Catalog and Status of the Quality of Medical Evidence for the most Important Decisions in
the Management of Hematologic Malignancies in Adults:
Years: 1966 to 1996
Send comments regarding this catalog to Dr. Ben
Djulbegovic at:bdjulbeg@hsc.usf.edu
| Decision | Intervention | Best Available Evidence | Reference | Comment |
| Acute lymphoblastic leukemia (ALL) | at least 27 randomized controlled trials (RCT) have been reported evaluating various forms of treatments | |||
| early pre-B, pre-T, T-cell ALL: | most authors do not tailor decision according to immuno-phenotype and some do not consider age an important variable in decision making | |||
| induction Rx: age:<60,CSF negative | chemoRx | II | Leukemia 1992;6(suppl
2):175, 178
Leukemia 1997;11 (suppl4) |
several RCT performed with other regimens but best regimen not identified |
| induction Rx:
age:<60, CSF positive |
triple i.t.Rx, followed by chemoRx | II | " | |
| induction Rx:
age:>60 year old |
chemoRx | II | Blood 1996;87:495 | optimal regimen not identified; most authors would give same chemoRx as in younger patients |
| mature B-cell ALL: | ||||
| induction Rx | chemoRx | II | Blood 1996;87:495 | ara-C based chemoRx; optimal dose of ara-C not identified (based on German protocol for Rx of mature B-cell ALL) |
| CNS prophylaxis (all types): | brain XRT+ i.t. chemoRx | II | Am J Med 1994;97:176 | |
| Consolidation: | ||||
| non-mature B-cell ALL | chemoRx | II | Leukemia 1992;6(suppl 2):175 | best regimen not identified; most authors suggest ara-C/etoposide based chemoRx |
| mature-B cell ALL | No | II | Blood 1996;87:495 | |
| Ph+ALL (<55 old, HLA donor available) | alloBMT | III | Bone Marrow Transplant 1996;16:663 | |
| Ph+ALL (<55 old, no donor available) | MUD vs autoBMT | III | " | |
| Ph+ALL (>55 old) | "standard" consolidation | III | Ann Intern Med 195;123:428 | |
| maintenance Rx: | ||||
| non-mature B-cell | yes | I | Br J Haemtol 1996;92;665 | 6-MP/methotrexate/vincristine/prednisone
(GIMMMA study 0183) (no positive effect from early intensive consolidation) |
| mature B-cell | no | II | Blood 1996;87:495 | |
| primary refractory ALL | chemoRx | III | Eur J Haematol 1990;44:240 | based regimen not identified (high-dose ara-C/mitoxantrone is recommended by some) |
| relapsed ALL: | ||||
| <60 years old | chemoRx followed by BMT | III | " | based regimen not identified (high-dose ara-C/mitoxantrone is recommended by some) |
| >60 year old | supportive care | III | Blood 1992;80:1813 | some authors would try chemo as in patients<60 |
| Acute myelogenous leukemia (AML) | at least 165 rct have been reported evaluating various forms of treatments | |||
| induction Rx: | ||||
| M3-subtype | ATRA | I | Blood 1993;82:3241
N Engl J Med 1997;337:1021 |
|
| all other FAB-subtypes | chemoRx | I | Semin Oncol 1997;24:57 | ara-C+idarubicin appears to produce highest remission rate (excellent summary in ref. listed) (meta-analysis published in the abstract form Blood 1995;86:434a) |
| AML following MDS | high-dose ara-C | II | J Clin Oncol 1992;10:41 | optimal "high" dose not identified; most authors recommend 3 gm/m2 (1.5 gm/m2 for patients older than 50) |
| consolidation Rx: | ||||
| average risk AML | high-dose ara-C | I | J Clin Oncol 1992;10:41 | average risk AML would refer to normal karyotype and the absence of favorable [inv(16),t(8;21),t(15;17)] or unfavorable (chromosome 5,7 abnormalities; prior MDS) characteristics |
| high-riskAML: | ||||
| < 55 year old (HLA donor available) | alloBMT | I | N Engl J Med 1995;332:217 | |
| >55 year old | autoBMT | III | J Clin Oncol 1992;10:41 | many other authors favor chemoRx |
| primary refractory AML: | ||||
| <55 year old (HLA donor available) | alloBMT | III | Blood 1992;80:1090 | |
| >55 year old | chemoRx | III | Blood 1990;76:473 | optimal regimen not identified |
| relapsed AML: | ||||
| after chemoRx | BMT | III | Semin Hematol 1995;32:132 | |
| after BMT | second BMT | III | Blood 1994;84:3605 | |
| Myelodysplastic syndrome (MDS) | at least 19 rct +1 meta-analysis have been reported evaluating the use various treatment options in the management of MDS | |||
| initial treatment for stable disease | observation | I | Ann Hematol
1992;65:162
(erratum in 1993;66:164) |
several rct evaluating effect of low-dose chemoRx and hormonal therapy over supportive care only resulted in no survival benefit. One rct trial, however, did report positive effects on CBC and survival with danazol over placebo (Arch Invest Medica 1989;20:183); other authors have not found danazol useful (Cancer 1994 Jun 15;73:3073, Am J Hematol 1995;48:233) |
| progressive disease: | numerous trials support no use of steriods, androgens
(Am J Hematol 1995;48:233), vitamin D3 (Int J Clin Pharmacol 1993;13:21, Eur J Haemtol 1990;45:255,) cis-retinoic acid (Blood 1988;71:703, Br J Haemtol 1987;66:77), etc | |||
| <55 year old (HLA matched donor available) | alloBMT | II | Blood 1993;82:677 | the goal of Rx is believed to be cure. DFS~45% at 3 years but mortality also approaches 40% |
| <40 year old (MUD available) | alloBMT | III | "
Leukemia Lymphoma 1995;17:95 |
not much experience; best data report DFS:49% at 2 yrs, mortality at 2 years 46% |
| <65 year old (donor not available) | AML-like treatment | III | Leukemia Lymphoma 1993;11:59 | brief CR, median survival 9-12 monts, DFS:20-25% at 2yrs; mortality 10-40% |
| >65 year old | supportive therapy
(with growth factors such as GM-CSF or erythropoietin) |
I | Leukemia Lymphoma
1995;18:457
Br J Haematol 1995;89:67 |
available level I evidence are of small power; however, no trial showed effect on survival; meta-analysis (Br J Haematol 1995;89:67) suggest that early use of erythropoietin (epo) in patients with low epo levels may be beneficial (reduce RBC transfusion requirement) |
| Myeloproliferative disorders: | ||||
| P. Vera: | 13 (4 big + 9 small ) randomized + pseudoRCT trials evaluating effects of various interventions were performed in the management of P. Vera | |||
| initial treatment: | phlebotomy | I | Semin Hematol
1986;23:132
(phlebotomy shown to be superior to chlorambucil and P32) |
this is one of 3 large randomized trials performed in P.
Vera; other trials are: 1) P32 vs busulphan:busulphan was
superior (Br J Cancer 1981;44:75; updated in Drugs
Experim Clin Research 1986;12:283)
2) hydroxyurea vs pipobroman: no difference (HU better tolerated) (Presse Med 1992;21:1753; updated Blood 1997; in press); 3) P32 vs P32 + HU as maintenance treatment: life expectancy was shorter with combination Rx (except for most severe cases when P32-induced remission lasted <2 years) (Blood 1997;89:2319) |
| second line treatment: | hydroxyurea | II | Semin Hematol 1997;34:17 | the most commonly used myelosupressive drug in PV; appears to highly efficacious drug with no mutagenic potential (in retrospective comparison with phlebotomy; see listed ref) |
| -interferon | II | Br J Haematol
1996;92:55
(analysis of 100 cases published in the literature) |
appears to be highly effective regimen; less studied than other modalities; effect on the natural history not determined; one small rct (N=22, cross-over design) concluded that IFN is superior of phlebotomy in controlling all clinical aspects of the disease (Ann Hematol 1994;68:247) | |
| prevention of thrombosis: | ASA+persantin | I | Semin Hematol 1986;23:172 | in a dose used ( 900 mg/d) increase rate of hemorrhagic complications noted; smaller doses are currently under study in a randomized trial; ticlopidine shows beneficial effect on laboratory markers, but it was not evaluated with the respect of clinical events of interest (i.e. DVTs, etc) |
| use of iron in P. Vera | iron | III | J Intern Med 1984;216:165 | there is a theoretical risk for the use of iron in P. Vera (stimulation of malignant clone); this does not appear to be case by anecdotal data; also it does not appear that induced iron deficiency increases hyperviscosity (ref) |
| surgery in P. Vera | stable disease for 3-4 months prior surgery | III | N Engl J Med 1963;23:1226 | retrospective data indicate increase risk for surgery in uncontrolled disease |
| treatment of pruritus | histamine blockers vs IFN vs aspirin photomochemoRx | II | Semin Hematol
1986;23:132
Br J Haematol 1995;89:313 Ann Hematol 1996;73:91 |
P. Vera Study group included H1-blockers (cyproheptadine) or H2-blockers (cimetidine) in its protocol. In one cross over study aspirin (500 mg/d) was more effective than placebo; no effect on bleeding reported in this small study (Acta Dermatovener (Stockholm) 1979;59:505-512) IFN was effective in 12 out 15 patients in the study cited. Psoralen + UV-A light controlled pruritus in 10 of 11 patients (maintenance Rx was generally required) |
| Essential Thrombocythemia | only one rct evaluating effect of HU (vs placebo) (see below) was published in the literature in the treatment of ET | |||
| initial treatment: | ||||
| young asymptomatic patient with platelets<1.5M | Observation | III | Cancer 1991;67:2658 | natural history of a disease does not suggest increased risk of mortality in this group of patients |
| asymptomatic elderly patient (>60 years old) or the patient with previous history of thrombosis or symptoms with platelets<1.5M | hydroxyurea | I | N Engl J Med 1995;332:1132-6 | patients with platelets>1.5M are considered to be increased risk for thrombohemorrhagic complications and also should be treated (level evidence III evidence:J Clin Oncol 1990;8:556) |
| initial treatment in patients with platelets>900 K, or second line treatment | anagrelide | II | Am J Med 1992;92:69-76
Semin Hematol 1997;34:51 |
no comparative trial between anagrelide ans HU exists; anagrelide was also effective in those patient in whom HU or IFN failed |
| " | -interferon | II | Lancet 1988;2:70 | no comparative trial between IFN ,anagrelide and HU exists; |
| use of antiplatelet prophylaxis | ASA (low dose:300 mg/d) | II | N Engl J Med 1995;333:802-803 (letter) | most authors favor use of some antiplatelet agents; ticlopidine is also used; no comparison between these two agents exist |
| acute hemorrhagic complications | plateletpheresis with platelet infusion | III | Transfusion 1979;19:147 | dramatic anecdotal data support this practice |
| splenectomy | absolute contraindication | III | Illand HJ and Laszlo J. Myeloproliferative disorders:Polycythemia Vera, Essential Thrombocythemia and Idiopathic Myelofibrosis. In:Hoogstraten B, ed. Hematologic Malignancies. Springer-Verlag:Berlin,1986:51-52 | dramatic anecdotal data support this practice |
| surgery in ET | heparin in prophylaxis | III | " | surgery is considered of very high risk in ET; optimal regimen of anticoagulant prophylaxis is not established |
| Myelofibrosis | 2 rct were published evaluating effects on androgens on IMF | |||
| asymptomatic patient | Observation | III | Cancer 1991;67:2658 | there is no evidence that any treatment modify course of natural history of Myelofibrosis |
| treatment of symptomatic patient: | androgens vs. | III | N Engl J Med
1966;274:420
N Engl J Med 1961;264:104 |
data on efficacy not clear; it may be of some help in 50% cases. In one small randomized trial which included also other diseases characterized by marrow failure no positive effect was seen with nandrolone (Archives of Internal Medicine 1977;137:65); in other trial that also included other disease that can cause marrow-failure anemia four (29%) of 14 responded well to fluoxymesterone therapy; no effect on survival was seen (Archives of Internal Medicine 1982;142:1533) |
| " | steroids vs. | III | Am J Med Sci 1962;243:697 | no positive treatment effect seen in most of studies; may be beneficial if hemolytic anemia is cause of anemia |
| " | vitamin D3 vs. | III | Lancet 1984;1:78 | some effects seen in some studies; not confirmed in others (Br J Haematol 1986;62:399, Br J Haematol 1987;66:579) |
| " | hydroxyurea vs. | III | Br J Haematol 1991;77:252 | small study, with 10 patients reported; improvement in some symptoms noted in 8 patients |
| " | busulphan vs. | III | Am J Med Sci 1988;295:472 | 3 patients studied, with some improvement
other agents reported in anecdotal cases include chlorambucil and 6-thioguanine (J Coll Physicians Lond 1981;15:17) |
| " | low-dose XRT vs. | III | Cancer 1986;58:1204 | responses usually transient and hematopoietic toxicity is frequently significant; one report ( listed ref) suggest combining with HU |
| " | -interferon vs. | III | Eur J Haematol
1987;39:228
Eur J Haematol 1990;52(suppl):12 |
most other reports are also small case reports; it is difficult to establish the role of IFN in the treatment of IMF |
| " | splenectomy vs. | III | Am J Med 1990;33:128 | decision analysis splenectomy support splenectomy only for palliative treatment; no evidence that it prolongs survival. |
| BMT (allo) | III | Br J Haematol
1992;82:772
Br J Haematol 1989 71:158 |
few data exists to allow any meaningful conclusion
prognostic system (based on retrospective data, not validated in other studies) has been devised to assist in prognosis and selection of patients for BMT (Blood 1996;88:1013; Blood 1997;89:2219,letter) | |
| " (with anemia only) | eryrthropoietin vs. | III | Br J Haematol 1994;86:893 | most data come from small case-reports series; majority of reports show no efficacy and caution possible adverse effects secondary to stimulation of extramedullary hematopoiesis (Lancet 1991;337:188). One case report, however, shows positive effect in 2 patients (Blood 76:271a) |
| " | Supportive treatment + iron, folic acid, vitamins as indicated | III | Am J Med 1978;65:655 | these decisions are derived from "usual" clinical reasoning; one report (ref), that was never reproduced, described positive effect of pyridoxine in 40% with anemia |
| Chronic Myeloid Leukemia | at least 57 RCT evaluating different modalities of the treatment in CML were published in the literature | |||
| initial treatment: | ||||
| <55 old (HLA matched or one antigen mismatch donor available) | alloBMT | II | Blood 1996;87:3069
(review) |
age cut-off not accepted by all authors; data on preparative regimens are of level I (see ); some retrospective data suggest that the patient should be transplanted in the center performing >5 procedures/ year (Blood 1992;79:2771) |
| <45 old (MUD available) | alloBMT | III | " | " |
| optimal timing of BMT | within 1 year of diagnosis | III | " | decision analysis suggest that timing of BMT is a function of a patient age, success of BMT procedure and a prognostic group of a disease (updated Seattle data suggest that the critical prognostic cut-off time may be 3rd year or later (Blood 1994;83:2752) |
| donor not available | -interferon±ara C | I | N Engl J Med
1994;330:820
Lancet 1995;345:1392 Blood 1994;84:4064 Blood 1995;86:906 N Engl J Med 1997;337:223 |
in 4 randomized trial IFN was more successful than hudroxyurea or busulfan retrospectively. Optimal of dose of IFN is not established. Most data suggest that 5 MU/m2 is optimal dose. One single arm study (level II evidence) suggest that 2 MU/m2 daily for one month, then tiw could be equally effective (Ann Intern Med 1994;121:736); recent data (N Engl J Med 1997;337:223) suggest that IFN with ara-C may be superior to IFN alone |
| salvage therapy after BMT: | donor lymphocyte infusion | III | Blood 1993;82:3211
N Engl J Med 1994;330:100 |
small single arm studies also published; second BMT is also alternative but carry high mortality risk (~65%); another strategy is to stop cyclosporine and administer IFN which appears not to have any effect long-term (level III evidence) |
| how to assess effect of therapy | pcr for bcr/abl gene rearrangement q 2-3 months | III | Blood 1993;81:1089
Blood 1995;85:2632 |
conflicting data from different studies in terms of the possiblity of detecting disease relapse prior obvious hematological relapse |
| Hairy Cell Leukemia | 17 (3 rct updated/reported on 9 different occassions) were published | |||
| initial treatment: | ||||
| asymptomatic patient | close follow-up | III | Semin Oncol 1987;11 (suppl 2):479 | natural history of disease indicates long-term survival in 20-25% of patients |
| patient presenting with massive splenomegaly | splenectomy | III | Cancer 1988;62:2420 | retrospective data indicate positive effect of splenectomy in some(highly selected) patients |
| treatment of progressive and symptomatic disease | cladribine | II | N Engl J Med 1990;322:1117 | Randomized trials indicates effectiveness of IFN as well as pentostatin in this disease. There are 3 randomized trial in HCL: pentostatin vs inteferon (IFN) (J Clin Oncol 1995;13:974), splenectomy vs IFN (Am J Hematol 1992;41:13) and low-vs high-dose IFN (Blood 1991;78:3133) cladribine, however, was so highly efficacious that represented an important "quantum leap" in treatment innovations being accepted now as a treatment of choice for HCL |
| relapse, not responsive to cladribine | -IFN vs pentostatine vs fludarabine | III | Leukemia 1995;9:929 | few data exist to support the use of any agent over another in this setting, but appears that there is no cross-resistance between pentostatin and cladribine. One report (see ref) described 3 patients responding to -IFN after failing cladribine |
| Chronic Lymphocytic Leukemia | at least 40 RCT evaluating different modalities of the treatment in CLL were published in the literature | |||
| initial treatment: | ||||
| in early stages | observation | I | Blood 1994;75:1414 | survival appears to be worse in treated group |
| progressive and advanced disease | chlorambucil (low dose)
(vs. CVP vs CHOP vs Fludarabine vs high-dose chlorambucil) |
I | Nouv Rev Fr Hematol 1994;30:343 | Chlorambucil is still recommended because inconsistent results from randomized trials. CHOP was superior to CVP in stage C in French trial (Nouv Rev Fr Hematol 1988;30:449) but not to chlorambucil in Danish trial (Nouv Rev Fr Hematol 1988;30:433); CVP was not better than chlorambucil in stage B (Blood 1990;75:1422); finally fludarabine demonstrated a higher response rate to CHOP,CAP or chlorambucil, but longer follow-up is needed to determine if this higher CR will result in improvement in survival (Blood 1995; 86:607a ;Blood 1994;84:461a;Blood 1993;82:199a). In recent European randomized trial of patients with Binet stage B or C, fludarabine showed higher CR than CAP (60 vs 44%); in previously untreated group median duration of CR was 179 days for CAP and was not reached for fludarabine; this may translate into survival advantage for fludarabine which was 4.3 years for CAP and still has not been reached for fludarabine (p=0.087) (at 4.3 years 67% of patients treated with fludarabine are alive) (Lancet 1996;347:1422-38). However, in this trial 5% mortality was noted in fludarabine group (which was not differrent from CAP toxicity) but it is almost certainly higher than for chlorambucil. Finally, recent RCT evaluating high-dose CLB showed its superiority over CHOP (Cancer 1997;79:2107). |
| second line Rx: | purine analogue (fludarabine vs cladribine vs pentostatin) | II | Blood 1993;82:1695
J Clin Oncol 1995;13:983 |
most data exists regarding the use of fludarabine in CLL, but no comparative data exists between fludarabine and other purine analogues |
| salvage after one purine analogue failed | e.g. cladribine after fludarabine failed | II | N Engl J Med 1994;330:319 | a study on 28 patients suggest that cladribine is ineffective in this setting; small study on 4 patients sugegst opposite (E Negl J Med 1992;327:1056) |
| <65 years old, with good performance status | autoBMT | III | Blood 1995;86:1813 | patients with mixed characteristics, some had purged marrow |
| <55 year old, with good performance status (HLA donor available) | alloBMT | III | Ann Intern Med 1996;124:311 | no comparison between auto and allo-BMT exists; very few data on MUD transplant exists |
| salvage therapy | splenectomy vs splenic XRT | III | Am J Med 1992;93:435 | retrospective data suggest that these modalities may prolong survival; one randomized trial (Nouv Rev Fr Hematol 1988;30:423) showed increased survival for irradiated patients |
| Multiple Myeloma | There are at least 127 RCT published in the literature evaluating efficacy of various treatment modalities. There is also one meta-analysis of 18 rct evaluating combined chemoRx vs melphalan+prednisone, see J Clin Oncol 1992;10:334-342) , 2 studies dealing with treatment vs no therapy in early stages of myeloma, 3 studies researching effect of high-dose therapy with stem-cell/auto-BMT support, 17 rct studying effect of IFN in various phases of thedisease with different chemoRx, 6 rct establishing efficacy of various treatments (mainly diposphonates) on skeletal-related complications in myeloma, and 3 studies evaluating efficacy of various other treatment modalities in MM (such as IgG, epo and G-CSF in procurement of stem cell for high dose Rx) | |||
| initial Rx: | ||||
| stage I, asymptomatic patients | observation | I | Eur J Haematol
1993;50:95
Br J Cancer 1994;70:1203 |
no difference in survival in comparison with immediate
treatment
(some preliminary report on the subject published in Blood 1992;79:113) |
| < 65 year old, stage II, good performance status (PS) | autoBMT | I | N Engl J Med 1995;335:91 | appears to be superior to combined chemoRx |
| <50 years old with HLA donor available | alloBMT | II | J Clin Oncol 1995;13:1312 | mortality up to 30%; it is not clear that alloBMT can cure MM |
| >65 year old or poor PS | melphelan+prednisone | I | J Clin Oncol 1992;10:334 | a meta-analysis integrated results from 18 randomized trials to show that M+P is likely equivavalent in efficacy to combined chemoRx regimens |
| maintenance Rx: | -inteferon | I | Ann Intern Med 1996;124:212 | conflicting results with respect to increase in survival; IFN likely increases median remission time but not survival ; there are at least 17 rct evaluating efficacy of IFN in myeloma (for editorial and reference list on these trials, see Ann Intern Med 1996;124:264) Maintenance treatment with melphalan-prednisone was shown not be effective in rct (Br J Cancer 1988;57:94) |
| salvage Rx: | ||||
| resistant disease | high dose sterioids | III | Ann Intern Med 1986;105:811 | most authors would not use it as a first line Rx in relapsed patients |
| relapsed disease (< 6 months) | VAD | III | Mayo Clin Proc 1994;69:7787 | widely used regimen for relapsed disease, and sometimes as a first line Rx; one small rct (N=47, prematurely closed because of poor accrual) suggested no difference between VAD vs VAD+IFN. Also no obvious advantage over historical data with high-dose steroids suggested (Am J Clin Oncol 1985;18:475) |
| progressive on second line Rx | high-dose melphalan
(with auto BMT/stem cell cell support) |
III | Blood 1996;82:838 | favored currently by many authorities |
| other treatments: | diphosphonates to prevent skeletal related complications | I | N Engl J Med 1996;334:488 | pamidronate (IV) and clodronate (po) (Lancet 1992;340:1049) shown to reduce skeletal complications in stage II and III myeloma; no positive effects was seen for etidronate (Eur J Med 1993;2:449) |
| high dose IgG for prevention of infections | I | Lancet 1994;343:1059 | treatment successful in reducing the risk of infections | |
| erythropoietin to treat anemia | I | Arch Intern Med 1995;155:2069 | epo effective and safe in patients with the anemia of myeloma | |
| plasmapheresis in kidney failure | I | Archives of Internal Medicine 1990 ;150:863 | Plasmapheresis and chemotherapy lowered the serum myeloma protein value much more rapidly than chemotherapy alone. | |
| Waldenstrom's disease | one small pseudo-randomized study (N=11) was reported evaluating two types of plasmapheresis (Clin Nephrol 1995;43:335) | |||
| asymptomatic patient | observation | III | Blood 1994;83:1452 | natural history suggest long-term survival for these patients; it is not clear that any known modality can change the natural history of this disease |
| symptomatic patient | purine analogue
(cladribine vs fludarabine) |
III | Leukemia Lymphoma 1993;11:105 | more experience exists with cladribine; no direct comparison between these two drugs exist |
| presentation with hyperviscosity syndrome | plasma pheresis followed by chemotherapy | III | J Lab Clin Med
1992;119:69
Clin Nephrol 1995;43:335 |
although there are not many patients reported in the literature, physiological basis for this treatment is quite convincing ; second reference cited evaluated at random effect of conventional plasm exchange with cascade filtration (Clin Nephrol 1995;43:335) |
| symptomatic cryoglobulenemia or neuropathy with lymphoma | plasma pheresis followed by chemotherapy | III | Blood 1994;83:1452 | as above; goal would be to reduce IgM for at least 3 months |
| Hodgkin's Disease | at least 132 rct were performed in evaluation of Rx of
HD:
1) early stages (33 trials, including one meta-analysis: Cancer 1990;65:1155 2) advanced stages/others:95 3) relapsed/resistant disease:4 | |||
| initial Rx: | ||||
| early stage HD (IA-IIB, not bulky, with 1 or two symptoms, ESR<30 mm/h) | XRT | I | J Clin Oncol 1993;11:2258 | staging laparotomy can be avoided in patients with favorable prognostic characteristics; recent data favors chemoRx+XRT over XRT (level I evidence); (Proc Am Soc Clin Oncol 1997;16:13a) |
| early stage HD (IA-IIB, not bulky, with 3 B symptoms, ESR>30 mm/h) | ABVDx3,XRT,ABVDx3 | I | J Clin Oncol 1993;11:2258 | no staging laparotomy is necessary; ABVD+XRT superior to MOPP+XRT |
| IIB bulky disease | MOPP,XRT,ABVD | III | J Clin Oncol 1991;9:227
Haematologica 1987;72:327 |
longer follow-up exists for MOPP+XRT, which is still favored by many |
| IIIA2-IVB disease | ABVD | I | N Engl J Med 1992;337:1478 | superior to MOPP and was less toxic than MOPP/ABVD |
| IIIA1 | chemoRx (MVPP) | I | J Clin Oncol 1984:2:892 | some level II evidence suggest excellent long-term DFS with MOPPX2 followed by XRT (J Clin Oncol 1986;6:1293) |
| salvage treatment: | ||||
| primary treatment failure with limited extent disease | wide field XRT | III | Ann Oncol 1994;5:101
J Clin Oncol 1987;5:550 |
this decision will be faced in a few highly selected patients who failed either after XRT or chemoRx (for a review see: Oncology 1996;10:233 |
| primary treatment failure with extensive disease | autoBMT/PBSC | III | Blood 1993;81:1137 | Most data comes from retrospective studies. One rct (see below) included both primary resistant disease and patients that relapsed with 1 year of Rx |
| relapse after XRT | chemotherapy | I | J Clin Oncol 1986;4:838 | retrospective data suggest that doxorubicin-containing regimens are superior to other chemRx; randomized trial cited showed no advantage of doxorubicin-containg regimens over others |
| relapse after chemo:<12 months | autoBMT/PBSC | I | Lancet 1993;341:1051 | this is only rct that evaluated high-dose vs standard treatment in this setting. Decision analysis sugegst that autoBMT should be reserved for second relapse (J Cl Oncol 1992;10:200) |
| relapse after chemo>12 months | non-cross resistant chemoRx | III | J Clin Oncol 1992;10:210 | 24% patients alive at 22 years |
| residual mediastinal mass | acting upon result of Ga scan | III | Med Hypotheses 1992;38:166 | decision analytic evidence |
| Cutaneous T-cell Lymphoma (CTCL) | more than 57 modalities alone or in combinations were recommended in the literature as possible treatment options for CTCL. However, only 7 RCT trials (1 major rct only) have ever been performed in this disease (see below) | |||
| initial treatment: | ||||
| early (skin only) disease (IA,IB) | mechloretamine, followed by PUVA, followed by TSEB vs | I | N Engl J Med 1989;321:1784 | listed RCT was performed showing no advantage of aggressive chemoRx over topical treatment in early disease |
| " | PUVA vs | II | Acta Dermatol Venereol 1989;69:536 | PUVA was compared with PUVA+retinoids; some improvement noted (see also review Oncology 1992;6:31) |
| " | extracorporeal photochemotherapy vs | III | J Clin Oncol 1991;9:1298 | studies difficult to interpret-many patient treated with other therapies while undergoing photopheresis |
| " | topical carmustine | III | J Am Acad Dermatol
1990;22:802 |
can be used in patients allergic to mechloratamine |
| advanced disease (II-IV) | single-agent chemoRx vs | III | Ann Intern Med
1994;121:592
(review article) |
multiple agents described (MTX, cyclophosphamide, chlorambucil, vincristine, doxorubicine, VB-16, etc); no RCT compared efficacy of one agent vs another |
| " | combination chemoRx vs | I | Cancer Treat Rep 1979;63:647 | this small RCT (N=24) compared one combination over another-no difference in efficacy was noted; however, no RCT compared single agent with combined chemoRx; therefore, it is not clear that combined chemoRx is superior to single-agent Rx |
| " | interferon vs | II | J Clin Oncol 1990;8:155 | optimal dose not known; a rct comparing high- vs low-dose Rx prematurely halted due to accrual problem (J Am Acad Dermatol 1989;20:395); most authors believe that low dose Rx is equal to high-dose Rx (for review see Ann Intern Med 1994;121:592) |
| " | interferon+PUVA vs | II | J Natl Cancer Inst 1990;82:203 | highest response rate and longest CR (80%) noted so far |
| " | IFN+retinoids vs | II | Ann Intern Med 1994;121:592 | no rct have been done to determine if combination is superior to IFN alone (single arm studies suggest no major advantage) |
| " | retinoids | II | " | it appears that activity of retinoids is similar to that of single-agent cytotoxic chemotherapy and IFN. One rct (Acta Dermatol Venereol 1987;67:232) showed no difference between 13 cis-retinoic acid with etretinate. No rct compared any of retinoids with chemoRx, IFN or PUVA. |
| salvage Rx: | ||||
| pentostatin vs | III | review articles:
Blood 1996;88:2385 Ann Intern Med 1994;121:592 |
poor response in SS; has also been combined with IFN (J Clin Oncol 1992;10:1907) | |
| cladribine vs | III | " | small series (Blood 1996;87:906) | |
| fludarabine vs | III | " | no direct comparison exists with other purine analogues (J Natl Cancer Inst 1990;82:1353); has also been combined with IFN (J Clin Oncol 1994;12:2051) | |
| monoclonal antibodies+immonoconjugate vs | III | " | few patients studied with some promising activity | |
| IL-2 with or without fusion toxin vs | III | " | theoretically IL-2 should be detrimental; however, responses were noted in small series (5 of 7 patients responded with 3 patients experiencing CR: Arch Dermatol 1995;131:574) | |
| young patients, with advanced disease, good PS | autoBMT | III | " | small series with a short lived response and short follo-up (Bone Marrow Transplant 1991;7:133, Clin Exper Dermatol 1995;20:73) alloBMT has never been studied in this disease |
| NonHodgkin's Lymphoma | at least 177 RCT were performed in evaluation of Rx of NHL | |||
| Low-grade Lymphoma | ||||
| initial therapy: | ||||
| early stage disease (I/II) | XRT | II | Semin Oncol 1990;17:51 | a review article |
| advanced stages, asymptomatic, stable disease | observation | II | N Engl J Med 1984;311:1471 | There is also level I evidence showing that in follicular NHL (small-cell or mixed with a low tumor burden) observation (with delayed Rx) does adversely influence survival at 5 yrs in comparison with alkylating agent or IFN (J Clin Oncol 1997;15:1110) |
| advanced, symptomatic disease | chlorambucil vs CVP vs inteferon+doxorubicin based chemoRx | I | Semin Oncol
1990;17:51
N Engl J Med 1993;329:1608 N Engl J Med 1993;327:1336 |
addition of IFN to chemoRx seems to be superior to chemoRx alone in one trial ; however,no difference in survival existed after 5 years in another trial (n Engl J Med 1993;329:1821) |
| salvage therapy (relapsed disease) | purine analogues
(fludarabine vs cladribine) |
II | J Clin Oncol
1994;12:788
Semin Hematol 1994;31:28 |
no direct comparison between these two purine analogues exists |
| relapsed, responding disease,<65 years old | autoBMT | II | J Clin Oncol 1994;12:1177 | small series reported in the literature |
| young patient, HLA donor compatibile donor available | alloBMT | II | J Clin Oncol 13:1096 | small number of patients had alloBMT so far; mortality ~20% |
| follow-up (follicular NHL) | molecular markers for detection of minimal residual disease ( by detection of t(14;18) | III | J Clin Oncol
1993;11:1668
N Engl J Med 1991;325:1525 |
conflicting data on prediction of relapse; healthy people also can have this translocation detected (Blood 1995;85:2528) |
| Aggressive NHL: | ||||
| initial treatment: | ||||
| early stages (IA/E) | CHOP+XRT | I | Proc Am Soc Oncol 1996;15:411 | superior to CHOPx8 for stage I |
| advanced stages | CHOP vs MACOP-B vs m-BACOD vs ProMACE-CytaBOM | I | N Engl J Med
1992;327:1342
N Engl J Med 1993;328:1002 |
no regimen superior than other; recent data from small RCT showed that high-dose therapy chemoRx is superior to MACOP-B (N Engl J Med 1997;336:1290) |
| slow-responsive disease | CHOP | I | N Engl J Med 1995;332:1045 | equally effective to autoBMT |
| salvage therapy (relapsed disease) | autoBMT | I | N Engl J Med 1995;333:1540 | superior to conventional treatment |
| systemic KI-1 ALCL | F-MACHOP+XRT+
autoBMT |
II | Blood 1996;87:1243 | DFS:100% at 3 yrs |
| mantle-cell lymphoma | chemoRx | III | J Clin Oncol 1995;13:2819 | no optimal regimen identified; current trials focus on high-dose treatment with autoBMT/PBSC rescue |
| Rapidly progressive NHL | ||||
| initial therapy: | short-duration, high-intensity cyclophosphamide based chemoRx | II | J Clin Oncol 1991:9:941 | best regimen not identified; many regimens reported in the literature |
| consolidation therapy: | ||||
| patients with poor prognostic features (such as CNS involvement) | BMT | III | J Clin Oncol 1994;12:2415 | small series both with auto or alloBMT reported |
| CNS prophylaxis | methotrexate i.t. | III | J Clin Oncol 1991;9:1973 | some authors use in all patients, other only in high-risk patients (high LDH, tumor mass>10 cm) |
| salvage treatment (relapsed disease) | autoBMT | III | J Clin Oncol 1994;12:2415 | few data exists for small, non-cleaved cell NHL |
| NHL in HIV+ patient | ||||
| CNS disease | XRT | III | Ann Intern Med 1993;119:1093 | median survival without Rx: 1 month, with XRT:3 months |
| oustside CNS disease | chemoRx | I | Proc ASCO 1995;14:288 | equivalent results between reduced dose chemoRx or standard chemorx (i.e. m-BACOD) with growth factor support |
| CNS prophylaxis | methotrexate it | III | Cancer Control 1995;March/April:97-103 | recommended if marrow is involved or histology is small,non-cleaved cell |
| use of antiviral therapy during chemoRx | No | III | " | PCP prophylaxis is recommended, again based on indirect data |
| Extranodal NHL | ||||
| gastric | CHOP ± XRT | III | Med Ped Oncol
1991;19:48
J Clin Oncol 1988;6:1125 |
some authors argue that surgical resection provides a survival advantage (Oncology 1993;7:29); this decision will also be have to be made on level III data |
| colorectal | surgery followed by chemoRx ± XRT | III | " | "; note that small-bowel and colonic lymphoma are usually diagnosed at operation |
| gastric MALT NHL | antibiotics | II | Ann Intern Med 1995;122:767 | |
| skin, B-cell NHL:localized | XRT | III | J Clin Oncol 1996;14:549 | |
| skin, B-cell NHL:multiple lesions | CHOP | III | " | |
| intravascular lymphomatosis | chemoRx | III | J Clin Oncol 1994;12:2573 | various regimens used |
| splenic lymphoma with violus lymphocytes | splenectomy | III | Br J Haematol 1991;78:206 | |
| posttransplant NHL | reduce
immunosupression+
acyclovir+chemoRx if there is no response |
III | Blood 1995;86:3333 | ProMACE-CytaBOM used in cited report |
| primary CNS lymphoma | high-dose methotrexate-based chemoRx | III | J Clin Oncol 1992;10:635 | based survival reported (median survival:41 months) |
| ocular NHL | XRT | III | Mayo Clinic Proc
1993;68:1003
Mayo Clinic Proc 1993;68:1081 |
most of NHL are of low-grade histology |
| primary spinal NHL | XRT | III | Mayo Clin Proc 1995;70:256 | 9 patients reported in the literature |
| testicular NHL:IPI1 | CHOP+ CNS prophylaxis followed by XRT | III | J Clin Oncol 1995;13:1367 | |
| testicular NHL:IPI>1 | experimental chemoRx | III | " | none of patients with IPI>1 remained in remission after 8-9 years in this retrospective study |
| other important decisions in the management of NHL | ||||
| use of IPI to tailor treatment | III | N Engl J Med
1993;329:987
Blood 1994;83:1165 |
index derived on large set of retrospective, of similarly but not identically treated patients | |
| use of REAL classification to tailor therapy | III | Blood 1994;84:1361
Blood 1997;89:3909 |
needs prospective verification of its clinical validity | |
| follow-up tests and timing | physical exam, vs lab and imaging studies | III | J Clin Oncol 1991;9:1196 | physical exam, LDH and gallium scan had best operating test characteristics in detection of relapse in high-gade NHL; this has never been studied in other types of NHL; similarly how often patient need to be followed has never been systematically studied |