132:254-9. Salihi R, Leunen K, Limbergen EK et al. Neoadjuvant chemotherapy followed by large cone resection as fertility sparing therapy in stage iB cervical cancer. Gynecol Oncol 2015; doi: 10.1016/j.ygyno.2015.05.043. Amant F, Van Calsteren K, Halaska MJ et al. Gynecological cancers in pregnancy: guidelines of an international consensus meeting. Int J Gynecol Cancer 2009; 19:S1-S12. Giacalone PL, Laffargue F, Benos P et al. Cisplatinum neoadjuvant chemotherapy in a pregnant woman with invasive carcinoma of cervix. Br J Obstet Gynaecol. 1996 Sep; 103(9):932-4. Caluwaerts S, VAN Calsteren K, Mertens L et al. Neoadjuvant chemotherapy followed by radical hysterectomy for invasive cervical cancer diagnosed during pregnancy: report of a case and review of the literature. Int J Gynecol Cancer. 2006 Mar-Apr; 16(2):905-8. de Lima CA, Barcelos ACM, Paschoini MC et al. Conservative treatment of uterine cervical adenocarcinoma of pregnancy. Case report. Case Rep Obstet Gynecol 2013; doi: 10.1155/2013/692017. Epub 2013 Dec 17. Chun KC, Kim DY, Kim JH et al. Neoadjuvant chemotherapy with paclitaxel plus platinum followed by radical surgery in early cervical cancer during pregnancy: three case reports. Jpn J Clin Oncol. 2010 Jul;40(7):694-8. Kong TW, Lee EJ, Lee Y et al. Neoadjuvant and postoperative chemotherapy with paclitaxel plus cisplatin in the treatment of FIGO stage 1B cervical cancer in pregnancy. Obstet Gynecol Sci. 2014 Nov;57(6):539-43.
21.
22.
23.
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24. Favero G, Lanowska M, Schneider A et al. Laparoscopic pelvic lymphadenectomy in a patient with cervical cancer stage Ib1 complicated by a twin pregnancy. J Minim Invasive Gynecol. 2010 Jan-Feb;17(1):118-20. 25. *Fruscio R, Villa A, Chiari S, et al. Delivery delay with neoadjuvant chemotherapy for cervical cancer patients during pregncncy: a series of 9 cases and literature review. Gynecol Oncol. 2012 Aug;126(2):192-7. 26. Smyth EC, Korpanty G, McCaffrey JA, et al. Small-cell carcinoma of the cervix at 23 weeks gestation. J Clin Oncol Jun 20 2010;28(18):e295–7. 27. Tewari K, Cappuccini F, Gambino A et al. Neoadjuvant chemotherapy in the treatment of locally advanced cervical carcinoma in pregnancy: a report of two cases and review of issues specific to the management of cervical carcinoma in pregnancy including planned delay of therapy. Cancer 1998;82(8):1529–34. 28. Karam A, Feldman N, Holschneider CH. Neoadjuvant cisplatin and radical cesarean hysterectomy for cervical cancer in pregnancy. Nat Clin Pract Oncol 2007;4(6):375–80. 29. Rabaiotti E, Sigismondi C, Montoli S, et al. Managment of locally advanced cervical cancer in pregnancy: a case report. Tumori 2010;96(4):623–6. 30. Lai CH, Hsueh S, Chang TC, et al. Prognostic factors in patients with bulky stage IB or IIA cervical carcinoma undergoing neoadjuvant chemotherapy and radical hysterectomy. Gynecol Oncol 1997;64(3):456–62. 31. Li J, Wang LJ, Zhang BZ, et al. Neoadjuvant chemotherapy with paclitaxel plus platinum for invasive cervical cancer in pregnancy: two case report and literature review. Arch Gynecol Obstet 2011;284(3):779–83. 32. Peculis LD, Ius Y, Campion M, etal. Stage 1B2 adenosquamous cervical cancer diagnosed at 19 weeks gestation. Aust N Z J Obstet Gynaecol. 2015;55(1):94-7. 33. Bader AA, Petru E, Winter R. Long-term follow-up after neoadjuvant chemotherapy for high-risk cervical cancer during pregnancy. Gynecol Oncol 2007;105(1):269–72. 34. Marana HR, de Andrade JM, da Silva Mathes AC, et al.Chemotherapy in the treatment of locally advanced cervical cancer and pregnancy. Gynecol Oncol 2001;80(2):272–4. 35. Palaia I, Pernice M, Graziano M, et al. Neoadjuvant chemotherapy plus radical surgery in locally advanced cervical cancer during pregnancy: a case report. Am J Obstet Gynecol 2007;197(4):e5–6. 36. *Boyd A, Cowie V, Gourley C. The use of cisplatin to treat advanced-stage cervical cancer during pregnancy allows fetal development and prevents cancer progression: report of a case and review of the literature. Int J Gynecol Cancer 2009;19(2):273–6. 37. Benhaim Y, Pautier P, Bensaid C, et al. Neoadjuvant chemotherapy for advanced stage cervical cancer in a pregnant patient: report of one case with rapid tumor progression. Eur J Obstet Gynecol Reprod Biol 2008;136(2):267–8. 38. Seamon LG, Downey GO, Harrison CR, et al. Neoadjuvant chemotherapy followed by postpartum chemoradiotherapy and chemoconsolidation for stage IIIB glassy cell cervical carcinoma during pregnancy. Gynecol Oncol 2009;114(3):540–1.
ACCEPTED MANUSCRIPT . Cervical cancer is the most common gynecological cancer in pregnancy. . A multidisciplinary approach is vital in the management of this condition. . Neoadjuvant chemotherapy (NACT) helps delay delivery until fetal maturity is achieved.
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. In selected cases , NACT , may allow fertility preservation.
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. Cisplatin is the most widely studied chemotherapy agent in pregnancy
PII:
S1521-6934(15)00190-X
DOI:
10.1016/j.bpobgyn.2015.10.008
Reference:
YBEOG 1555
To appear in:
Best Practice & Research Clinical Obstetrics & Gynaecology
Received Date: 29 July 2015 Accepted Date: 9 October 2015
Please cite this article as: Ilancheran A, Neoadjuvant Chemotherapy In Cervical Cancer In Pregnancy, Best Practice & Research Clinical Obstetrics & Gynaecology (2015), doi: 10.1016/ j.bpobgyn.2015.10.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Associate Professor Arunachalam Ilancheran
Division of Gynecologic Oncology Department of Obstetrics & Gynaecology National University Hospital
TE D
Singapore
M AN U
MBBS, M MED, FRCOG, MD, FAMS
Email: [email protected]
AC C
EP
Tel: (65) 67724274 Fax: (65) 67794753
Conflicts of Interest: (None)
SC
Neoadjuvant Chemotherapy In Cervical Cancer In Pregnancy
RI PT
ACCEPTED MANUSCRIPT
RI PT
ACCEPTED MANUSCRIPT
Abstract
M AN U
SC
Cervical cancer is the most common gynecological cancer encountered in pregnancy. The standard treatment of early cervical cancer is usually surgical removal of the cervix(in selected cases) or more commonly, the uterus. However, when cervical cancer occurs in pregnancy, definitive surgical treatment often needs to be postponed so that the fetus reaches maturity. Neoadjuvant chemotherapy (NACT) is an innovative way of managing these patients. It helps in controlling the disease and at the same time help delay the timing of delivery in these patients. This paper will review the history of NACT and review the literature. Practice points and agenda for further research will be presented.
Cervical cancer in pregnancy Neoadjuvant chemotherapy
AC C
EP
Fertility preservation
TE D
Key words
ACCEPTED MANUSCRIPT
Neoadjuvant chemotherapy in cervical cancer in pregnancy.
RI PT
Introduction The standard of care in the treatment of cervical cancer is surgery in early stages and chemoradiation in the more advanced stages. Surgery may involve only the removal of the cervix, in cases where fertility preservation is important, or a hysterectomy when this is not a consideration. With chemoradiation, fertility preservation is not possible currently.
M AN U
SC
When cervical cancer is diagnosed in pregnancy, it presents a complex situation for the patient and her physician. It needs a multidisciplinary approach that involves the gynecologic oncologist, radiation oncologist, medical oncologist, the obstetrician, pathologist and most importantly, the patient. Her concerns for the health of the unborn fetus, herself and future fertility will all have a great impact on the final mode of treatment. The same considerations present a very difficult situation for the treating physician. Among these, the most difficult is the need for fertility preservation. Fertility preservation is usually considered only in early stage (stages 1 & 2A) cervical cancer in pregnancy.
Chemotherapy in pregnancy
TE D
Neoadjuvant chemotherapy (NACT) is an innovative way of managing cervical cancer in pregnancy. It helps in controlling the disease and at the same time may help delay the timing of delivery in patients whose fetus hasn’t reached state of viability. It may also help in reducing tumour size which can help in performing fertility sparing procedures like trachelectomy. This review will highlight the types of drugs used in NACT, their effects on the fetus and the mother and the efficacy of NACT in treating cervical cancer in pregnancy by reviewing the published literature.
1
EP
Chemotherapy had been used in pregnancy since early 1950’s . The first clinical experience with
AC C
chemotherapy during pregnancy was reported by Aviles et al in 1988 2. They treated women with hematological malignancies during pregnancy where any delay in treatment would have been fatal to the mother and child. The biggest fear of using any chemotherapy is the potential teratogenic effects of these agents and the risk of miscarriage. The teratogenicity of any drug depends on the timing of exposure, the dose, and the degree to which the drug crosses the placenta. The most vulnerable period 3
appears to be the period of organogenesis, weeks 2-8 after conception . First trimester use of chemotherapy may result in spontaneous abortion, fetal death and fetal malformations. When the drugs are given in the second and third trimester, there is increased risk of intrauterine growth restriction and low birth weight. However, long term studies have shown no significant effect on learning disabilities or any hematological or immunological abnormalities. In a prospective study of 70 children who were exposed to chemotherapy in utero, the general health, cognitive development and 4
cardiac outcome levels were comparable to the general population (median follow-up: 22 months) . On the other hand, it is well known that prematurity is associated with impaired cognitive function and it
ACCEPTED MANUSCRIPT
should be avoided whenever possible. The decision to use chemotherapy during pregnancy must balance the risk to the fetus versus prolonging maternal survival.
SC
RI PT
Many different types of chemotherapy agents have been used in pregnancy, depending on the malignancy being treated. In this article, we will confine ourselves to the agents that have been used to treat cervical cancer in pregnancy. These mainly include cisplatin, vincristine, and bleomycin . More recently there have been reports of use of carboplatin and paclitaxel in these patients. The most widely used drug of these has been cisplatin. Whilst the side effects of cisplatin in the non-pregnant patients are well documented, the effects of cisplatin on the fetus has not been well studied. Most reports on use of cisplatin in pregnancy have either been small, retrospective studies or individual case reports. The pharmacokinetics of drugs in pregnancy is not very well understood. During pregnancy, many changes occur in the physiology, such as absorption, distribution and metabolism. These alterations are more pronounced during the third trimester of pregnancy which may alter the efficacy and toxicity of 5
the chemotherapeutic agents . Knowledge about the transplacental passage of chemotherapy agents in the humans is very limited. Also the metabolism of platinum in pregnant patients may be different from
M AN U
6
TE D
the non-pregnant women. In the first study of its kind, Marnitz et al measured cisplatin concentrations in 7 patients presenting with cervical cancer in pregnancy. Synchronous samples from maternal blood, umbilical cord blood and amniotic fluid were taken. All patients had delivered healthy babies. The cisplatin concentrations in the umbilical cord and amniotic fluid were 31-65 and 13-42% of the maternal blood respectively. The authors concluded that there was a significantly lower level of cisplatin in the umbilical cord blood and amniotic fluid compared to maternal blood and that these findings give additional security to use neoadjuvant cisplatin chemotherapy in pregnancy. However, they emphasized that long term oncologic and pediatric followup is essential to confirm the safety of this practice. In animal studies, it has been found that that less than 2% of maternal plasma levels of taxanes are found in the fetal plasma and in the case of carboplatin, fetal plasma concentrations reach up to 60% of 7
AC C
EP
maternal levels .
NACT in cervical cancer
In 1999, concurrent chemotherapy was accepted as the standard of care in the treatment of high-risk early stage and locally advanced cervical cancer, after the publication of 5 randomized trials which 8-12 showed the superiority of this treatment over conventional radiotherapy alone . In a systematic 13
review and meta-analysis of 19 randomized trials, Green et al besides confirming the superiority of chemoradiation over radiation alone, also stated that the most striking finding in their meta-analysis was the highly significant reduction in the incidence of distant metastasis in the chemoradiotherapy group.
ACCEPTED MANUSCRIPT
The rationale for the use of neoadjuvant chemotherapy for locally advanced cervical carcinoma is 14
based on the following observations :
RI PT
1. Tumor size is an important factor determining radiation responsiveness. Primary chemotherapy may lead to a tumor bulk reduction and thus improve local control by irradiation or surgical resection. 2. Neoadjuvant chemotherapy may control micrometastases in distant sites as well as in regional lymph nodes, early in the course of the disease.
SC
3. Tumor vascularization and bone marrow reserve are compromised by irradiation. Therefore, better response rate to up-front, more aggressive chemotherapy may be tolerated and a better vascularity promotes a higher concentration of drug delivery to the tumor bed before pelvic irradiation. 15-17
.
M AN U
More recently, NACT has been used in fertility sparing surgery in cervical cancer
NACT in pregnancy
TE D
Treatment of cervical cancer in pregnancy depends on the stage of the disease, the gestational age at diagnosis, the patient’s desire to maintain the pregnancy and the histology. When fetal viability has not been attained, delaying delivery raises concern about progression of the disease. The use of NACT in these circumstances is an attractive option that allows the pregnancy to progress to viability and, at the same time, possibly, keeping in check the progression of the tumour. 18
The guidelines from an International Consensus Meeting on Gynecological Cancers in Pregnancy , have recommended NACT under the following circumstances:
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1. In node negative stage 1B1, less than 2 cm, treated during second trimester of pregnancy in patients wishing to preserve pregnancy. 2. In Stage 1B1 (2-4 cm), NACT can be used either in node negative patients as before or be given primarily before nodal assessment by lymphadenectomy. 3. In stages 1B2-2B, NACT is used till maturity and delivery.
The guidelines recommend that the chemotherapy regime should be cisplatin based. The addition of paclitaxel may increase the response rates. The combination of carboplatin and paclitaxel may be less toxic to the patient. In a review of the English literature up to early 2015, we found reports of 39 cases of cervical cancer in pregnancy that have been treated with NACT. (Table 1)
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Table 1 Neoadjuvant chemotherapy in cervical cancer during pregnancy Stage Chemotherapy/cycles Response to Treatment Followup Status chemotherapy (mths) at last visit Giacolone IB1 Cisplatin CR CS RH 12 NED 19 PLND 1996 PALND Caluwaerts IB1 Cisplatin PR CS RH 10 NED 20 PLND 2006 PALND de Lima 1B1 Cisplatin, Vincristine PR CS, RH, 24 NED 21 PLND, adj 2013 CT Chun IB1 Cisplatin, PR CS RH 49 DOD 22 Paclitaxel PLND 2010 PALND Kong et al 1B1 Cisplatin, Paclitaxel PR CS, RH, 104, 24 NED 23 (n=2) PLND, Adj 2014 CT Favero IB1 Cisplatin NA NA 12,10,5 NED=3 24 (n=5) NA=2 2010 Fruscio IB1 Cisplatin PR=3, SD=1 CS RH 41-65 NED=4 25 (n=4) 2012 Smyth IB2 Adriamycin, PR CS NA NED Cyclophosphamide 201026 Tewari IB2 Cisplatin, PR CS RH 24 NED 27 Vincristine PLND 1998 Karam IB2 Cisplatin NR CS RH 14 NED 28 PLND 2007 PALND Chun IB2 Cisplatin PR Cs RH 60 NED 22 Paclitaxel PLND 2010 PALND Rabaiotti IB2 Cisplatin SD CS 24 DOD 29 XRT 2010 30 IB2 Cisplatin SD CS RH x 2 52 DOD Lai 1997 (n=2) Vincristine PR 59 DOD Bleomycin 31 IB2 Cisplatin PR CS, XRT 21 NED Li 2011 (n=2) Paclitaxel CS 13 x2 Fruscio IB2 Cisplatin, Vincristine SD CS RH XRT 21 NED 25 (n=5) Cisplatin PR CS RH 13 NED 2012
Baby
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Well
Well
Well
Well
Well
NA Well Well Well Well
Well
Well NA
Well x 2 Well x 5
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Cisplatin, Paclitaxel
Peculis 32 2015 Tewari 27 1998 Bader 33 2007 Chun 22 2010
IB2
Cisplatin, Adriamycin
CR
IIA
Cisplatin Vincristine Cisplatin Vincristine Carboplatin Paclitaxel
PR
Marana 34 2001
IIB
Cisplatin Bleomycin
Declined treatment after delivery PR
IIA IIA
PR PR
27 153 113 35
DOD NED NED NED
Well
20
NED
Well
5
DOD
Well
80
NED
Well
48
AWD
Well
13
DOD
Well
RI PT
1B2
CS RH CS RH CS RH XRT CS, RH, PLND, Adj CT CS RH PLND CS RH PLND CS RH PLND CS RH PLND PALND CS
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PR PR SD PR
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Cisplatin Cisplatin,Paclitaxel
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Palaia IIB Cisplatin RH PLND 10 NED Well 35 Paclitaxel 2007 Boyd IIB Cisplatin NA XRT 15 NED Well 36 2009 Benhaim IIIB Vincristine PD CT XRT 10 DOD Well 37 2008 Seamon IIIB Cisplatin PR XRT 48 NED Well 38 Vincristine 2009 (CR=Complete Response; PR=Partial Response; SD=Stable Disease; CS=Cesarean section; RH=Radical hysterectomy; RHND=Radical Hysterectomy; PLND=Pelvic Lymph Node Dissection; PALND=Para Aortic Lymph Node Dissection; XRT=External Radiotherapy; Adj CT=Adjuvant chemotherapy; NED=No Evidence of Disease; DOD=Died Of Disease)
Conclusion
Though no randomized trials exist, the available information suggests that NACT is an attractive and viable option in the management of cervical cancer in pregnancy. The vast majority of the patients had response to the chemotherapy allowing prolongation of the pregnancy. The most common drug used was cisplatin although the duration of therapy varied among the authors. Fetal well-being was not compromised in any of the cases reported. This last observation is an important one in counseling mothers going for NACT; for often the worry uppermost in their mind is the teratogenic effects on the unborn child.
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Practice Points.
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. Cervical cancer is the most frequently encountered gynecological malignancy in pregnancy. . The patient MUST be managed by a multidisciplinary team comprising the obstetrician, gynecologic oncologist, medical oncologist, radiation oncologist and social worker. . It is safe to continue the pregnancy, until it reaches maturity, in the presence of cervical cancer.
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. Cisplatin is a safe drug to use in pregnancy in the neoadjuvant setting.
Research agenda
. To evaluate the role of other drugs like carboplatin, which is less toxic to mother, in neoadjuvant setting.
References
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. To explore the role of fertility preserving surgery after NACT in pregnancy.
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1. Thiersch JB, Therapeutic abortions with a folic acid antagonist, 4-aminopteroylglutamic acid (4amino P.G.A) administered by the oral route. AJOG, 63:1298-304, 1952. 2. Aviles A, Niz J. Long-term followup of children born to mothers with acute leukemia during pregnancy. Med Pediatr Oncol 1988; 16:3-6. 3. Williams S, Schilsky RL. Antineoplastic drugs administered during pregnancy. Sem Oncol 2000; 27:618:22. 4. *Amant F, Van Calsteren K, Halaska MJ et al. Long term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: An observational study. Lancet Oncol 2012; 13:256-64. 5. *Amant F, Han SN, Gziri NM et al. Chemotherapy during pregnancy. Curr Opin Oncol 2012; 24:580-6. 6. Marnitz S, Kohler C, Oppelt P etal. Cisplatin application in pregnancy: first in vivo analysis of 7 patients. Oncology 2010; 79(1-2):72-7. 7. Van Calsteren K, Verbesselt R, Devilieger R et al. Transplacental transfer of paclitaxel, docetaxel, carboplatin and trastuzumab in a baboon model. Int J Gynecol Cancer 2010; 20:1456-64. 8. Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC Jr, et al:Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy
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in stage IIB-IVA carcinoma of the cervix with negative paraaortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999; 17: 1339–1348. Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 340: 1137–1143. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al: Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999; 340: 1144–1153. Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL 3rd, et al: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999; 340:1154–1161. Peters WA 3rd, Liu PY, Barrett RJ 2nd, Stock RJ, Monk BJ, Berek JS, et al: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000; 18:1606–1613. Green JA, Kirwan JM, Tiernwy JK et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and metaanalysis. Lancet 2001; 358:781-96. Edelmann, David Z.; Anteby, Shaoul O. Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer--Where Does It Stand?: A Review. Obstet Gynecol Surv 1996; 51:305-313. Robova H, Halaska MJ, Pluta M et al. Oncological and pregnancy outcomes after high-dose density neoadjuvant chemotherapy and fertility sparing surgery in cervical cancer. Gynecol Oncol 2014; 135:213-6. Kobayashi Y, Akiyama F, Hasumi K. A case of successful pregnancy after treatment of invasive cervical cancer with systemic chemotherapy and conization. Gynecol Oncol 2006; 132:254-9. Salihi R, Leunen K, Limbergen EK et al. Neoadjuvant chemotherapy followed by large cone resection as fertility sparing therapy in stage iB cervical cancer. Gynecol Oncol 2015; doi: 10.1016/j.ygyno.2015.05.043. Amant F, Van Calsteren K, Halaska MJ et al. Gynecological cancers in pregnancy: guidelines of an international consensus meeting. Int J Gynecol Cancer 2009; 19:S1-S12. Giacalone PL, Laffargue F, Benos P et al. Cisplatinum neoadjuvant chemotherapy in a pregnant woman with invasive carcinoma of cervix. Br J Obstet Gynaecol. 1996 Sep; 103(9):932-4. Caluwaerts S, VAN Calsteren K, Mertens L et al. Neoadjuvant chemotherapy followed by radical hysterectomy for invasive cervical cancer diagnosed during pregnancy: report of a case and review of the literature. Int J Gynecol Cancer. 2006 Mar-Apr; 16(2):905-8. de Lima CA, Barcelos ACM, Paschoini MC et al. Conservative treatment of uterine cervical adenocarcinoma of pregnancy. Case report. Case Rep Obstet Gynecol 2013; doi: 10.1155/2013/692017. Epub 2013 Dec 17. Chun KC, Kim DY, Kim JH et al. Neoadjuvant chemotherapy with paclitaxel plus platinum followed by radical surgery in early cervical cancer during pregnancy: three case reports. Jpn J Clin Oncol. 2010 Jul;40(7):694-8. Kong TW, Lee EJ, Lee Y et al. Neoadjuvant and postoperative chemotherapy with paclitaxel plus cisplatin in the treatment of FIGO stage 1B cervical cancer in pregnancy. Obstet Gynecol Sci. 2014 Nov;57(6):539-43.
21.
22.
23.
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24. Favero G, Lanowska M, Schneider A et al. Laparoscopic pelvic lymphadenectomy in a patient with cervical cancer stage Ib1 complicated by a twin pregnancy. J Minim Invasive Gynecol. 2010 Jan-Feb;17(1):118-20. 25. *Fruscio R, Villa A, Chiari S, et al. Delivery delay with neoadjuvant chemotherapy for cervical cancer patients during pregncncy: a series of 9 cases and literature review. Gynecol Oncol. 2012 Aug;126(2):192-7. 26. Smyth EC, Korpanty G, McCaffrey JA, et al. Small-cell carcinoma of the cervix at 23 weeks gestation. J Clin Oncol Jun 20 2010;28(18):e295–7. 27. Tewari K, Cappuccini F, Gambino A et al. Neoadjuvant chemotherapy in the treatment of locally advanced cervical carcinoma in pregnancy: a report of two cases and review of issues specific to the management of cervical carcinoma in pregnancy including planned delay of therapy. Cancer 1998;82(8):1529–34. 28. Karam A, Feldman N, Holschneider CH. Neoadjuvant cisplatin and radical cesarean hysterectomy for cervical cancer in pregnancy. Nat Clin Pract Oncol 2007;4(6):375–80. 29. Rabaiotti E, Sigismondi C, Montoli S, et al. Managment of locally advanced cervical cancer in pregnancy: a case report. Tumori 2010;96(4):623–6. 30. Lai CH, Hsueh S, Chang TC, et al. Prognostic factors in patients with bulky stage IB or IIA cervical carcinoma undergoing neoadjuvant chemotherapy and radical hysterectomy. Gynecol Oncol 1997;64(3):456–62. 31. Li J, Wang LJ, Zhang BZ, et al. Neoadjuvant chemotherapy with paclitaxel plus platinum for invasive cervical cancer in pregnancy: two case report and literature review. Arch Gynecol Obstet 2011;284(3):779–83. 32. Peculis LD, Ius Y, Campion M, etal. Stage 1B2 adenosquamous cervical cancer diagnosed at 19 weeks gestation. Aust N Z J Obstet Gynaecol. 2015;55(1):94-7. 33. Bader AA, Petru E, Winter R. Long-term follow-up after neoadjuvant chemotherapy for high-risk cervical cancer during pregnancy. Gynecol Oncol 2007;105(1):269–72. 34. Marana HR, de Andrade JM, da Silva Mathes AC, et al.Chemotherapy in the treatment of locally advanced cervical cancer and pregnancy. Gynecol Oncol 2001;80(2):272–4. 35. Palaia I, Pernice M, Graziano M, et al. Neoadjuvant chemotherapy plus radical surgery in locally advanced cervical cancer during pregnancy: a case report. Am J Obstet Gynecol 2007;197(4):e5–6. 36. *Boyd A, Cowie V, Gourley C. The use of cisplatin to treat advanced-stage cervical cancer during pregnancy allows fetal development and prevents cancer progression: report of a case and review of the literature. Int J Gynecol Cancer 2009;19(2):273–6. 37. Benhaim Y, Pautier P, Bensaid C, et al. Neoadjuvant chemotherapy for advanced stage cervical cancer in a pregnant patient: report of one case with rapid tumor progression. Eur J Obstet Gynecol Reprod Biol 2008;136(2):267–8. 38. Seamon LG, Downey GO, Harrison CR, et al. Neoadjuvant chemotherapy followed by postpartum chemoradiotherapy and chemoconsolidation for stage IIIB glassy cell cervical carcinoma during pregnancy. Gynecol Oncol 2009;114(3):540–1.
ACCEPTED MANUSCRIPT . Cervical cancer is the most common gynecological cancer in pregnancy. . A multidisciplinary approach is vital in the management of this condition. . Neoadjuvant chemotherapy (NACT) helps delay delivery until fetal maturity is achieved.
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. In selected cases , NACT , may allow fertility preservation.
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. Cisplatin is the most widely studied chemotherapy agent in pregnancy