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NON HODGKIN'S LYMPHOMA & HODGKIN'S DISEASE INDEX
The Lymphomas are a heterogeneous group of neoplasms that arise in the lymphoreticular system. The incidence of Hodgkin’s Disease in the UK is 3/100,000, approximately half that of NHL currently standing at 6/100,000 but rising. In Hodgkin’s Disease the neoplastic cell takes the form of mononuclear Hodgkin’s cells and the characteristic multinucleate Reed-Sternberg cell, which must be identified for histological diagnosis. The histological classification of Non Hodgkin’s Lymphoma is more diverse and subject to a degree of controversy. The most widely accepted classification is the Working Formulation but more recently the Revised European-American Lymphoma (REAL) Classification has been devised. It has the advantage of incorporating all nodal and extranodal lymphoid tumour, including Hodgkin’s disease and it incorporates newer categories of lymphoma. The ‘aggressiveness’ and response to treatment vary widely within the sub types of these neoplasms. SYMPTOMS OF A LYMPHOMA Isolated or generalised lymphadenopathy in the absence of local or systemic infection. Particularly if associated with wait loss, sweating excessively at night or unexplained temperatures.
OTHER INVESTIGATIONS The following investigations are often required at this time:- 1. Full history and clinical examination, with particular reference to clinically assessable disease, e.g. lymph nodes, spleen, liver, Waldeyer’s ring etc. 2. Baseline bloods - FBC, U+E, LFT, LDH, ESR. Consider HIV test, with appropriate counselling and consent, if patient in high risk category. 3. Baseline imaging, CXR, other imaging as indicated usually CT scan chest, abdomen & pelvis 4. Bone marrow aspirate and trephine: All patients with NHL Evidence of bone marrow impairment on FBC with Hodgkin's. 5. Lumbar puncture (see section - management of the CNS in lymphoma) for patients with:- - High grade lymphoma (i.e. lymphoblastic T or B cell, Burt’s & Burt’s like T or B. - Intermediate & high grade lymphoma involving a high risk site: - Anatomical proximity to CNS e.g. Orbit, base of skull or extradural space. - Testes - Clinical evidence of CNS infiltration. 6. Histology review at Cambridge, all newly diagnosed patients - send to Dr Arno. 7. If chemotherapy is likely, offer sperm banking if required by the patient and if delay is acceptable (Bourn Hall or locally if available). - see sperm banking
STAGING OF LYMPHOMAS - How advanced they are? NON HODGKIN LYMPHOMA - Ann Arbor classification Stage I Involvement of a single lymph node region (I) or of a single extra-lymphatic organ or site (IE)
Stage II Involvement of two or more lymph node regions (number to be stated) on the same side of the diaphragm (II) or localised involvement of extra-lymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (IIE)
Stage III Involvement of lymph node regions on both sides of the diaphragm (III) which may also be accompanied by localised involvement of extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIE) or both (IIISE)
Stage IV Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lynph node enlargement. Organ should be identified by symbols: N Lymph nodes / L Lung / H Liver / P Pleural / O Bone / M Marrow / S Spleen B SYMPTOM = Night sweats, unexplained weight loss >10% in the previous 6 months, unexplained pyrexia >38 0C. (Pruritis and alcohol induced pain can be associated with Lymphoma but are not B-symptoms)
[A] STAGE [A] STAGE - SEE ANN ARBOR STAGE
[B] HISTOLOGICAL CLASSIFICATION RYE (Lukes et el Can Res. 1966. 26; 1311). Also see REAL classification (within NHL section)
[C] POOR PROGNOSTIC FACTORS IN HODGKIN’S DISEASE (EORTC-H2 TRIAL Tubiana et al 1984. J.Rad. Onc. Biol & Phys 10:197 & Haybittle et al , Lancet 1: 967-972, 1985):- >40 Years Lymphocyte depleted & mixed cellularity histological types Number of involved sites Raised ESR (>40 mm in the Ist hour) B-symptoms Bulk disease - Mediastinum (>7.5cm or > 1/3 the transverse diameter of the chest) - Abdomen (mass > 10 cm)
[D] MANAGEMENT PLAN FOR PATIENTS WITH HODGKIN’S DISEASE
STAGE IA + IIA The results of radiotherapy in pathologically confirmed stage 1/II disease are good with 5 year survival of 80%. However, laparotomy has been replaced by a policy adjuvant chemotherapy in patients with predictive factors for stage III/IV (Horwich & Peckham 1987):- 1. Bulky mediastinal lymphadenopathy 2. More than three nodal sites involved above the diaphram. 3. Lymphocyte depleted histology. 4. Radiological evidence of splenic involvement
a. Good risk - a. Good risk - Definition: One site or two adjacent sites of disease only. Not lymphocyte depleted histology.
Treatment:- Mantle or inverted Y radiotherapy (Gospodarowicz et al, Eur. J. Cancer 28A (11): 1841, 1992. Patients > 60 yrs - Involved field radiotherapy alone (IFRxT) Suprahyoid Lymphadenopathy only - IFRxT alone (Bessel et al Radiother. Onc. 22, 190-4, '91. Lymphocyte depleted with two or more sites of disease or raised ESR - < 60 years 3 cycles CLVPP POBLOE + IFRT, >60 yrs patients; CHLVPP x3 + IFRxT
c. Poor Risk Definition:- Bulky mediastinal mass. TreatmentTreatment:- ChlVPP/PABLOE (Min 6 ) + IFRT
Relapse after RXT - ChlVPP/PABLOE Relapse after ChlVPP or equivalent - Adriamycin based chemotherapy (ABVD or ChlVPP/ PABLOE) (EVAP after LOPP) Relapse after Adriamycin based regimens < 2 yrs remission consider High Dose Chemotherapy
STAGE IB, IIB - IVB
ChlVPP/PABLOE +/- IFRT# Patients > 60Yrs ChlVPP alone +/- IFRT If possible.
<24 months >24 months Non cross resistant chemo +/- RT RT if localised and unirradiated or HD chemo + PBSC Non cross resistant chemo (eg PABLOE/EVAP after LOPP or Chlvpp)
Re-induction + high dose chemotherapy or Palliative chemo/RT
* The choice of chemotherapy for the non trial patients has been based on the following evidence. ABVD for six months is as effective as MOPP/ABVD or MOPP alone (CR rates at 5 years 61%, 65% and 50% respectively) ABVD is less toxic and less likely to course male sterility or myelodysplasia or leukaemia. (Cancer and leukaemia group B - Canellos et al. 1992 New England J. Med. ;327;21,pp1478. In an attempt to further reduce bleomycin and anthracycline related toxicity the BNLI and Central Lymphoma group performed a randomised trial which is demonstrating superior results with ChlVPP/PABLOE than PABLOE alone (which is similar to ABVD) (Trial completed June 1996 not yet published, but CR rate and DFS better). Therefore the recommended first line chemotherapy is Chlvpp/POBLOE. Chemotherapy is given until a CR is acheived then two further cycles to minimum of 6 cycles
Indications for high dose chemotherapy Patient should be referred to Dr Robert Marcus for consideration for high dose chemotherapy for the following indications (Linch et al 1993, Lancet; 341:1051):-
[a] 1st remission <12months [b] Progression on primary chemotherapy [c] Relapse after two previous modalities
INTRODUCTION The management of NHL is broadly split into the folowing categories according to [A] stage, [B] clinically based prognostic factors and [C] histological features:- [1] Indolent NHL - Early stage [2] Indolent NHL - Advanced stage [3] Indolent NHL - With lymphocytosis (10x10 9/l) [4] Aggressive NHL - Early stage - No poor prognostic features [5] Aggressive NHL - Early stage - With poor prognostic features [6] Aggressive NHL - Advanced stage [7] Very aggressive NHL [8] Other lymphomas
[A] STAGE - Ann Arbor staging system (As Hodgkins Disease)
[B] PROGNOSTIC FACTORS FOR AGGRESSIVE NHL (The international NHL prognostic factors project N. Eng. J. Med. (1993) 329:987. (Multivariate factors) Stage III-IV LDH > 500 IU/ml WHO PS 2-4
> Two extranodal sites (if > 60 yrs of age) Allocate I point and calculate the CR rates from the following table
Other prognostic factors include (univariate analysis): B-symptoms, Abdominal mass > 10cm, B2 microglobulins elevated, Slow response to chemotherapy, bone marrow involvement.
[B] Histological features Working formulation classification of non-Hodgkin s lymphomas Rosenberg S.A et al. Cancer 49: 2112-35, 1982
WORKING FORMULATION RAPPAPORT TERMINOLOGY
A Malignant Lymphocytic small Diffuse well differentiated Lymphocytic consistent with lymphocytic chronic lymphocytic leukaemia plasmacytoid B Malignant Lymphoma, follicular Nodular poorly differentiate/ lymphocytic Predominantly small cleaved cell diffuse areas sclerosis C Malignant Lymphoma follicular Nodular mixed lymphocytic / Histiocytic Mixed, small cleaved and large cell diffuse areas sclerosis
D Malignant Lymphoma, Nodular histiocytic follicular Predominantly large cell diffuse area / sclerosis E Malignant Lymphoma, diffuse Diffuse poorly small cleaved cell differentiated lymphocytic F Malignant lymphoma, diffuse Diffuse mixed Mixed, small and large cell lymphocytic-histiocytic sclerosis epitheloid cell component G Malignant Lymphoma, diffuse Diffuse histiocytic Large cell cleaved cell / sclerosis
H Malignant Lymphoma Diffuse histiocytic large cell, immunoblastic plasmacytoid / clear cell polymorphous epitheloid cell component I Malignant Lymphoma Diffuse lymphoblastic lymphoblastic convoluted cell J Malignant Lymphoma Diffuse undifferentiated small non-cleaved cell Burkitt's follicular areas
REAL CLASSIFICATION (BLOOD, 1994. Vol.84, No. 5, pp.1361-1392 & Pileri et al Current opinion in oncology 1995,7:401)).
B-cell B-cell chronic lymphocytic leukaemia Lymphocytic small B-cell lymphoma Plasmacytoid and myeloma Hairy cell leukaemia Marginal zone B-cell lymphoma Follicle center lymphoma, follicular (grades 1&2) T-Cell Large granual lymphocytic leukaemia Adult T-cell lymphoma or leukaemia (Smouldering) Mycosis fungoides, Sezary’s syndrone
B-cell B-cell pro-lymphocytic leukaemia Mantle cell lymphoma* Follicle centre lymphoma, follicular (grade3) T-cell T-cell CLL, prolymphocytic leukaemia Adult T-cell lymphoma, leukaemia (Chronic) Angiocentric ymphoma* Angio-immunoblastic lymphoma*
B-cell Diffuse large B-cell lymphoma T-cell Peripheral T-cell lymphoma, unspecified Intestinal T-cell lymphoma Anaplastic large-cell lymphoma Adult T-cell lymphoma or leukaemia (acute and lymphomatous)
B-cell Precursor B-cell lymphoblastic lymphoma, leukaemia Burkitt’s lymphoma High grade B-cell lymphoma, Burkitt’s - like T-cell Precursor T lymphoblastic lymphoma, leukaemia
Lymphocyte predominance Others * These types should be referred to Dr Marcus
KIEL CLASSIFICATION
MANAGEMENT PLAN FOR NHL [1] INDOLENT , LOCALISED. (Low grade WF A-C, Stage I, II, 1E, IIE ) 10-15%.
[2] INDOLENT, ADVANCED STAGE ( Low grade WFA-C, Stage III- IV) 85% of cases ‘Wait-and-see ‘Wait-and-see - No B-symptoms, slow disease course, no symptoms related to occlusion or compression. ( 25% spontaneous remission rate - Rosenberg 1985 JCO 3:299.). Median times to therapy; Follicular large cell diffuse, 17 months, mixed 48 months, follicular small cleaved cell 72 months. Treatment 1st Line 2nd Line 3rd line
WFA Chlb Chlb (LDFI)* Fludara#
*LDFI = long disease free interval (>1 yr) *SDFI = short disease free interval (<1 yr) Flud = Fludarabine (Hochester et al JCO 1992. 10: 28-34. Redman et al 1992. 10: 790-4. - 50 % RR in relapsed low grade lymphoma. Awaiting BNLI /EORTC trial Flud v CVP for first line use. BNLI shortly to start Flud v Chlb + Anthracycline for first relapse. Best results for CR in CLL.
[3] LYMPHOMA / CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) Staging for CLL (MRC)
(Each of the following count as one area - lymph node > 1cm, splenic enlargement, liver enlargement) ( Secondary couses of anaemia eg iron, folate & B12 must be excluded) Stage A - Observation. Stage B & C treatment (as WFA above or oral Fludarabine study) if.:- 1 Previously untreated and clear evidence of disease progression 2 Previously treated patients who: a Have not received an anthracycline or anthracenedione, eg mitozantrone. b Are considered not to be resistant to chlorambucil c Have relapsed off therapy and require further treatment because of disease progression
[4] AGGRESSIVE NHL, LOCALISED DISEASE (WFD-H, STAGE I/II/IE ) -- NO POOR PROGNOSTIC FEATURES (see page 10) Ist line (WF D:-H) <60years old - CHOP (x3)* + IFRT (SWOG - Miller 1996, 87% OS at 4 years - 3 cycles of CHOP then
IFRT)
2nd line or subsequent relapses BEAM + ABMT or ECP or DHAP or other cross resistant chemotherapy.
[5] AGGRESSIVE NHL, LOCALISED DISEASE (WFD-H, STAGE I/II/IE ) -- WITH POOR PROGNOSTIC FEATURES (2 of 3 features - see page 10) 1st Line (WFD-H) >60 <60 years CHOP (x 6-8) +/- IFRT* > 60 years PMitCEBO +/- IFRT* * Radiotherapy to sites which may compromise the patient on relapse i.e. extradural space, mediastinum, bone
2nd line or subsequent relapses BEAM + ABMT or ECP or DHAP or other cross resistant chemotherapy
[6] AGGRESSIVE NHL ADVANCED STAGE (WFD-H, III /IV) These patients should be referred to a regional centre These patients should be referred to a regional centre [6] VERY AGGRESSIVE NHL These patients should be referred to a major lymphoma centre
THE CNS IN LYMPHOMA CNS prophylaxis and mangement of CNS involvement in systemic lymphoma .
Low grade lymphomas are not at significant risk of developing CNS disease. The risk with intermediate grade is (6.5%) and high grade lymphomas is (16.7%). The following groups have a higher risk of CNS involvement, usually at relapse. (Liang R; Chiu E; Loke SL Hematol Oncol ; 8(3):141-5 1990) Orbital disease 43% Testis 40%, Peripheral blood 33% Bone 29% Nasal/paranasal sinuses 23% Bone marrow 20% CSF examination should be part of staging of all patients with intermediate and high grade lymphomas with these risk sites, particulary if young and associated with bulky retroperitoneal disease.
Full ALL like prophylactic treatment of the CNS should be given to patients with Burkitt’s or lymphoblastic lymphoma. Prophylaxis should be considered in patients with paranasal or base of skull, extra dural and testicular lymphoma .This should consist of intrathecal methotrexate 12.5 mg once or twice weekly up to x 9 and moderate dose intravenous methotrexate given in conjunction with the treatment programme for the sytemic disease, followed by cranial radiotherapy (24 Gy in 12 daily fractions) in patients with paranasal sinus or testicular disease.
Intrathecal chemotherapy Methotrexate 12.5mg it Take CSF sample for cytology prior to chemotherapy. Treatment is 2 x weekly until CSF remission, then once a week x 4 and subsequently every 2 weeks until RT if indicated to a total of 12 - 16. If the patient is in systemic remission at attainment of CSF remission, then craniospinal RT should be considered as consolidation therapy to a dose of up to 35 Gy/20F, modified if necessary in the light of previous RT. If spinal RT not possible, then cranial RT should still be considered. Localised lymphomatous masses should be considered for RT even in the palliative setting although the prognosis is poor. In palliation the recommended dose is 20 Gy in 5#.
PRIMARY EXTRANODAL LYMPHOMAS
Treatment policy:- A. Age <65 - combined modality therapy with [1] CHOD/BVAM chemo then [2] RxT. B. Severely disabled and/or > 65 - RT alone.
A1. Chemotherapy; CHOD/BVAM (JCO;Vol.14,No.3, pp945-954) A2. Radiotherapy - Total dose 54Gy in 30F to primary site:-
Brain: Phase I - - 9Gy in 5F to tumour site Phase II - 45Gy in 25F to whole brain. C2/3 interspace (Include optic nerve extension into orbits if csf +ve) Spinal cord: (if CSF +ve) - 35Gy min in 21F over 5 weeks (To S2/S3 interspace, with a gap change at the 7th and 14th fraction)
[B] Radiotherapy alone Phase I - 45 Gy in 25F to whole brain (supine cast) Phase II - 10 Gy in 10F to tumour site.
RECURRENT CEREBRAL LYMPHOMA High dose methotrexate - see chemotherapy protocols
A full examination under anaesthetic is required. For paranasal or basilar skull sinus disease CNS prophylaxis should be considered. There is an association between B-cell lymphomas of the Weldeyers ring andgastrointestinal lymphoma (Ree et al 1980. Cancer, 46,1528). Barium meal examination should be considered in the initial staging, RxT should include the whole Weldeyer’s ring, but otherwise treat as NHL above. Very elderly with stage I or IIE Weldeyer’s ring disease would probably best be treated with RxT alone.
LOW GRADE Low grade B-cell gastric lymphomas is characterised by an indolent natural history and a tendency to remain localised for a long period of time. Pathologically lesions may be multifocal in the gastric mucousa with sites remote from the main tumour mass. These have been characterised as part of the histological appearances found in mucosal associated lymphoid tumours MALT of the stomach (Isaacson 1987, Histopathology11:445) Diagnosis is best made by endoscopic biopsy rather than gastrectomy.
Treatment Follow resectionFollow resection. If complete resection has occured with only the proximal gastric nodes involved the prognosis is excellent (Sheppard JCO 1988, 6:253), but there is a tendency for the re-appearance of the MALT lesions (Wotherspoon 1993Lancet, 3442:575.) All patient should have treatment for Helicobacter pylori. Then either observed or given Chlorambucil. Alternatively patients may be entered into the LYO3 trial (see appendix). Following incomplete resection or endoscopic biopsy. All patient should have treatment for Helicobacter pylori. Then given Chlorambucil. Alternatively patients may be entered into the LYO3 trial (see appendix). Anti-H.Pylori treatment - omeprazole 20mg daily, Clarithromycin 250 mg bd, tinidazole 500 mg bd for 2 weeks. In the 10% of people were this is not successfull - colloidal bismouth 120mg qds, metronidazole 400 mg tds, tetracycline 500mg qds & omeprazole 20mg od.
HIGH AND INTERMEDIATE GRADE Patient who are able to undergo complete surgical resection of their tumour have a better survival than those with partial or no resection (Morton 1993, Cancer 67:776). Following complete resection +/- adjuvant CHOP or LYO4 study (see appendix) Following incomplete resection CHOP x3-6 or LYO4 study (see appendix).
For patients with early stage AIDS, ie few or no significant other HIV-related complications, treatement should be as for HIV negative lymphoma. If patient has more severe HIV-related problems or a poor performance status, the prognosis is poor and treatment should be palliative. Particular problems in HIV-related lymphoma: 1. Bone marrow reserve is limited due to HIV-related marrow impairment and concomitant medication, particularly AZT. 2. Patients are particularly radiosensitive and this may be a severe problems if mucous membranes are treated and may justify palliative chemotherapy where RT would be the treatment of choice in HIV-ve patients. 3. The prognosis of HIV-related cerebral lymphoma is particularly poor.
HODGKINS DISEASE
List of abbreviations ChlVPP = Chlorambucil, Vinbl, Procarb, Pred LOPP = Chlorambucil, Vct, Procarbazine PA(BL)OE = Pred, Adria, Bleo, Etoposide. ChlVPP/PA(BL)OE = Cloram, Vinbst, Procarb, Pred, Adria, Bleo, Etop. VAPEC-B = Vct, Adria, Pred, Etop, Cyclo, Bleomycin. ABVD = Adria, Bleo, Vinc, DTIC MBE = Melph, BCNU, Etop + ABMT BEAM = BCNU, Etoposide, Araa-c, Melphalan + ABMT MiniBEAM = BCNU, Etoposide, Araa-c, Melphalan ECP = Etop, Cisplat, Pred HDMP = High dose methylprednisolone CEP = CCNU, Etoposide, Chlorambucil, Prednisolone.
Summary of protocols
Chlorambucil 6mg/msq/d (max 10mg) O 10 days Procarbaxine 100mg/msq/d O 10 days Vincristine 1.4mg/msq(max 2mg) iv Days 1 & 8 Prednisolone 40 mg/m2 O 14 days
Adriamycin 25mg/msq iv Day 1, 15 Bleomycin 10mg/ iv Day 1, 15 Vinblastine 6mg/(max 10mg) iv Day 1, 15 DTIC 375mg/ iv Day 1, 15
Vincristine 1.4mg/msq (max 2 mg) iv day 1 and day 8 Epirubincin 50mg/msq iv day 1 Etoposide 200mg/msq PO daily for 4 days or 100mg/msq iv daily for 4 days Prednisolone 100mg PO daily for 8 days Drug Modification for VEEP Severe neuropathy (WHO) grade 2 indicates replacement of VINCRISTINE by VINBLASTINE 6mg/msq (max 10mg) iv day 1 and day 8. Increase ETOPOSIDE to 5 days if on all of days 8-10-15 WBC > 1.5 X 10/L and PLT > 100 X 10/L. Decrease ETOPOSIDE to 3 days if on any of days 8-10-15 WBC< 1.0 X 10/L or PLT < 50 X 10/L.
Prednisolone 50mg/day Oral daily for 4 wks then tailed to zero over sub 10 wks Ketoconazale 200mg bd Oral daily for 6 weeks Co-trimoxazole 960mg bd Oral thrice weekly for 6 weeks Cyclophos 350 mg/m2 IV Week 1 only Adriamycin 35 mg/m2 IV Week 1 and 3 Vincristine 1.4 mg/m2 IV Week 2 and 4 Bleomycin 10 mg/m2 IV Week 2 and 4 Etoposide 100 mg/m2 Oral daily for 5 days at week 3 only.
Dose reductions - Granulocyte count < 1 x 109/l and or platelet count < 100 x 109/l. Delay one week then restart at full dose. Dose reduction by 25% should only be employed after CTC grade 3 (severe) or life threatening infection
Etoposide 50 mg/msq/d* O d 1-10 Cisplatin 60mg/msq i.v. over 4h d 1 Prednisolone 100 mg/d O d 1-5
Chlorambucil 6mg/msq/d (max10mg) O 14 days Procarbazine 100mg/msq/d (max 200mg) O 14 days Prednisolone 40 mg/m2/d O 14 days
Adriamycin 40 mg/m2 iv d1 Vct 1.4 mg/m2 iv d1+8 Pred 40 mg/m2 (max 60mg) O d1-10 Etoposide 200 mg/m2 O d1-3* Bleomycin 10 mg/m2 iv d1+8 (Ist 4 courses) * If nadir (day 10-14) wbc <1.0 x 109/l decrease etoposide to 2 days. If nadir wbc > 1.5 x 109/l increase etoposide to 4 days.
Start with ChlVPP (wk 1 +2) then a 2 weeks gap before PABLOE (wk 5 +6). Then leave only a weeks gap between the last day of PABLOE and the next ChlVPP (of the next cycle). A minimum of 6 courses are required (3 ChLVPP and 3 PABLOE ) and at least 2 after complete remission. Remember to modify the next PABLOE dose depending on the nadir count in weeek 7. Summary:- Regimen Chlvpp Nil PABLOE Nil ET seq Chlvpp Week 1 & 2 3 & 4 5 & 6 7 ........ 8
CCNU 80 mg/m2 oral on day 1 only q 6weeks Etoposide 100 mg/m2 oral per day for 5 days q 3 weeks Chlorambucil 5mg/m2 oral per day for 5 days q 3 weeks Prednisolone 40 mg/m2 oral per day for 5days q 3 weeks
NON HODGKINS LYMPHOMA List of abbreviations Chlb = Chlorabucil Chlb-E = Chlorambucil , epirubicin CVP = Cyclophosphamide, Vincristine, Prednisolone CHOP = Cyclophosphamide, Adriamycin, Vincristine, Prednisolone ChlOP = Chlorambucil, Vincristine, Prednisolone HDMP = High dose Methylprednisolone PACEBO = Cyclo, Adria, Etoposide, Bleomycin, Pred. PMitCEBO = Cyclo, Mitoxantrone, Etoposide, Bleomycin, Pred. ECP = Etop, Platinum, Pred. CHOD/BVAM= Cyclo, Adria, Vct, Dex, / BCNU, Vct, cytarabine, Mtx MACOP-B = Mtx, Adria, Cyclo, Vinc, Pred, Bleo PACEBOM = Pred, Adria, Cyclo,Etop, Bleo, Vinc, Mtx DHAP = Dex, Cisplatin, Ara-C, BEAM = High dose BCNU, Etoposide, Ara-C, Melphalan VANDERBILT = Cyclo, Etop, Vinc, Dox, Bleo, Mtx, Pred (McMaster , JCO 9:941-946 1991)
Summary of protocols
Chlorambucil 10 mg po daily for 14 days every 4 weeks Prednisolone 10 mg daily for 14 days every 4 weeks
Cyclophosphamide 750 mg/msq IV stat day Vincristine 2 mg IV stat day 1 Prednisolone 10 mg qds po days 1 to 14 with the cycle repeated every 3 weeks
Cyclophosphamide 750mg/msq iv Day 1 Adriamycin 50mg/msq iv Day 1 Vincristine 1.4mg/msq (max 2mg) iv Day 1 Prednisolone 100mg po Day 1-5
CHOD:- Adriamycin 50mg/msq iv Cyclophosphamide 750mg/msqiv Vincristine 1.4mg/msq iv (max 2mg) Dexamethasone 4 mg qds oral d1-7
BVAM:- Methotrexate 1.5 g/m2 iv With Folinic Acid 15mg orally 6 hourly X6 starting at 24 hours BCNU 100mg/m2 iv Cytarabine 3 g/m2 iv
Nystatin susp. 1 ml orally QDS Septrin 2 tab orally BD, Dose reductions of A and C, if neutrophils less than 100. Modify protocol if age over 60 years. Rxt starts 10-14 days after last ARA-c
Agent Dose Day Route Time Dexamethasone 40mg 1-4 IV 15 mins Cisplatin 100mg/msq1 IV-CI 24 hours Cytarabine 4g/msq IV 2 g/msqin 200ml (Ara-C) normal saline 3 hours q12 hrs X 2
Fludarabine phosphate 25mg/msq IV daily for 5 days either by 30 minute infusion or as a bolus over a few minutes, repeated every 28 days (see appendix for full details)
Methylpred 1.5g o/iv d 1-5 Cimetidine cover required.
Methotrexate 400mg/msq total dose given as 100mg stat then 300mg/msq in 500mls n saline +20 mmol KCL over 4 hours With Folinic Acid 15mg orally 6 hrly X6 starting at 24 hrs Adriamycin 50mg/msq iv Cyclophosphamide 350mg/msq iv Vincristine 1.4mg/msq iv (max 2mg) Bleomycin 10mg/msq iv Prednisolone 60mg daily, orally for 10 weeks, then reduce gradually Nystatin susp. 1 ml orally QDS Septrin 2 tab orally BD Dose reductions of A and C, if neutrophils less than 100. Modify protocol if age over 60 years
Methotrexate (high dose) 2 g/msq IV 1. Pre-hydration and alkalinisation 1L Dextrose saline + 70ml of 8.4% Na bicrb - 1L every 4 hrs X2 2. Methotrexate 2 g/msq in 1L N. saline over 6 hrs IV 3. Post-hydration + alkalinisation 1L N. Saline + 70ml 8.4% Na bicarbonate 1L every 6 hrs If pH < 7 add oral bicarbonate 3g orally 3 hrly and/or iv bicarbonate by infusion 4. Folinic acid rescue at 24 hours from start of Methotrexate infusion 15mg/msq 6 hrly x 8 initially iv, then orally if tolerated. 5. Methotrexate levels at 24, 48 and 72 hrs. Continue folinic acid if levels fail to fall by 48 hrs post infusion
[A] MANTLE
This includes the occipital, submental, submandibular, anterior amd posterior cervical and supra-cavicular nodes. In addition, it covers the infrra-clavicular, axillary, medial-pectoral, paratracheal and mediastinal lymph nodes. Standard field from tip of mastoids to bottom of T10 Mark involved nodes on the simulator No humeral shielding on ipsilateral side if node involvement, otherwise - Standard humeral shield Cervical cord shielding from posterior field from 20 Gy unless it is close to involved nodes (To bottom of C7). Dorsal spine shielding from posterior field from 30 Gy mpd unless a mediastinal mass is present which was not treated with prior chemotherapy. Anterior shield to cover larynx (bottom of C5) Allow adequate clearance of infraclavicular nodes, i.e. 2cm below clavicle. Lateral border follows inside of rib cage with approx 0.5 cm lung showing laterally or lower border 4th rib 8-10 cms width to allow clearance of retrocrural nodes. Patient treated supine and prone at 142cm FSD or supine and undercouched at 100-110cm FSD
Routine - 35 Gy mpd in 20# in 4 weeks specified at mid point tattoo. Boost to 45 Gy to involved field in NHL. Dose plotted for neck/supraclav., axillae and field centre and areas should not exceed 40 Gy in NHL and 35Gy in Hodgkin’s. In order to reduce the axillary dose the treatment width may be reduced to the inner aspect of the humeral head (if no axillary disease) for the last 1-2 fractions. In order to reduce the neck dose the upper boarder of the field may be reduced to the sternal notch (provided no cervical disease) for the last 1-2 fractions. NB If this is contemplated, the patient must be planned and treated on a machine which has full asymmetrical diaphrams. Post chemotherapy - 6 week gap between chemotherapy and radiotherapy. Dose to previously involved site(s) to 35 Gy in 17#.
[B] INVERTED Y
Para-aortic, pelvic, inguinal nodes and spleen. Standard field bottom of T10 to bottom of ischial tuberosities (appropriate gap calculations from previous mantle field). Check clinically that inguinal nodes included. Paraaortic strip 8-10 cm wide to cover nodes at renal hila (plan with IVP) Pelvic field to cover iliac node chains. Shielding Midline pelvic sheilding - bladder, small bowel, uterus and ovaries if transposed. Lateral blocks - small bowel , kidneys. Scrotal shielding - testes Standard dose Routine - 35 Gy mpd in 20# in 4 weeks. Boost to 40 Gy to involved field in NHL Post chemotherapy - 35 Gy in 17# only. Palliative RT 20-25 Gy/10F or 20Gy/5F.
[C] INVOLVED FIELD RADIOTHERAPY
Mark involved nodes on the simulator Map out radiologically involved areas from pre-treatment scans on simulator film. Put in target volume to include involved nodes + 1-2cm laterally + 5cm along node chain.
Post chemotherapy - 35 Gy in 17# only. Palliative RT 20-25 Gy/10F or 20Gy/5F.
CARE OF PATIENT DURING RADIOTHERAPY Patients to be reviewed weekly during radiotherapy including weight and FBC. Prophylactic antiemetic given to abdominal fields. Metochlopramide or domperidone 10-20mg tds. If vomiting occurs for U&E’s. Dysphagia - mucaine, Nystatin 1ml qds and aspirin mucilage. Diarrhoea and colicky abdominal pain - Low fibre diet. Loperamide.
CARE OF PATIENTS DURING CHEMOTHERAPY Oral hygeine should be empasised. Mouth washes used regulary together with Nystatin 1ml qds. Patients should carry an information card stating that he or she is currently undergoing a course of chemotherapy. Patients should fully understand the importance of self referral in the event of pyrexia, other signs of infection or bleeding.
FOLLOW UP POLICY All patients by the last week of radiotherapy neeed to have a clear understanding of follow up arrangements. These may either be standard follow up or progression to further therapy. Standard follow : 4 weeks with FBC, U&E’s CxR. + Arrange post treatment CT 8 weeks including a review post therapy CT scan Then three monthly 1st year with FBC and CxR CT scans at 1 and 2 years. Remember that hormonal failure can occur in various systems when performing clinical assessments. e.g TFT’s yearly post mantle.
STUDY PROTOCOLS
[1] UKLG LYO7 - MINIMAL INITIAL THERAPY (MIT) FOR "EARLY" HODGKIN’S DISEASE A multicentr randomised trial of short neoadjuvant chemotherapy (VAPEC-B) plus involved field radiotherapy (MIT) versus mantle radiotherapy. OBJECTIVES 1. Overall and Hodgkin’s specific survival at 5, 10 and 15 years. 2. Freedom from relapse/progression at 5 an 10 years. 3. Quality of life (selected centre) 4. Late effects of treatment on key organ function.
ELIGIBILITY CRITERIA 1. Males and females between 16 - 75 years. 2. Histologically proven Hodgkin’s Disease of clinical stage IA or IIA with no mediastinal bulk. 3. No previous treatment.
CHEMOTHERAPY VAPEC-B see chemotherapy section RADIOTHERAPY Involved field - see radiotherapy section
CONTACT NUMBERS Dr MV Williams Addenbrooke’s Hospital, Cambridge. 01223 217020 Dr JA Radford The Christie Hospital, Manchester. 0161 446 3000 ex 3753
RANDOMISATION Dr G Vaughan Hudson BNLI 0171 631 4787 or 0171 380 9428
[2] BNLI-1 - Study of poor risk intermediate or high grade NHL
Objectives Of Study To assess in a prospective randomised trial the value of early intensification with autologous bone marrow or stem cell support in patients with poor prognosis intermediate/high grade Non-Hodgkin's Lymphomas.
Study Design Patient randomisation, 3 cycles of CHOP followed by response assessment. If responding patient proceeds to next stage which is either further CHOP to CR + 2 (min 6) cycles or BEAM + ABMT as decided at randomisation.
1 Patient Selection Age 16 - 65 years No medical conditions prohibiting intensive therapy. No systemic treatment for cancer in previous 5 years. Histology follicular large cell lymphomas diffuse mixed cell lymphomas diffuse large cell lymphomas diffuse immunoblastic lymphomas All histology to be reviewed by panel (to be established). this can be done after randomisation and where necessary patients will subsequently be excluded from the study. Poor prognostic features defined as the presence of 2 or 3 of : i stage III/IV ii LDH > normal iii Performance status 2-4 (ECOG - WHO) Full clinical staging to include CT scanning of abdomen and bone marrow trephine biopsy.
Randomisation (within 2 weeks of starting chemotherapy): Dr G Vaughan Hudson. Tel 071 631 4787 or 071 380 9428 (direct lines) Fax 071 380 9427
Beam + ABMT High dose therapy and ABMT to be carried out in weeks 9 or 10. Although this is a very narrow window, the early randomisation will allow "booking of harvest dates" two months in advance. Full details in protocol folder.
[3] BNLI - 2 Study of chemotherapy in elderly patientss (PAdriaCEBO v PMitCEBO) BNLI - 2 Study of chemotherapy in elderly patientss (PAdriaCEBO v PMitCEBO)Aims Of Current Trial 1 To create a database on unselected elderly patients with high grade NHL 2 To establish the CR rate, overall survival and disease specific survival obtained with an eight week seven drug regimen 3 To compare the efficacy of PAdriaCEBO and PMitCEBO 4 To determine whether the substitution of adriamycin by mitozantrone results in less toxicity and improved quality of life.
Patient Eligibility A Inclusion Criteria i Age 60-85 years ii All histology to be reviewed by central BNLI panel iii Stage IB - IV
Exclusion Criteria i Patients must be free from any other irreversible medical condition that would drastically limit their lifespan or porhibit the sue of combination chemotherapy. ii Patients with significant non/para malignant renal/hepatic/cardiac dysfunction. iii Lymphoblastic and Burkitt's lymphoma.
Randomisation To be carried out by telephone to the BNLI Secretariat on 071 631 4787 (direct line) or 071 636 8333 Ext 3233/3234 before starting any therapy
Details of Protocol - see chemotherapy protocols
[4] LYO3 study - A protocol for a randomised trial of observation versus chlorambucil after anti-heliocbacter therapy in low grade gastric lyphoma. All patients have anti-heliobacter treatment (see above) [A] CR - observation or Chlb [B] PR - observation or Chlb Randomisation number 0171 631 4787.
[5] LYO4 study - A study to investigate the benefit of adjuvant chemotherapy following resection of localised gastrintestinal intermediate and immunoblastic high grade NHL and to assess the effect of the depth of penetration of the tumour on survival. All patients are required to have complete surgical rescetion [A] T1-2, N0,M0 either CHOP x3 or observation only [B] T3-4, n0-2, M0 either CHOP x3 or CHOP x6 CLINICAL Co-ORDINATOR - Dr David Cunningham RMH Sutton. Randomisation number 0171 631 4787.
[6] LY09 study - A randomised trial of chemotherapytherapy in advanced Hodgkin’s disease Eligibility: Stage IB, IIB, III & IV. Stage IA with bulky disaese ( Def: Mediastinal mass > 1/3 rd the interthoracic ratio at d5/6. or a nodal mass > 10 cm). Stage IIA with 3 or more sites of disease or bulky disease. [A] ABVD [B] ChlVPP/PABLOE or hybrid BEACOP.
GUIDELINES FOR THE USE OF FLUDARABINE IN CLL AND LOW GRADE NHL Introduction Fludarabine phosphate is a fluorinated nucleotide analogue of 9-ß-D-arabinofuranosyladeine (Ara-A). Fludarabine phosphate is rapidly dephosphorylated on injection. It is taken up by cells and is then phosphorylated intracellularly to give the active triphosphate 2-F-Ara-ATP. When 2-F-Ara-ATP is incorporated into DNA, DNA synthesis is effectively terminated due to inhibition of a number of enzymes including ribonucleotide reductase, DNA primase, DNA polymerases and DNA ligase. When incorporation of Fludarabine nucleotides into DNA reaches a critical level, programmed cell death or apoptosis is activated and the cell dies. The prognosis for the low grade lymphoproliferative malignancies, (IWF A, B, C) and chronic lymphocytic leukaemia has essentially remained unchanged over the last 15 years with a median survival of 3 - 10 years from initial diagnosis depending on stage. No curative therapy is currently available. The finding that Fludarabine phosphate shows high activity in these conditions is encouraging and prompted a number of phase I and II studies involving investigators on both sides of the Atlantic. Two phase II trials in particular demonstrated the significant single agent activity of Fludarabine in previously treated CLL. These studies were carried out at The National Cancer Institute at Bethesda, Maryland in collaboration with the MD Anderson Cancer Centre in Houston, Texas and the Southwest Oncology Group at Ohio State University, Columbus, Ohio. High response rates were achieved in both untreated patients and in relapsed patients some of whom had become resistant to alkylating agents and in some patients 2nd line drugs such as Vincristine and Doxorubicin. In these patients Fludarabine as a single agent was able to achieve response rates comparable to those of 1st line drugs such as Chlorambucil in previously untreated patients. In low grade lymphoma two thirds of patients will respond to Fludarabine with approximately 20% of patients achieving a complete remission. Follicular lymphomas have a higher response rate than patients with diffuse histology. The response rate was higher in patients who had received only one prior treatment regimen. The activity of Fludarabine had also been reported in the context of Waldenstrom's macroglobulinaemia and Sezary syndrome. The results of a recent multicentre prospective randomised trial of Fludarabine vs CAP for the treatment of CLL stages B and C have now been reported. Fludarabine provides an effective and well tolerated therapy for patients with advanced CLL and compare favourably with CAP. As 2nd line therapy Fludarabine induced a significantly higher rate of complete and partial remissions. No improvement in overall survival has yet been demonstrated. Multicentre randomised prospective comparisons of Fludarabine vs CVP in low grade lymphoma have yet to be reported. Our recommendations are as follows 1) in CLL Fludarabine should be considered in patients who have relapsed after therapy with Chlorambucil or who show disease progression on Chlorambucil therapy. 2) low grade NHL all eligible patients should continue to be recruited to the EORTC/BNLI CVP vs Fludarabine study which is comparing these agents as 1st line therapy for stage III/IV NHL. While more definitive data is awaited, Fludarabine should be used as a 3rd line agent in low grade NHL after Chlorambucil and Anthracycline based regimens.
Treatment schedule Fludarabine phosphate 25 mg/m2 iv daily for 5 days given either by 30 minute infusion or as a bolus over a few minutes repeated every 28 days.
Dose modification Low neutrophil and platelet counts may be due to the disease. If the physician considers that a fall in counts are due to treatment the dose may be modified as indicated below. If the neutrophil count falls below 1 x 109/l or platelets below 50 x 109/l, the dose should be reduced by 50% or the full treatment may be given over 3 days. If neutrophils fall below 0.5 x 109/l or platelets below 20 x 109/l, treatment should be discontinued, and resumed as soon as the counts are to the clinicians satisfaction. Renal impairment - if the creatinine is raised, the creatinine clearance should be measured. If >70 ml/min give full dose, 30 - 70 ml/min give 50% dose and, 30 ml/min exclude.
Adverse Effects The main side effect of Fludarabine phosphate is myelosuppression. Therefore cytopenia with neutropenia, thrombocytopenia and leucopenia may occur. Pulmonary infiltrates have been reported in 6 cases at the National Cancer Institute. Consideration should be given to the use of prophylactic Co-trimoxazole to prevent pneumocystis carinii infection. Irradiated blood products are recommended in view of case reports of fatal graft vs host disease in patients treated with Fludarabine. A single patient has been reported to have suffered a serious neurological disturbance causing blindness. Other possible side effects are fever, chills, nausea, emesis, malaise, fatigue, anorexia, weakness, hearing loss, numbness, pneumonia, cough, shortness of breath, diarrhoea, stomatitis, gastro intestinal bleeding, rashes, rare peripheral neuropathy, rare wrist drop.
Duration of treatment Give 3 cycles and review. If there has been partial or complete response continue to 6 cycles. If there has been no response discontinue. Progressive disease - consider other treatment modalities.
GUIDELINES FOR PREVENTION OF INFECTION FOLLOWING SPLENECTOMY The following Guidelines are Published by the Drug and Therapeutics Committee:- 1. Prophylaxis with penicillin V 250mg bd p.o. should be given for a minimum of two years following splenectomy. No alternative need be prescribed for patients allergic to penicillin although erthromycin 250mg bd p.o. is suitable if tolerated. 2. Patients should be given a supply of antibiotics for self-administration at the onset of any respiratory infection. These should be: Augmentin 1 tab. tds for the majority of patients OR Cefuroxime axetil 250mg bd for penicillin-allergic patients (patients should be reminded to check the expiry date on the pack and request a replacement when necessary). 3. Patients should be advised to have annual influenza vaccinations and to be meticulous about malaria prophylaxis, if and when it is required. 4. Patients should carry a card stating that they have had a splenectomy. 5. Pneumococcal vaccine - a single dose is recommended (see notes).
Notes: 1. Lifelong penicillin. - The risk of overwhelming sepsis appears to decrease over time and this accounts for the advice, given by some authorities, which stresses the importance of prophylaxis in the first two years after splenctomy. It is probably unreasonable to expect lifelong compliance with antibiotic prophylaxis. Oral penicillin V for two years is a practical recommendation, as part of a package of advice. There are, however, many published and unpublished anecdotes and reports of fatal infection twenty or more years after splenectomy. 2. Antibiotics for early self-medication - Because fatal infections may be caused by organisms other than the pneumococcus (such as Haemophilus influenza type b) the patients, whether taking prophylaxis or not, should have a supply of antibiotics to be taken at the first sign of a respiratory infection. Amoxycillin plus clavulanic acid (Augmentin) covers penicillinase-producing H influenza, pneumonococcae and a variety of other pathogens. 3. Influenza Vaccine - As many serious bacterial respiratory tract infections are secondary to viral infection, splenectimised patients should either receive annual influenza vaccination or be included in high-priority lists for vaccination in epidemic years. 4. Malaria - This is a particular hazard to people without spleens and if it is not practical for them to avoid malaria zones, they must take the strictest precautions against infection. 5. The Hib vaccine (against H influenza type). - The is not at present licensed for use in adults. If and when it is, it will remain to be seen whether it is effective in splenectomised individuals. 6. Meningococcal Vaccine. - The majority of infections in the UK are due to the type b meningococcus and are not prevented by the vaccine which is currently available. The vaccine might be appropriate for some overseas patients. 7. Pneumococcal vaccine - The case for this is not very strong, even when it is given before splenectomy and in the immunocompetent. The available vaccine does not cover all stereotypes and antibody response is unpredictable even in the immunocompetent patient. Antibody level estimation is not helpful as it correlates poorly with the protective effect. A single dose only is recommended, as the risk of severe local systemic reactions outweighs the small boosting effect of second and subsequent doses. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||