Chemotherapy and Fertility

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Chemotherapy and Fertility

• Tanya Wildes, M.D.
• January 6, 2006

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Case 1

• 2000 (age 24) - NSVD
• September 2002 (age 26) - diagnosed with Hodgkins
  Disease
• ABVD x 4 cycles -gtNR
• Doxil/Gem/Navelbine x 3 -gtCR1
• May 2003 - BEAM/ASCT
• August 2003 becomes pregnant
• May 2004 - NSVD

3
Case 2

• 31 yo F presented to ED with sore throat
• WBC at presentation 249K
• Her first two questions were
• Will I lose my hair?
• Will I be able to have children?

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Infertility and the cancer patient

• As advances in therapy lead to improved survival,
  goals may expand to minimizing long term
  toxicities
• Loss of fertility can have significant long term
  emotional impact on patients
• Loss of fertility may be temporary or permanent
• Options for preserving or restoring fertility are
  emerging

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• A constant number of resting primordial follicles
  enter the growth phase at any given time,
  independent of pituitary gonadotropins
• Later stages of maturation require FSH and LH
• Follicles either mature to ovulation or become
  atretic

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Pathophysiology of ovarian damage following
chemotherapy

• Though well described, mechanisms of gonadotoxic
  effects of chemotherapy are not well understood
• Cell cycle specific agents exert effects on the
  growth and maturation of ovarian follicles

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Pathophysiology of ovarian damage following
chemotherapy

• Non-cell cycle specific agents such as alkylating
  agents are more toxic to the ovaries than are
  cell cycle specific agents.
• Biopsies of patients who are undergoing therapy
  with cyclophosphamide show the complete absence
  of ova with fibrosis.
• In animal studies, follicular destruction
  increases exponentially with increasing doses of
  cyclophosphamide.

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Premature ovarian failure (POF)

• Symptoms
• Amenorrhea
• Vasomotor symptoms
• Genitourinary symptoms
• Osteoporosis
• May occur immediately during chemotherapy or be
  delayed

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Effect of age on risk of premature ovarian failure
Mattle, Eur J Haem 2005.
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Chemotherapy associated amenorrhea

• Mediated through ovarian failure
• Restoration of menses after chemotherapy is age
  dependent
• 50 of patients under age 35 will resume
  menstruation after chemotherapy.
• 0-11 of patients over 40 will resume
  menstruation after chemotherapy.

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Effects of chemotherapy on fertility

• Resumption of menses does not ensure fertility
• Irregular menses and amenorrhea do not imply
  infertility
• In retrospective series of breast cancer patients
  lt age 35 who underwent chemotherapy with
  5FU/adriamycin/cyclophosphamide
• 21 patients became pregnant
• Only 64 of these had resumed regular
  menstruation

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Impact of dosing schedule

• HyperCVAD
• Cyclophosphamide 300mg/m2 bid D1-3
• N7, early death and OCP users excluded
• 5/7 (71) had resumed menses at median 5 months
  after chemotherapy (range 1-15 months)
• 1/7 was on OCPs for 3 years after chemotherapy,
  then conceived
• 3/7 (43) conceived
• MegaCHOP
• Cyclophosphamide dose 2-3g/m2
• 12/13 (92) recovered ovarian function
• 8/12 (66) conceived

Seshadri Leuk Research 2005 Dann Human
Reproduction 2005
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German Hodgkins Lymphoma Study
N 405
HD 7 Stage I or II No risk factors
HD 9 Stage IIB or IIA Risk factors Or IIIB/IV
HD 8 Stage IA/B or IIA Risk factors Or IIB or
IIIA No risk factors
A COPP/ABVD x 4 N32
A EFRT N32
B BEACOPP x 8 N53
A COPP/ABVD X2 EFRT N94
B ABVD x 2 EFRT N26
C Escalated BEACOPP x 8 N74
B COPP/ABVD X2 IFRT N94
Behringer, JCO 2005.
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German Hodgkins Lymphoma Study

• Baseline characteristics
• Age range 16-40
• Age lt 30 in 60.5 of patients
• Regular menses in 89.6
• 7.9 reported irregular menses prior to therapy
• Only 0.5 were menopausal
• Overall 54.8 did not take OCPs
• In patients lt age 30, 46.5 did not take OCPs
• In patients gt age 30, 67.5 did not take OCPs

Behringer, JCO 2005.
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Menstrual status after therapy
Behringer, JCO 2005.
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Menstrual status after therapy
Behringer, JCO 2005.
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Menstrual status by age at beginning of therapy
Behringer, JCO 2005.
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Menstrual status by age at beginning of therapy
Behringer, JCO 2005.
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Impact of oral contraceptives during chemotherapy
Behringer, JCO 2005.
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Prognostic factors for amenorrhea after treatment
Behringer, JCO 2005.
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Conclusions from German Hodgkins Lymphoma Study
Group

• Chemotherapy regimen and dosing schedule impacts
  menstruation after chemotherapy
• Age impacts rates of amenorrhea after
  chemotherapy
• Use of OCPs may be protective

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Fertility after treatment for acute leukemia

• Retrospective review of 101 patients who had
  survived 10 years from diagnosis
• 31 were female lt age 40
• 26/31 (84) resumed regular menses
• All 5 who did not had received TBI as
  conditioning for transplant
• 15 of the women conceived

Micallef, Br J Haem 2001
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Options for preserving fertility

• Ovarian protection
• Embryo cryopreservation
• Oocyte cryopreservation
• Ovarian tissue cryopreservation
• In vitro oocyte maturation

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Ovarian protectionGnRH analogues

• Theory after initial flare of LH/FSH,
  downregulation of pituitary GnRH receptors
  results in prepubertal levels

Mattle, Eur J Haem 2005.
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Ovarian protectionGnRH analogues

• Trials ongoing to address this issue
• OPTION Ovarian Protection Trial in Oestrogen
  Non-responsive Premenopausal Breast Cancer
  Patients Receiving Adjuvant or Neo-adjuvant
  Chemotherapy (Scottish Cancer Network)
• PROFE German Hodgkins Study Group
• RCT goserelin vs microgynon in Hodgkins patients
  receiving escalated BEACOPP

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Ovarian protectionOral contraceptives

• 1981 Chapman and Sutcliff demonstrated
  preserved ovarian function during chemotherapy in
  women on combination contraceptive pills
• Ovarian biopsies showed no decline in the number
  of primordial follicles
• Ongoing study PROFE

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Embryo cryopreservation

• The only established method for fertility
  preservation
• Drawbacks
• Requires ovarian stimulation
• May be theoretically harmful in
  hormone-sensitive tumors
• Requires in vitro fertilization
• Requires partner or sperm donation
• Delay in harvest may delay chemotherapy

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Oocyte cryopreservation

• May be a more attractive option to patients
  without a partner
• Drawbacks
• Requires stimulated ovulation
• Success rates lt2

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Ovarian tissue cryopreservation

• Whole ovary transplantation or cortical strips
• Case (Lancet 2004) successful pregnancy in
  patient with HD after orthotopic autologous
  ovarian transplant after 6 years of
  cryopreservation
• Case (NEJM 2005) successful pregnancy after
  syngeneic ovarian transplant between monozygotic
  twins discordant for POF

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Ovarian tissue cryopreservation

• Drawbacks
• Requires laparoscopy and general anesthesia
• Autografted material could potentially harbor
  malignant cells

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In vitro oocyte maturation

• Eliminates risks of ovarian stimulation prior to
  harvest
• Eliminates risk of reimplanting residual tumor
  cells

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Male fertility

• Testicular damage is drug and dose related
• Drugs implicated in gonadal damage include

Howell. J NCI 2005.
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Howell. J NCI 2005.
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Fertility after testicular cancer treatment

• Risk factors for infertility after chemotherapy
• Radiation therapy - Fecundity ratio 0.35
• Cryptorchidism Fecundity ratio 0.17

• Huyghe E, Cancer 2004.

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Male fertility after allogeneic transplant

• N64, median age 27 8
• 18/64 (28) of males had at least one child prior
  to BMT

Anserini P,BMT 2002.
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Male fertility after allogeneic transplant
Anserini P,BMT 2002.
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Options for preserving male fertilitySperm
banking

• Cryopreservation
• Historically, 3 samples collected with 48 hours
  of abstinence between collections
• Oligospermia or cryptospermia
• IVF-ICSI
• In vitro fertilization intracytoplasmic sperm
  injection

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Options for preserving male fertilitySperm
retrieval

• TESE testicular sperm extraction
• Early studies have been encouraging for use of
  TESE for azoospermic patients prior to
  chemotherapy, followed by cryopreservation

Shin D J NCI 2005.
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Male fertilityOn the horizon

• Spermatogonial stem cell harvest and
  transplantation
• In vitro maturation of stem cells

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References

• Anserini P et al. Gonadal function post
  transplantation Semen analysis following
  allogeneic bone marrow transplantation.
  Additional data for evidence based counseling.
  BMT 2002 30447-451.
• Behringer K et al. Secondary amenorrhea after
  Hodgkins lymphoma is influenced by age of
  treament, stage of disease, chemotherapy regimen,
  and the use of oral contraceptives during
  therapy a report from the German Hodgkins
  Lymphoma Study Group. JCO 2005 23(30)
  7555-7564.
• Dann EJ et al. Fertility and ovarian function are
  preserved in women treated with an intensified
  regimen of cyclophosphamide, adriamycin,
  vincristine and prednisone (Mega-CHOP) for
  non-Hodgkin lymphoma. Human Reproduction 2005
  20(8) 2247-9.
• Howell SJ, SM Shalet. Spermatogenesis after
  cancer treatment damage and recovery. J NCI
  2005 3412-17.
• Huyghe E, et al. Fertility after testicular
  cancer treatments Results of a large multicenter
  study. Cancer 2004 100732-737.
• Mattle V et al. Female fertility after cytotoxic
  chemotherapy- protection of ovarian function
  during chemotherapy of malignant and
  non-malignant diseases. Eur J Haem 2005
  7577-82.
• Micallef IN et al. Long-term outcomes of patients
  surviving for more than ten years following
  treatment for acute leukaemia. British Journal of
  Haematology. 2001 113443-5.
• Seshadri T et al. The effect of HyperCVAD
  chemotherapy regimen on fertility and ovarian
  function. Leukemia Research epublished 2005.
• Shin D et al. Treatment options for the infertile
  male with cancer. J NCI 2005 4348-50.
• Singh KL et al. Fertility in female cancer
  survivors pathophysiology, preservation and the
  role of ovaran reserve testing. Human
  Reproduction Update 2005 11(1) 69-89.