148                                                                                                                                       Germ Cell Tumors

 

26.        Germ Cell Tumors

 

26.1         Germ cell tumors of the female

 

26.1.1.     General considerations

                 Malignant germ cell tumors constitute approximately 5% of all ovarian cancers

 

                 Ovarian germ cell tumors

      - Dysgerminoma                                                                                                                                                         

      - Embryonal carcinoma                                                                                                                                

      - Endodermal sinus tumor                                                                                                                           

      - Choricarcinoma                                                                                                                                           

      -Mature teratoma                                                                                                                                    

      - Immature teratoma (grade 1, 2, 3)                                                                                                              

      -Mixed germ cell tumors

 

      with the exception of stage I dysgerminoma all patients with malignant germ      

      cell tumors require postsurgical chemotherapy.

 

                  Literature: for review e.g.

                         ABU-RUSTUM and AGHAJANIAN, Semin. Oncol. 25 (1998): 235-242

                          WILLIAMS, Semin, Oncol. 25 (1998):  407-413

26.1.2      BEP

Cisplatin                    20 mg /m2                 i.v.(1 h inf)                        d 1-5

Etoposide                100 mg/m2                   i.v. (1 h inf)                       d 1-5

Bleomycin                30 mg                         i.v. (bolus)                        d 1, 8, 15

                To be repeated every 3 weeks (3-6 courses)

                *      Dose reduction to 80 mg/m2 for patients with prior radiotherapy

 

                Literature:

                        WILLIAMS et al, N Engl. J. Med. 316 (1987): 1435-1440

 

26.1.3      PVB

Cisplatin                    20 mg /m2                 i.v.(1 h inf)                        d 1-5

Vinblastine                12 mg/m2                  i.v. (bolus)                         d 1

Bleomycin                20 mg/m2                   i.v. (bolus)                        d 1, 8, 15

                                 (max 30 mg)

                To be repeated every 3 weeks (3-4 cycles)

                *   Dose reduction to 9 mg/m2 for patients with prior radiotherapy

               

                 Literature:

            COLOMBO et al, Obstet. Gynecol. 67 (1986): 265-268

 

26.1.4      VAC

Vincristine                 1.5 mg /m2                 i.v.(bolus)                        d 1(+5)

                             (max 2 mg)

Dactinomycin       0.3-0.35mg/m2                 i.v. (short inf)                 d 1-5

                              (max 0.5 mg)

Cyclophosphamide      150 mg                      i.v. (bolus)                        d 1-5

                To be repeated every 4 weeks (6 cycles)                                                                                                                                  

 

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            Literature:

                        SLAYTON et al, Cancer 56 (1985): 243

 

26.1.5      PEI ( as salvage therapy)

Ifosfamide               1200 mg/m2                   i.v.                                  d 1-5

                                                                     With mesna uroprotection

Etoposide                75 mg/m2                       i.v. (1 h inf)                    d 1-5

Cisplatin                 20 mg /m2                       i.v.(1 h inf)                     d 1-5

               To be repeated every 3-(4) weeks

           

            Literature:

                        LOEHRER et al, Ann. Intern. Med. 109 (1988): 540 – 546

 

25.2.      Germ cell tumors of the male

 

26.2.1  General considerations

 

Royal Marsden Hospital staging system for  t esticular cancer

Stage                 Details

I                         No evidence of metastasis

IM                     Rising concentrations of serum markers with no other evidence

                           of metastasis

II                         Abdominal node metastasis

           A               ≤ 2 cm in diameter

           B                2-5 cm in diameter

           C                ≥ 5 cm in diameter

III                         Supradiaphragmatic nodal metastasis

           M               Mediastinal

            N               Supraclavicular, cervical, or axillary

           O                No abdominal node metastasis

           ABC           Node stage as defined in stage II

IV                          Extralymphatic  metastasis

           Lung

           L 1               ≤ 3 metastases 

           L2                ≥ 3 metastases , all ≤  2 cm in diameter

           L3                ≥ 3 metastases,one or more of which are ≥ 2 cm in diameter

           H +, Br+, Bo+ Liver, brain, or bone metastases

 

Prognosis of metastatic germ cell cancer
Non-seminomatous grem cell tumors

 Seminomatous

Good prognosis
Primary site is testis or retroperitoneal  area, and

Any primary site , and

No non-pulmonary visceral

metastases, and

No non-pulmonary visceral

metastases, and

Low serum concentrations of alpha

fetoprotein , human chorionic gonadotrophin , or lactate dehydrogenase

Any tumor marker with normal alpha fetoprotein

 

 

150                                                                                                                                       Germ Cell Tumors

 

Intermediate prognosis

Primary site is the testis or retroperitoneal  area, and

Any primary site , and

No non-pulmonary visceral

metastases, and

No non-pulmonary visceral

metastases, and

Intermediate concentrations of the tumor markers 

Any tumor marker with normal alpha fetoprotein

Poor prognosis

Primary site is the mediastinum, or

No patients are classed as having a poor prognosis 

Non- pulmonary visceral metastases  or

 
High concentrations of the tumor  markers

 

  Two groups of testicular germ cell tumors have to be distinguished: non –   

  seminomatous testicular cancer (approx. 55%) and seminomas (approx. 45%).

 

  For early stage non-seminomatous testicular cancer surgery is the mainstay of   

  primary treatment. Dependent on the risk profile adjuvant chemotherapy can be  

  an accepted option after complete surgical removal of the primary tumor as well  

  as of retroperitoneal metastases (≤ 5 cm diameter).

 

  More advanced stages are treated with three or four cycles of cisplatin-based

  chemotherapy (in case of patients with poor prognosis high-dose therapy is also  

  evaluated in clinical trials). Conventional (but also high-dose) chemotherapy

  predominates the salvage therapy of testicular germ cell tumors which is often 

  followed by resection of residual disease.

 

  Adjuvant standard therapy of early stage seminoma (stage I and II A/B) is  

  radiotherapy (alternatives are carboplatin monotherapy or- in case of no risk

  factors-a watch-and wait strategy). Standard therapy for more advance stages (II

  B residual tumor 3 cm-III) is cisplatin- based combination chemotherapy.

 

  Literature: for review e.g.

ALBERS et al, World  J. Urol. 19 (2001): 76-81 (adjuvant chemotherapy in stage I and II testicular cancer)

            BEYER et al, World J. Urol. 19 (2001): 90 – 93 (salvage chemotherapy)

CLASSEN et al, J. Cancer Res. Clin. Oncol. 127 (2001): 475-481 (treatment of early stage seminoma)

            DEARNALEY et al, Br. Med. J. 322 (2001): 1583- 1588

            FLECHON et al, Crit. Rev. Oncol. Hematol. 37 (2001): 35 – 46

            NICHOLS, World J. Urol. 19 (2001): 90-93

            SOBECKS and VOGELZANG, Semin. Oncol. 26 (1999): 106 – 118 (  

            high- dose CT)

            WEISSBACH, Urol. Int. 63 (1999): 46 – 56

 

25.2.2.                            Non-seminomatous t esticular tumors

 

26.2.2.1  Good and intermediate prognosis

BEP

Cisplatin                20 mg /m2                   i.v.(30 min inf)               d 1-5 or

                               50 mg /m2                   i.v.(30 min inf)               d 1+2

Etoposide               100 mg/m2                  i.v. (1 h inf)                    d 1-5 or

                               165 mg/m2                  i.v. (1 h inf)                    d 1-3

Bleomycin              30 mg                        i.v. (bolus)                      d 1(or2), 8, 15

                           

    To be repeated every 3 weeks (good prognosis : 3 cycles , intermediate     

    prognosis : 4 cycles) or every 4 weeks  (adjuvant in stage II: 2 cycles with

    bleomycin given weekly )

 

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                Literature:

                        BEHNIA et al, Eur. J. Cancer 36 (2000): 472 – 475 (adjuvant treatment ,  

                        stage II)

De WIT et al, J. Clin. Oncol. 19 (2001): 1629-1640 (randomized 2 x 2 factorial trial of the EORTC/ MRC of 3 or 4 cycles of BEP and of a 3- or 5- day schedule in good prognosis patients)

                        EINHORN et al, J. Clin. Oncol. 7 (1989): 387-391

                        LOEHRER et al, J. Clin. Oncol. 13 (1995): 470-476

                        NICHOLS et al, J. Clin . Oncol. 16 (1998): 1287 – 1293

                        SAXMAN et al, J. Clin. Oncol. 16 (1998): 702 – 706

TONER et al, Lancet 357 (2001): 739-745 (randomized trial of the Australian and New Zealand Germ Cell Trial Group comparing two BEP regimens)

                       

26.2.2.2  Intestified protocols for poor prognosis patients

    POMB/ ACE

Vincristine                   1 mg /m2                  i.v.(bolus)                        d 1

                                   (max 2 mg)

Methotrexate                300 mg/m2              i.v.(12 h inf)                     d 1

Folinic acid                  15 mg                      i.v. (x 4 every 12 h )        d 2+3

Bleomycin                   15 mg                       i.v. (24 h inf)                   d 2

Cisplatin                      120 mg /m2              i.v.(12 h inf)                     d 4

    After 2 weeks interval

Dactinomycin               0.5mg                       i.v. (bolus)                      d 1-3

Cyclophosphamide       500 mg/m2               i.v. (30 min inf)              d 3

Etoposide                     100 mg/m2                i.v. (1 h inf)                    d 1-3

                POMP and ACE given alternatingly after the first two cycles which are both   

                POMB

 

                Literature:

                        BOWER et al, Ann. Oncol. 8 (1997): 477- 483

           

                BEP/EP

Cisplatin                  20 mg /m2                   i.v.(30 min inf)                  d 1-5

Etoposide                 100 mg/m2                  i.v. (1 h inf)                      d 1-5

Bleomycin                30 mg                         i.v. (bolus)                        d 1, 8, 15

    To be repeated evey 3 weeks (4 cycles), followed by 2 cycles of EP (using the    

    same dose of cisplatin and etoposide, but omitting bleomycin)

 

                Literature:

                        KAYE et al, J. Clin. Oncol. 16 (1998): 692-701

 

                Dose- escalated VIP

Cisplatin                  30 mg /m2                    i.v. (1 h inf)                       d 1-5

Etoposide                 200 mg/m2                   i.v. (1 h inf)                      d 1-5

Ifosfamide               1600 mg/m2                  i.v. (1 h inf)                      d 1-5

                                                                     With mesna uroprotection

                To be repeated every 3 weeks (4 cycles). With GM-CSF support (10 µg/kg 

                s.c./d) starting the first day after chemotherapy for 10 days.

 

                Literature:

                        BOKMEYER et al, J. Clin. Oncol. 17 (1999): 3450-3456

 

 

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                 T- BEP

Paclitaxel                   175 mg/m2             i.v. ( 1 h inf)                       d 1

Cisplatin                    20 mg.m2                i.v.(30 min inf)                  d 1 – 5

Etoposide                   100 mg/m2             i.v. ( 1 h inf)                      d 1 – 5

Blemycin                   30 mg                     i.v. (bolus)                         d 1, 8, 15

                  To be repeated every 3 weeks ( 4 cycles) with G-CSF support

 

                  Literature:

De WIT et al, int. J. Cancer 83 (1999): 831 – 833 (experimental regimen of a randomized phase II/III EORTC trial)

 

26.2.2.3.    Salvage therapy

                   VIP (PEI)

Ifosfamide                 1200 mg/m2            i.v. ( 1 h inf)                     d 1-5

                                                                 with mesna uroprotection

Etoposide                  75 mg/m2                 i.v. ( 1 h inf)                      d 1-5

Cisplatin                   20 mg/m2                 i.v. (30 min inf)                 d 1-5

                 To be repeated every 3 weeks

                

                 Literature:

                        LOEHRER et al, J. Clin. Oncol. 4 (1986): 528 – 536

                        MOTZER et al, Cancer 66 (1990): 2476- 2481

             

      VeIP

Vinblastine                 0.11 mg/kg                i.v. (bolus)                    d 1+2

Ifosfamide                  1200 mg/m2               i.v. (1 h inf)                  d 1 – 5

                                                                      With mesna uroprotection

Cisplatin                    20 mg/m2                    i.v. (30 min inf)            d 1 – 5

      To be repeated every 3 weeks ( 4 cycles)

 

       Literature:

            LOEHRER et al, J. Clin. Oncol. 16 (1998): 2500 – 2504

       

       TIP

Paclitaxel                     250 mg/m2               i.v. (24 h inf)                d 1

Cisplatin                      20 mg/m2                 i.v. (30 min inf)            d 2 – 6

Ifosfamide                   1200 mg/m2              i.v. (1 h inf)                 d 2 – 6

                                                                     With mesna urorotection

      To be repeated every 3 weeks ( 4 cycles) with G- CSF support

 

       Literature:

              MOTZER et al, J. Clin. Oncol. 18 (2000): 2413 – 2418

 

26.2.2.4      High- dose chemotherapy with hematopoietic stem cell support

   As consolidation in patients with incomplete response to first – line therapy,    

   as salvage therapy in relapsed patients, and as up-front therapy in high-risk   

   patients with poor prognosis (investigational). E.g.

 

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                  CEI

Carboplatin             375 mg/m2             i.v. (1 h inf)                        d 1 – 4 *

Etoposide                600 mg/m2             i.v. (1 h inf)                        d 1 – 4 *

Ifosfamide               2500 mg/m2          i.v. (22 h inf)                       d 1 – 4 *

                                                             With mesna uroprotection

                  *    The 4 th treatment day was omitted in patients who experienced severe    

 cutaneous, renal, or CNS toxicity .

                 

                  Literature:

   BEYER et al, Cancer 79 (1997) : 161 – 168

   RICK et al, Eur. J. Cancer 34 (1998) : 1883 – 18888

   SIEGERT et al, Clin. Oncol. 12 (1994): 1223 – 1231

 

                  CEC

Carboplatin               600 mg/m2          i.v.(45 – 90 min inf)          d – 8 , -6, -4

Etoposide                  600 mg/m2              i.v.(45 – 90 min inf)          d – 8 , -6, -4

Cyclophosphamide   50 mg/m2            i.v.(45 – 90 min inf)          d – 8 , -6, -4

                  Followed by hematopoietic stem cell support on day 0. To be repeated 4 – 6      

                  weeks afte hematologic reconstitution in the absence of prohibitive toxicity in  

                  responding patients.

 

                 Literature:

                        MOTZER et al, J. Clin. Oncol. 15 (1997): 2546 – 2552

 

26.2.3       Seminoma

 

26.2.3.1     Stage 1 seminoma (adjuvant therapy)

                 

Carboplatin                   400 mg/m2               i.v. (1 h inf)                            d 1

                  To be repeated once after 3 – 4 weeks

 

                  Literature:

                        REITER et al, J. Clin. Oncol. 19 (2001): 101 – 104

 

 

26.2.3.2.    Advanced metastatic seminoma

                   EP (first-line therapy)

Cisplatin                     20  mg/m2            i.v. (30 min inf)                   d 1 – 5

Etoposide                    100 mg/m2           i.v. ( 1 h inf)                        d 1 – 5

                  To be repeated every 3 weeks

 

                  Literature:

                        BAJORIN et al, J. Clin. Oncol. 11 (1993): 593 – 606

 

                 VeIP (salvage therapy)

Vinblastine                  0.11 mg/kg               i.v. (bolus)                       d 1 + 2

Ifosfamide                   1200 mg/m2              i.v. (1 h inf)                     d 1 – 5

                                                                     With mesna uroprotection

Cisplatin                      20 mg/m2                 i.v. (30 min inf)                d 1 – 5

                  To be repeated every 3 weeks

              

                  Literature:

                        MILLER et al, J. Clin. Oncol. 15 (1997): 1427 – 1431

 

 

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