Table 2.
Studies involving adolescent patients.
| Author (Study Design) | Number of Patients(Disease) | Age range(years) | Chemotherapy protocol | GnRHa (dosage/posology-duration) | Treatment arms (patients per arm) | Outcome measures | Follow-up duration |
|---|---|---|---|---|---|---|---|
| Gilani et al. (82) (Phase III, randomized clinical trial) |
30 (Ovarian malignancies) |
12–40 | Three to seven courses of one of the following regimens: VAC; BEP; TC; CP | Triptorelin depot, 3.75 mg, i.m., administered 7 days before starting chemotherapy and every 28 days during chemotherapy treatment |
1. Chemotherapy + triptorelin (15) 2. Chemotherapy alone (15) |
Resumption of menses and serum FSH level < 20 mIU/ml at 6 months post- chemotherapy |
6 months |
| Cheng et al. (98) (Phase II, open label, non-randomized clinical trial) |
60 (Hematologic malignancies, mainly HD and AML) |
15–39 | HSCT myeloablative (cyclophosphamide+TBI; etoposide+TBI; busulfan+ cyclophosphamide; busulfan+ melphalan; busulfan+ fludarabine; carmustine, etoposide, cytarabine, and melphalan) or non-myeloablative (fludarabine+melphalan; fludarabine+cyclophosphamide; cyclophosphamide; melphalan+arsenic) conditioning regimens | Leuprolide 22.5 mg in a 3-month depot i.m. injection, given within 2 months before stem cell transplantation. The second dose of leuprolide was given 3 months after the first injection. | 1. Leuprolide + HSCT conditioning regimen (60) | Resumption of menses and monitoring of FSH, LH, and estradiol levels | 355 days (median; range 102–1,676 days) |
| Castelo-Branco et al. (89) (Open label, comparative, non-randomized, prospective study) |
56 (HD) |
14–45 | C-MOPP-ABV; C-MOPP-ABV+RTP; C-MOPP-ABV+MINE-ESHAP+ASCT; C-MOPP+ABVD; ABVD; ABVD+RTP; ABVD+MINE-ESHAP+ASCT; ABVD+RTP+MINE+ESHAP+ ASCT; C-MOPP/ABV+RTP+ ASCT; ABVD+C-MOPP+RTP |
Triptorelin depot, 3.75 mg, i.m., 1–2 weeks before starting chemotherapy and every 4 weeks during chemotherapy treatment + 2.5 mg daily tibolone | 1. Chemotherapy + triptorelin + tibolone (30) 2. Chemotherapy alone (26) |
Resumption of menses; monitoring of serum levels of FSH, LH, 17β-E2, and inhibin B during and after chemotherapy; bone mineral density loss monitoring | NM |
| Blumenfeld et al. (99) (Prospective non-randomized study with historical control) |
36 (HD and NHD) |
15–40 | MOPP/ABV(D), CHOP, C-MOPP, or ABV with or without radiotherapy | Triptorelin depot, 3.75 mg i.m., administered 7–10 days before starting chemotherapy and monthly during chemotherapy treatment, until its conclusion or for a maximum of 6 months |
1. Chemotherapy + triptorelin (18) 2. Chemotherapy alone (18) |
Resumption of menses and regular cyclic ovarian function; ultrasonographic monitoring of ovarian folliculogenesis and ovulation; monitoring of FSH, LH, estradiol, progesterone, and prolactin levels |
up to 4 years (up to 8 years for historical control group) |
| Blumenfeld et al. (92) (Prospective non-randomized study with concurrent and historical controls) |
111 (HD) |
15–40 | ABVD; MOPP/ABV(D); Standard BEACOPP; Escalated BEACOPP | Triptorelin depot, 3.75 mg i.m., administered 2-7 days before starting chemotherapy and monthly during chemotherapy treatment up to a maximum of 6 months |
1. Chemotherapy + Triptorelin (65); 2. Chemotherapy alone (46) |
Resumption of menses and cyclic ovarian function; incidence of spontaneous pregnancies; primordial follicle count on both ovaries; FSH, LH, E2 and P levels monitoring | 8 years (mean–range 2–15 years) |
| Pereyra Pacheco et al. (88) (Prospective non-randomized study with historical controls) |
16* (HD, NHD, AML) |
14.7–20 | ICE+BMT; CAVPE+BMT; CCOPP+CAVPE+ESHAP+ ICE+ BMT; CAPVE+BMT; CAVPE+ICE +BMT; CVPP; ABVD; CVPP X 1 + ABVD X 5 |
Leuprolide depot, 3.75 mg i.m., starting 5-7 days before chemotherapy and monthly during chemotherapy treatment, until 30 days after the end of treatment | 1. Chemotherapy (±BMT) + leuprolide (12) 2. Chemotherapy (±BMT) alone (4)* |
Resumption of menses and regular cyclic ovarian function; FSH, LH, and estrogens level monitoring; incidence of spontaneous pregnancies; bone density loss monitoring | up to 5 years (up to 6 years in control group) |
| Blumenfeld et al. (94) (Prospective non-randomized study) |
83 (HD, NHL, leukemias and other diseases) |
14–40 | Conditioning chemotherapy (busulfan and cyclophosphamide; TBI and etoposide; busulfan, cyclophosphamide, fludarabine and antithymocyte globulin; BEAC; or BEAM) before stem cell transplantation | Triptorelin depot, 3.75 mg i.m. 7–14 days before starting gonadotoxic therapy and monthly during chemotherapy | 1. Conditioning chemotherapy + triptorelin (47) 2. Conditioning chemotherapy alone (36) |
Resumption of menses and cyclic ovarian function; FSH, LH, E2, and P levels monitoring; ultrasonographic monitoring of ovarian antral follicles and stimulated endometrium; spontaneous pregnancies |
7 years (median-range 2–13 years) for triptorelin arm and 8 years (median -range 2-13 years) for controls |
| Blumenfeld et al. (96) (Retrospective case-control study) |
474 (HD, NHL, leukemias and other diseases) |
14–40 | ABVD (± MOPP); BEACOPP/escalated BEACOPP; BMT; CHOP/CVAD | Triptorelin depot, 3.75 mg i.m., administered 7-14 days before starting chemotherapy and monthly during chemotherapy treatment | 1. Chemotherapy + triptorelin (286) 2. Chemotherapy alone (188) |
Spontaneous pregnancy rate; resumption of menses; FSH, LH, E2, and P levels monitoring; ultrasonographic monitoring of ovarian folliculogenesis and ovulation | up to 25 years (range 2–25 years) |
| Meli et al. (100) (Retrospective observational study) |
36 (ALL; AML; HD; NHL; solid tumors) |
11–18 | Chemotherapy protocols containing alkylating agents (cyclophosphamide; procarbazine; ifosfamide; carmustine; mitoxantrone; melphalan; busulfan; thiotepa; treosulfan; muphoren) ± radiotherapy or high-dose chemotherapy and HSCT | Triptorelin depot, 3.75 mg i.m. monthly during chemotherapy or 11.25 mg every 3 months, for 3 to 12 months (median, 8 months) | 1. Chemotherapy + triptorelin (27) | Resumption of regular spontaneous menstrual cycle; FSH, LH, E2 and P levels monitoring; ultrasonographic visualization of ovarian follicles or corpora lutea; spontaneous pregnancies | 7 years from diagnosis (median -range 2-18 years); 5 years from stop therapy (median -range 1–17 years) |
| Gini et al. (101) (Retrospective and Cross-sectional study) |
97 (HD or NHL) |
16–50 | ABVD or ABVD-like regimens, RCHOP, or VACOP-B ± radiotherapy; second-line regimens followed by HSCT | NM | 1. Chemotherapy + oral contraceptives or GnRHa 2. Chemotherapy alone |
Resumption of menstrual activity; use of oral contraceptives or GnRHa during chemotherapy; number of pregnancies and offsprings after therapy | NM |
*In the study there is another historical control group of premenarchal patient not treated with GnRHa, not mentioned here (n=5).
NM, not mentioned; HD, Hodgkin’s disease; NHL, non-Hodgkin lymphoma; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; ABV, doxorubicin, bleomycin, and vinblastine; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; ASCT, autologous stem cell transplantation; BEAC, BCNU, etoposide, cytarabine, cyclophosphamide; BEACOPP, bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; BEAM, BCNU, etoposide, cytarabine, melphalan; BEP, bleomycin, etoposide, cisplatin; BMT, bone marrow transplantation; CAVPE, cyclophosphamide, adriamycin, vincristine, prednisone, etoposide; CCOPP, CCNU (lomustine), cyclophosphamide, vincristine, procarbacine, prednisone; CHOP, cyclophosphamide, adriamycin, vincristine, prednisone; C-MOPP, cyclophosphamide, vincristine, procarbazine, prednisolone; CP, taxol, cisplatin; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; CVPP, cyclophosphamide, vinblastine, procarbazine, prednisone; ESHAP, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin; HSCT, hematopoietic stem cell transplantation; ICE, ifosfamide, carboplatin, etoposide; MINE, mesna, ifosfamide, mitoxantrone, and etoposide; MOPP, mechloroethamine; vincristine; procarbazine, prednisolone; R-CHOP, rituximab, cyclophosphamide, adriamycin, vincristine, prednisone; RTP, radiotherapy; TBI, total body irradiation; TC, taxol, carboplatin; VAC, vincristine, dactinomycine, cyclophosphamide; VACOP-B, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin.