42                                                                                                                           Hodgkin’s Lymphoma(HL) ______________________________________________________________________________________

8.             Hodgkin’s Lymphoma (HL)

8.1               General considerations

The diagnosis of Hodgkin’s lymphoma (HL) is based on a histological examination of a lymph node biopsy and the identification of Reed- Sternberg cells. Accutate initial staging and determination of prognostic factors is essential in order to classifying patients into groups that define the treatment strategy. Staging currently is based on the “ Cotswolds” modifications of the Ann Arbor Classification and prognosis is governed by the factors defined either by the International Prognostic Index (IPI) or the International Prognostic Factor project (IPFP) on Advanced Hodgkin’s Disease.

*   According to Lister and Crowther    

            In general, there are two main goals in the primary treatment of HL: (1) to

            further improve cure rates in those at high risk of treatment failure, and (2) to  

            reduce acute and long – term toxicities (incl. The risk of secondary tumors) in  

            those for whom less toxic treatment may be sufficient.

                 For localized disease stages (stage I + II) extended field radiotherapy as  

                 initial therapy is curative for the majority of cases. In the presence of a large

             mediastinal mass and / or of B – symptoms chemoradiotherapy is recommended.   

             It is also likely that mild chemotherapy (2 – 3 cycles) followed by limited field  

             radiotherapy will start to play a greater role in the treatment of eatrly stage

             patients in general.

Hodgkin’s Lymphoma  (HL)                                                                                                                                43  _____________________________________________________________________________________

Intermediate (stage III A) and advanced ( stage III B + IV) stages of HL have become a

            curable disease after the introduction of polychemotherapy regimens such as MOPP resp. COPP,

            ABVD and MOPP- resp. COPP-ABVD hydrid regimens with (stage III A) or without (stage III B +

            IV) limited field radiation, Based on efficacy and toxicity data from a number of randomized trials

            ABVD is currently designated as the standard chemotherapy for HL outside clinical trials.The

            number of cycles generally varies between four (stage III A without unfavorable prognostic factors)

            and six to eight (in stage III A with unfavorable prognostic factors and stage III B/IV). The

            introduction of intensified regimens (e.g. BEACOPP or Stanford V) in large clinical studies has    

           resulted in further improved response and survival rates for patients with advanced stage disease.         

           Myeloablative  chemotherapy with stem cell support has still to be considered experimental in first-

          line treatment.

            The outcome for elderly patients with current treatment is less favorable and development of  

             effective that cause less toxicity is important to improve results. At present, also no optimal therapy

             for HIV- associated HL has been defined. With standard chemotherapy regimens CR rates remain

            below those reported in patients without HIV- infections and tolerance is poor.

            Three subgroups of patients with relapsed or refractory HL have to be separated having very

            different prognoses and treatment requirements. (1) patients who relapse following primary radiation

            therapy for localized HL and who respond satisfactorily to standard combination chemotherapy.(2)

            Patients who relapse after preceding response to primary chemotherapy and who might be best

            salvaged with aggressive approaches including high-dose chemotherapy with stem cell support. (3)

            patients with primary progressive HL, who have a very poor prognosis and who need new treatment

            strategies, including double transplantation or sequential high-dose chemotherapy.

            Literature: for review e.g.

                        BRANDT et al, Acta Oncol. 40(2001):  185-197 (systemic overview of chemotherapy

                        effects)

                        CARELLA, Clin. Lymphoma 2 (2002): 212- 221 (stem cell transplantation)

                        CONNORS, Ann. Oncol. 13 (Suppl 1)(2002): 92-95 (clinical trials for advanced HL in North

                        America).

                        CONNORS et al, Hematology (Am. Soc. Hematol. Educ. Program)(2001): 178- 193

                        FERME et al, Br. J. Cancer 84 (Suppl 2)(2001): 55-60 and Ann. Oncol. 13 (Suppl 1)(2001):              96-97 (clinical trials of the Groupe d’Etudes des Lymphomes de I’ Adulte,GELA)

                        GLOSSMANN et al, Curr. Treat. Options Oncol. 3 (2002): 283-290

                        HORNING, Ann. Oncol. 9 (Suppl 5) (1998): 97-101 (primary refractory disease)

                        JOSTING and DIEHL, Curr. Oncol. Rep. 3 (2001): 279 – 284 (early stage HL)

                        JOSTING et al, Ann. Oncol. 13(Suppl 1)(2002): 112 – 116 (primary progressive and

 relapsed HL )

                        KEWALRAMANI and MOSKOWITZ, Curr. Oncol. Rep. 3 (2001): 271-278 (upfront

 transplantation)

LISTER, Cancer Treat. Rev. 25 (1999): 157-159

                     * LISTER and CROWTHER, Semin. Oncol. 17 (1990): 696 - 703

LOEFFLER et al, J. Clin. Oncol. 16 (1998): 818-829 (meta-analysis of chemotherapy vs. combined modality treatment)

MINK and ARMITAGE , Oncologist 6 (2001): 247-256 ( stem cell transplantation )

SPECHT et al, J. Clin. Oncol . 16( 1998) 830 – 834 (meta- analysis of radiotherapy

and adjuvant chemotherapy in early stage disease)

TIRELL et al, Cancer Treat. Res. 104 (2001): 247 – 265

VACCHER et al, Eur. J. Cancer 37 (2001): 1306 – 1315 (HL in HIV- infected patients)

44                                                                                                                           Hodgkin’s Lymphoma(HL) ______________________________________________________________________________________

8.2               Adult patients

8.2.1    First- line chemotherapy

8.2.1.1 ABVD

                To be repeated every 4 weeks

                  Literature:

                        BONADONNA et al, Ann. Intern. Med. 104 (1986): 739- 746

                        BONADONNA and SANTORO, Cancer Treat. Rev. 9 (1982): 21-35

                        CHISESI et al, Ann. Oncol.13 (Suppl 1) (2002): 102-106 (randomized  

                        trial of ABVD vs  Stanford V vs MEC in unfavorable HL)

8.2.1.2     MOPP/ABV hybrid regimen

To be repeated every 4 weeks

Literature:

     FERME et al, Blood 95 (2000): 2246 – 2252

     GLICK et al, J. Clin. Oncol. 16 (1998): 19 – 26 .

     KLIMO and CONNORS, J. Clin. Oncol. 3 (1985): 1174 – 1182

8.2.1.3     ChlVPP/ EVA hyhrid regimen

               *  Max. 2 mg for patients ≥ 60 years, and 0.7 mg/m² for patients ≥ 70 years

             **  Dose escalated from 75 mg/m² in first cycle to 100 mg/m² in subsequent  

                   cycles if oral mucositis is not > CTC grade 1 after first exposure

                  To berepeated every 4 weeks(6 cycles, then radiotherapy to sites of previous  

                  bulk or residual radiographic abnormality).

                  Literature:

                        RADFORD et al, J. Clin. Oncol. 20 (2002): 2988 – 2994 (randomized

                        comparison) of ChIVPP/ EVA hybrid vs a weekly VAPEC – B regimen)

Hodgkin’s Lymphoma (HL)                                                                                                                        45 _____________________________________________________________________________________

8.2.1.4     COPP- ABVD alternating regimen

To be repeated every 8 weeks

Literature:

            SIEBER et al, J. Clin. Oncol. 20 (2002): 476 – 484

8.2.1.5     BEACOPP and BEACOPP “ escalate”

To be repeated every 3 weeks (8 cycles for advanced stage disease: 4 escalated and 4 base- line)

*Dose-escalated regimen with G-CSF support

Patients > 65 have not benefited from the BEACOPP regimen. For all others, tumor control and overall survival were markedly improved using BEACOPP compared to standard therapy (COPP/ABVD). G-CSF-supported dose escalation brings further benefit in tumor for control patients up to 60 years old.

Literature:

DIEHL et al, J. Clin. Oncol. 16 (1998): 3810-3821 and Ann. Oncol. 9  

(Suppl 5)(1998): 67-71

ENGEL et al, Ann. Oncol. 11(2000) : 1105-1114       

FRANKLIN and DIEHL, Ann. Oncol. 13 (Suppl 1) (2002): 98 – 101

8.2.1.6     Stanford V

With consolidative readitherapy

   *  Reduced to 4 mg/m² resp. 1 mg/m² during weeks 10 – 12 for patients ≥ 50 years  

      of age.

      ** Tapered by 10 mg every other day starting at week 10.

46                                                                                                                           Hodgkin’s Lymphoma(HL) _______________________________________________________________________

            Literature:

                        CHISESI et al, Ann. Oncol. 13 (Suppl 1) (2002): 102-106 (randomized

                        trial of  ABVD vs Stanford V vs MEC  in unfavorable HL)

                        HORNING et al, J. Clin. Oncol. 20 (2002): 630-637

8.2.2            Salvage and reinduction chemotherapy

8.2.2.1    MIME

            To be repeated every 3 weeks. In combination with G-CSF also efficient stem cell mobilization.*

            Literature:

                     * AURLIEN et al, Eur. J. Haematol. 66 (Suppl 64) (2001): 14 – 20

                        HAGEMEISTER et al, J. Clin. Oncol. 5 (1987) : 556 – 561

8.2.2.2     ICE

To be repeated every 2 weeks (2 cycles). With G- CSF support. For cytoreduction and stem cell

mobilization.

Literature:

            MOSKOWITZ et al, Blood 97 (2001): 616-625 and Cancer Chemother.

            Pharmacol. 49 (Supp 1) (2002): 9 – 12

8.2.2.3     IVE

        To be repeated every 3 weeks ( target total of 3 courses). With G-CSF support.

        For cytoreduction and  stem cell mobilization.

        Literature :

                    JACKSON et al, Leuk. Lymph. 37 (2000):  561 – 570

                    McQUAKER et al, Bone Marrow Transplant. 24 (1999): 715 – 722

                    PROCTOR et al, Eur. J. Haematol. 66 (Suppl 64) (2001): 28 – 32

8.2.2.4     Ifosfamide + Vinorelbine

        To be repeated every 3 weeks. With G-CSF support.

            Litrature:

                        BONFANTE et al, Br. J. Haematol. 103 (1998): 533 – 535 and Eur. J.

                        Haematol. 66 (Suppl 64) (2001): 51 – 55

8.2.2.5 DEXA- BEAM

            To be repeated every 4 weeks. With G- CSF support (2-4 courses followed by  

            high-dose therapy and hematopoietic stem cell rescue).

            Literature:

                        JOSTING et al, Ann. Oncol. 9 (1998): 289 – 295

                        SCHMITZ et al, Lancet 359 (2002): 2065 – 2071 (randomized comparsion

                        of aggressive conventional chemotherapy and of high- dose chemotherapy

                        with autologous stem cell transplantation)

8.2.2.6 ASHAP

              For 3 cycles ( in patients having at least stable disease after 2 cycles ) followed by

              high-dose therapy.

              Literature:

                        RODRIGUEZ et al, Blood 93 (1999): 3632 – 3636

8.2.3        hematopoietic stem cell transplantation

High-dose chemotherapy (e.g. CBV or BEAM) followed by autologous stem cell transplantation has resulted in long- term event-free survival in at least one third of selected patients with relapsed or refractory HL. No randomized trials have been performed versus allogeneic stem cell transplantation, but historical comparison showed a significantly lower relapse rate for allografting. This advantage, however, is offset by a high transplant-related morbidity and mortality. The use of nonmyeloablative regimens preceding allografting has been started to combine the postitive effects of a graft- versus- Hodgkin’s lymphoma effect with a better tolerability than that observed after conventional allografting.

Literature: for review and representative studies e.g.

            ANDRE et al, J. Clin. Oncol. 17(1999): 222-229 (comparison of

            conventional and high-dose therapy with autologous stem cell

            transplantation)

            ANSELMO et al, Ann. Haematol. 79 (2000): 79 – 82

            ARGIRIS et al, Ann. Oncol. 11 (2000):665 – 672

            CARELLA, Clin, Lymphoma 2 (20002): 212 – 221

            LAZARUS et al, Bone Marrow Transplant. 27 (2001): 387 – 396 (report

            from the ABMTR on autotransplantation for patients in first relapse or

            second remission)

            REECE, Cancer Contr.7 (2000): 266-275 and Curr. Opin. Oncol.

            14(2002): 165-170

            SCHMITZ et al, Lancet 359 (2002): 2065 – 2071 (randomized comparison

            of aggressive concentional chemotherapy and high-dose chemotherapy

            with autologous stem cell transplantation)

SUREDA and SCHMITZ, Ann. Oncol. 13 (Suppl 1) (2002): 128 – 132 (role of allogeneic stem cell transplantation)

SUREDA et al, J. Clin. Oncol. 19 (2001): 1395 – 1404

8.2.4                HIV- associated Hodgkin’s lymphoma

                  At present, no optimal therapy for HIV-associated Hodgkin’s lymphoma has been

defined. With standard chemotherapy regimens CR rates remain below those

reported in patients without HIV infections and tolerance is poor. Improved results

have been reported more recently by the use of intensive chemo(radio)therapy with

concomitant HAART (highly active antiretroviral therapy) and G-CSF support.

Literature:

                        GERARD et al, AIDS 17 (2003): 81-87 (retrospective single institution study

which showed that overall survival has significantly improved since

introduction of HAART)

SPINA et al, Blood 100 (2002): 1984 – 1988 (phase 2 study of Stanford V +

HAART + G-CSF)

VACCHER et al, Eur, J. Cancer 37 (2001): 1306 – 1315 (review)

8.2.4        Hodgkin’s lymphoma in the elderly

It is generally agreed that- compared to treatment in younger patients – higher rates of toxicity and more frequent early relapsed have to be expected in elderly patients.

Different combinations of effective therapies with low toxicity are therefore felt to be required. Liberal support with hematopoietic growth factors (G-CSF) is also considered necessary to reduce prolonged neutropenia.

Literature:

            PROCTOR et al, Ann. Oncol. 13 (Suppl 1) (2002): 133-137 (review)

            WEEKS et al. J. Clin. Oncol. 20 (2002): 1087-1093 (comparison of

            ChlVPP/ABV hybrid with ChlVPP alone)

VEPEMB

To be repeated every 4 weeks

Literature:

            PROCTOR et al, Ann. Oncol. 13 (Suppl 1) (2002): 133 – 137 (review)

8.3               Childhood Hodgkin’s lymphoma

8.3.1      General considerations

As for adults, HL is curable in the majority of cases in childhood and adolescense.

A number of therapeutic regimens are in use and the main challenge today is to minimize late toxicity without compromising the excellent survival rate. Over the last decade combined modality therapy permitted a reduction in the dose and field size of radiation as well as a reduction in the cumulative doses of cytotoxic agents.

Literature: for review and representative group studies e.g.

            KOBRINSKY et al, J. Clin. Oncol. 19 (2001): 2390 – 2396 (Children’s Cancer

            Group study CCG-5912: salvage therapy with dexamethasone, etoposide,

cisplatin, cytarabine and asparaginase – DECAL – followed by maintenance    

                        chemotherapy and transplantation)

                        LANDMAN-PARKER et al, J. Clin. Oncol. 18 (2000): 1500 – 1507 (French Society

                       of Pediatric Oncology study MDH 90: response- adapted chemotherapy with

 etoposide, bleomycin, vinblastine, and prednisolone before low-dose radiation therapy in localized childhood HL)

THOMSON and WALLACE, Eur. J. Cancer 38 (2002): 468 – 477 (review)

8.3.2      Studies GPOH-HD 90 and GPOH-HD 95

In stages l-llA 2 x OPPA (girls) resp. 2 x OEPA (boys)

In stages llB-lllA, lE, llEA 2 x OPPA (girls) resp. 2 x  DEPA (boys), and 2 x COPP

In stages lllB-lV, llEB, lllEA, lllEB 2 x OPPA (girls) resp. 2 x OEPA (boys)*, and 4 x COPP

Plus involved fiels radiotherapy (in study HD 95 only in patients with incomplete tumor

regression)

         * In stages lllB and lllEB OPPA was reintroduced for boys in study HD 95

           OPPA

           OEPA

           As OPPA with procarbazine replaced by

To reduce gonodatoxicity

COPP

            Literature:

                        GERRES et al, Cancer 83 (1998): 2217 – 2222

                        SCHELLONG, Ann. Oncol. 9 (Suppl 5) ( 1998): 115-119 and J. Clin. Oncol 19

 (1999): 3736 – 3744