linfoma testicular

8/10/2019 linfoma testicular

1/7


2/7

meninges, remain a major problem since they are denitely morecommon than in other aggressive lymphomas, and with 5- and 10- year risks of 20% and 35%, they constitute a dismal event. 1,7 Impor-tantly, thebest strategy to prevent CNS relapse remains to be dened.The addition of rituximab to cyclophosphamide, doxorubicin,vincristine, and prednisone every 21 days (R-CHOP21) or dose-dense CHOP every 14 days (CHOP14) signicantly improves OSand progression-free survival (PFS) compared with CHOP alonein either elderly or young low-risk patients with diffuse large B-celllymphoma (DLBCL). 13-15 However, no specic data are availablefor PTL patients.

Herein, we report the nal result of what is, to the best of ourknowledge, the rst prospective trial in PTL (IELSG-10), which ad-dressed the safety and efcacy of a combined treatment strategy thatincluded R-CHOP21 and both CNS and testicular prophylaxis. Thistrial was designedto prospectively evaluatethe treatment recommen-dations that could be drawn from the previous IELSG retrospectivestudy, 1 and it provides a contribution to dening a proper treatmentfor PTL.

PATIENTS AND METHODS

Study Design TheIELSG-10 trialwas a multicenterphaseII prospectivestudyaimedat

evaluating thePFSof theR-CHOP21regimenin combinationwithintrathecalmethotrexate (IT-MTX) and locoregional RT for the treatment of PTL. Thestudy was designed by the IELSG and conducted in collaboration with theItalian Lymphoma Foundation. The protocol was approved by the institu-tional review boards and/or ethics committees of each participating institu-tion.The studywas conductedin accordance withtheHelsinkideclaration.Allpatients gave written informed consent.

Patient Selection and Assessment Criteriaforeligibility werepreviously untreatedPTL withDLBCLhistol-

ogy, age 18 years, and Ann Arbor stage I or II (Fig 1). Bilateral testicularinvolvement at presentationwas considered a single extranodal site,and thosewithout nodal involvement were classied as stage I. Exclusion criteria wereEasternCooperativeOncologyGroup (ECOG) performancestatus 2,majororgan dysfunction, HIV seropositivity, malignancies within the last 5 years,poor cardiac function (left ventricular ejection fraction 50%), and CNSinvolvement at diagnosis.

Histologic diagnosis was centrally reviewed by D.N. according to theWHO classication. 16 Baselineassessment includedbonemarrow biopsy; fulllaboratory workup; HIV serology; testicularultrasound; chest, abdomen,andpelvis computed tomography scans; multiple-gated acquisition scan or echo-cardiography; and lumbar puncture with cytologic examination of the cere-brospinal uid.

Treatment Plan The trial design is shown in Figure 2. All patients had diagnostic orchi-

ectomy. The treatment consisted of a standard dose of R-CHOP21, whichincluded375mg/m 2 rituximab day 0 or day 1,750 mg/m 2 cyclophosphamideday 1, 50 mg/m 2 doxorubicin day 1, 1.4 mg/m 2 (maximum 2 mg) vincristineday 1, and 100 mg prednisoneday 1 to 5.All patients wererestagedafter threecourses of R-CHOP21. Stage I patients received six courses of R-CHOP21.

StageIIpatientsreceivedatotalofsixoreightcoursesofR-CHOP21iftheyhada complete response (CR) or partial response (PR) after the third course.Chemoimmunotherapy was delivered in an outpatient setting.

All patients were planned to receive CNS prophylaxis with IT-MTX, 12mg total dose, weeklyfor four times,during therst twoR-CHOP21 courses.At the end of chemoimmunotherapy, prophylactic irradiation to the con-tralateral testisat 25 to30Gy wasdeliveredto all patients. Patients with stageIIdisease at diagnosis,beyond prophylactic testicular RT,receivedinvolvedeldRT (IF-RT), which included the entire involved lymph node region with orwithout an adjacent lymph node region. Minimum IF-RT, for patients withlimited para-aortic lymph node involvement only, includes the centimeter-wide eld; maximum IF includes the inverted Y eld with para-aortic Iymph

Assessed for eligibility and assessed for phase II study treatment(N = 53)

Received RCHOP 3Received IT Mtx 4

Discontinuing Disease progression after IV RCHOP

(n = 1)

(n = 1)

Discontinuing Bilateral

orchiectomy Refusal

(n = 3)

(n = 1)(n = 2)

Discontinuing Refusal

(n = 2)(n = 2)

(n = 40)(n = 37)

Received RCHOP 3 (n = 39)

Received testicular RT (n = 36) Received testicular RT and/or IF-RT* (n = 9)

Received testicular RT and/or IF-RT* (n = 2)

Received RCHOP 3 (n = 11) Received RCHOP 5 (n = 2)

Received RCHOP 3Received IT Mtx 4

(n = 13)(n = 13)

Stage I(n = 40)

RPRCRP / RC

Stage II(n = 13)

Fig 1. CONSORT diagram. Flow of the 53patients enrolled onto the International Ex-tranodal Lymphoma Study Group 10(IELSG-10)study. (*) Details on radiotherapy(RT) are reported in section on feasibility. Instage II patients, 11 received prophylactictesticular RT and nine received retroperito-

neal lymph-node RT. CR, complete re-sponse; IF-RT, involved eld radiotherapy;IT-Mtx, intrathecalmethotrexate; IV, intrave-nous; PR, partial response; RCHOP, ritux-imab plus cyclophosphamide, doxorubicin,vincristine, and prednisone.

Vitolo et al

2 2011 by American Society of Clinical Oncology J OURNAL OF C LINICAL O NCOLOGY

Downloaded from jco.ascopubs.org on November 14, 2014. For personal use only. No other uses without permission.Copyright 2011 American Society of Clinical Oncology. All rights reserved.


3/7

node region and bilateral pelvic lymph nodes. Patients in CR afterR-CHOP21 received IF-RT at 30 to 35 Gy; IF-RT at 35 to 45 Gy wasadministered to those in CR unconrmed (CRu) or in PR at the end of thechemoimmunotherapy program.

Response Evaluation Intermediateresponsewas assessedafter the thirdcourse of R-CHOP21,

and nal response was evaluated after the end of chemoimmunotherapy andRT. CR, CRu and PR were dened according to Chesons 1999 criteria. 17 Noresponse was dened as any response less than a PR, progressive disease, ordeath during the treatmentperiod.

Sample Size and Study End Points

According to the evidence available when the study was planned, thesample size was calculated by using PFS as the primary end point. Given a5-year PFS of 48% reported in the previous IELSG retrospective analysis on373 unselected patients with PTL, the sample size was calculated to show animprovement of 20% in the 5-year PFS for the new treatment policy. Aone-arm trial that included 53 patientswasrequired to reject thenull hypoth-esis ofa 5-yearPFSof 50% underthe alternativehypothesis that thetrue5-yearPFSwas 70%, with a one-sided5% signicance level and80% power,assum-ing a 4-yearaccrual and 2-yearminimum follow-up.

OS,PFS,and time to progression(TTP)were calculated from thedateof diagnosis and dened according to the revised National Cancer Institute(NCI) criteria. 18 PFS includes all patients with an event dened as a progres-sion atanytime duringtreatment, less than a CR/CRuat theend of treatment,

relapse, or death from any cause. OS includes all patients, with an eventdenedas the death ofa patientdue toany cause.TTPis denedas the timefrom study entry until documented lymphoma progression or death as aresult of lymphoma.

Statistical Methods Cumulative survival curves were generated by using the Kaplan-Meier

method. 19 Estimated percent of event rates were derived from the Kaplan-

Meier estimates and reported with 95%CIs. Incidenceof CNSrecurrences inthepresenceofdeathasa competingriskand incidenceof lymphomaprogres-sion or death as a result of lymphoma (TTP) were estimated by using thecumulative incidence method. 20 In TTP, deaths from other causes weretreated as competing events. The follow-up was updated as of October 31,2009. All calculations were performed by using the cmprsk package of R software,version 2.6.0 (R Development Core Team 2007).

RESULTS

Patient Characteristics FromJune2001 to December 2006,53 consecutivepatientswere

enrolled(Table1).Themedian age was 64years (range, 22to 79years);40patients hadstageI and13 hadstageII disease. Four patients hadbilateral testicular involvement at diagnosis. Lactate dehydroge-nase or 2 -microglobulin levels above normal values were ob-served in six patients.

Feasibility Fifty-two of the 53 patients (98%) completed R-CHOP21 as

planned, and the remaining patient experienced early progressionafter four courses (Fig 1). There were no major protocol deviationsregarding chemoimmunotherapy; all patients received the schedulednumber of courses according to stage and response. Prophylactic

testicular RT was performed in 47 patients (89%; 36 stage I and 11stage II);six patientsdid notreceiveprophylactictesticularRT becauseof bilateral orchiectomy at diagnosis in one, disease progression inone, andrefusal in four.In stage II patients, nine receivedretroperito-neal lymph node RT.Median delivered doseoftesticularRTwas30Gy (range, 24 to 40 Gy), and median delivered dose of IF-RT to lymphnodes was 30Gy (range, 23to 45Gy).

CNSprophylaxis wascompletedasplannedin 50patients(94%),but it was discontinued in three patients because of poor tolerance(n 2) and toxicity (n 1). These three patients received one, two,and three IT-MTX doses, respectively.

Stage I

Stage II

RCHOP 3*

RCHOP 3*

RESTAGING

RCHOP 3

RCHOP 3

CR/PR

CR

PR RCHOP 5

Testicular RT

Testicular RT + IF-RT

Testicular RT + IF-RT

Fig 2. Plan of treatment for the Interna-tional Extranodal Lymphoma Study Group10 (IELSG-10) study. (*) CNS prophylaxis:12 mg intrathecal methotrexate during therst two courses of rituximab plus cyclo-phosphamide, doxorubicin, vincristine, andprednisone administered every 21 days(RCHOP21; days 1, 8, 15, 22). () Testicularradiotherapy (RT): prophylactic testicularirradiation including the contralateral tes-tis at 25-30 Gy; involved eld RT (IF-RT)at 30-35 Gy in stage II patients in com-plete response (CR) after RCHOP21, at35-45 Gy in stage II patients in CR uncon-rmed/partial response (PR) after RCHOP21.

Table 1. Clinical Characteristics

Characteristic No. of Patients %

Age, yearsMedian 64Range 22-79

Ann Arbor stageIE 40 75

IIE 13 25Bilateral testicular involvement 4 8Lymph node involvement 13 25ECOG performance status

0 47 891 4 72 2 4

B symptoms 2 4Elevated LDH serum level 6 12Elevated 2 -microglobulin serum level 6 14

Abbreviations: ECOG, Eastern Cooperative Oncology Group; LDH, lac-tate dehydrogenase.

Assessed in 50 patients; three missing.Assessed in 42 patients; 11 missing.

Primary Testicular Lymphoma: R-CHOP With IT-MTX and Testis RT

www.jco.org 2011 by American Society of Clinical Oncology 3Downloaded from jco.ascopubs.org on November 14, 2014. For personal use only. No other uses without permission.

Copyright 2011 American Society of Clinical Oncology. All rights reserved.


4/7

Response and Outcome Fifty-two patients (98%) achieved a CR, and only one experi-

enced progressive disease at nodal and extranodal sites during treat-ment and died. At a median follow-up of 65 months, nine patientsexperienced relapse. Relapses involved lymph node alone in two pa-tients, extranodal organs (pleura, skin, unknown) with or withoutlymphnodes in four patients, andCNS in three patients. Five of thesepatients died of lymphoma and four are currently alive in secondremission after salvage therapy. Overall, treatment failures were ob-served in nine of 40 patients with stage I disease and in one of 13patientswith stage IIdisease.This lastpatienthad bothextranodalandnodal relapse involving pleura and retroperitoneal lymph nodeswithin the RT eld (actual delivered dose, 38 Gy).

With a median follow-up of 65 months, the5-year PFSwas74%(95% CI, 59% to 84%; Fig 3A). CNS relapses occurred in three pa-tients: two of them hadisolated CNS relapses (one meningealandonebrain parenchymal disease) andonehada concurrent meningeal andlymph nodal relapse. The two patients with isolated CNS relapsereceived prophylactic IT-MTX as planned by the protocol; the thirdpatient received only two IT-MTX doses because of poor tolerance.

The 5-year cumulative incidence of CNS relapse, taking into accountthe competitive riskofdeath,was 6%(95% CI, 0%to 12%;Fig 4). Nocontralateral testis relapses were observed.

The 5-year OS rate was 85% (95% CI, 71% to 92%; Fig 3B). Tenpatients died: six of progressive disease, two of acute myelogenousleukemia after21and60months off therapy, oneof heart failure, andoneof gastric cancerafter 17 and9 monthsof follow-up. Overall, onepatient progressed and nine relapsed, so the 5-year cumulative inci-dence of lymphoma progression or death as a result of lymphoma(TTP) was 18% (95% CI, 7% to 29%; Fig 3C).

Toxicity and Safety Hematologic toxicity wasmildduringtheR-CHOP21treatment.

According to the WHO toxicity criteria, a grade 3 hematologictoxicity forneutrophilswasrecordedin 14 patients (26%),platelets infour (8%), andhemoglobin in two(4%). Grade 3 nonhematologictoxicitieswere reportedin 13patients(Table2).Grade 3 neurologictoxicity was observed in seven patients (13%): two had sensory neu-ropathy and one had motor neuropathy due to vincristine; fourpatients had severe headache after IT-MTX of whom one had a cere-brospinaluid leak andonea subduralhematoma. CNS prophylaxiswas interrupted in three of them. Severe infections were reportedin only two patients (4%): one patient had a staphylococcus sepsisafter the third course of R-CHOP21, and one had a bacterialpneumonia after the fourth course of R-CHOP21 and stoppedchemotherapywhile in disease progression.No deathsas a resultof toxicity occurred during treatment. Fatal late adverse events, pos-sibly associated with the treatment, occurred in three patients(6%): two acute myelogenous leukemia and one heart failure (seecauses of death in Table 3).

DISCUSSION

The IELSG-10 study is, to the best of our knowledge, the rst world-wideprospectivetrial onPTL.This trialshowed,in a cohortofpatientswith a prolonged follow-up, that a combined treatment with R-CHOP21 associated with CNS andtesticular prophylaxis is a promis-

ingapproach for PTL. This strategyis associated witha good outcomewith 5-year PFS, OS, and cumulative incidence of TTP of 74%, 85%,and18%, respectively.Aneffectivesystemiccontrol of thediseasewithno contralateral testis relapsesanda lowincidenceof CNS relapse wasachievedin thistrial.The acceptabletoxicity proleof thistreatmentisremarkable considering that, as usual for PTL, half the patients wereolder than age 65 years.

A

0

P r o g r e s s i o n - F

r e e

S u r v

i v a

l

( p r o

p o r t

i o n

)

Time Since Diagnosis (months)

1.00

0.75

0.50

0.25

12 3624 6048 8472 96

4953 54ksirta.oN 4274 933 14 1

B

0

O v e r a

l l S u r v

i v a

l ( p r o p o r t

i o n

)


1.00

0.75

0.50

0.25

12 3624 6048 8472 96

5253 74ksirta.oN 7294 1173 16 1

C

0

C u m u

l a t i v e

I n c

i d e n c e

o f P r o g r e s s

i o n


0.50

0.45

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

12 3624 6048 8472 96

Fig 3. (A) Progression-free survival (PFS), (B) overall survival (OS), and (C)cumulative incidence of time to progression (TTP, solid gold line; cumulativemortality without progression, dashed blue line); 5-year PFS, 74% (95% CI, 59%to 84%); 5-year OS, 85% (95% CI, 71% to 92%); and 5-year TTP, 18% (95% CI,7% to 29%). Vertical bars represent 95% CIs.

Vitolo et al




5/7

One limitation to our study should be noted. This is a phase IItrial that includes a relatively small consecutive series of patientswith PTL. Conversely, in a rare disease such as PTL, implementinga randomized phase III trial to make strong and denitive conclu-sions on efcacy is a complex issue,oftenunfeasible. Moreover, thelack of previous prospective studies on PTL led us to use, as bestavailable reference, the 5-year PFS of a historical group of patients,which was not completely comparable with the group of patientsenrolled on this phase II study. Thus, such a comparison should beviewed with caution.

A pattern of continuous relapses and disease-related deaths wasshown in several studies in PTLseries in localized stages. 3,4,21,22 In the

previousIELSGretrospectivestudy,1

thePFSprogressivelydeclinedat5 and10 years, from 48% to33%,respectively, in thewhole series, andfrom 54% to 36% in the subset of stage I patients. A similar behaviorwas also observed in a recent population-based retrospective study 4

with a 5- and 10-year disease-specic survival of 62% and 50%, re-spectively (PFS was not reported). Indeed, we observed four latelymphoma-unrelated deaths in relapse-free patients.

Notably, ve of tenrelapses were late events ( 2 years from theend of therapy), which is uncommon in most nodal and extranodalforms of DLBCL.23 This peculiar behavior of PTL underlines thenecessity of prolonged follow-up in these patients. Accordingly, themedian follow-up of this trial, which exceeds 5 years,may be notlongenough to detect all of the events.

Our treatment included three components: prophylactic RT tothe contralateral testis, addition of rituximab to CHOP, and CNS

prophylaxis. In the previousretrospective IELSG study,1

prophylacticRT to the contralateral testis appeared to prevent testicular relapses,which were reduced to 8% compared with 35% in those not irradi-ated. Positiveeffectof prophylactic RTto thecontralateral testis in thistrial further supports the inclusion of this strategy into internationalclinical recommendations for PTL. 24 In this study, the small numberof patients with stage II disease precluded proper assessment of therole of addingRT to retroperitoneal lymph nodes. Indeed, therole of RT after R-CHOP is still controversial in nodal DLBCL. 25

The addition of rituximab to CHOP chemotherapy may haveimproved outcome by preventing relapses with better control of mi-croscopic systemic disease that might have been present since theonset of the disease. The benet of the addition of rituximab in thetreatment of PTL was recently questioned by the population-basedretrospective study, which showed no difference in the outcome of patientswithPTLtreatedbefore andafter therituximabera,using the year 2000 as the cut point.4 However, this retrospective study waslimited by the lack of information regarding treatment delivered andwhat proportion of patients actually received rituximab-containingchemotherapyregimens.Although onlyrandomizedclinical trialscanaddress the impact of rituximab in PTL, these studies are difcult toperform because of the rarity of this disease. Many studies of patients with predominantly nodal DLBCL have provided strongevidence of the benet of the addition of rituximab to chemother-apy in DLBCL, which could be an indirect proof of a potentialbenet also in PTL. 13-15,26 Importantly, there is discordant publishedevidence on the role of rituximab in preventing CNS relapses inDLBCL. CNS recurrence rate was similar in 399 elderly DLBCL pa-tients treated with R-CHOP or CHOP. 27 Conversely, the analysisof CNS events in 1,222 elderly DLBCL patients treated in theRICOVER-60trial showed thattheaddition of rituximab to CHOP14is associated with a reduction of the relative risk of CNS disease to0.58.28 Although this question remains open, it is likely that a bettersystemic disease control in DLBCL patients treated with R-CHOPmightalso result in a reduced risk of CNS recurrences.

A retrospective series of 24 patients with PTL, treated before therituximab era with a similar trimodality strategy (doxorubicin-basedchemotherapy, testicular RT, and IT-MTX) has shown a 5-year PFS

Table 3. Late Possible Treatment-Associated Adverse Toxicities

Late ToxicityNo. of

PatientsAge

(years)

Time FromEnd of

Treatment(months) Outcome

AML 1 69 21 DeathMyelodysplasia with AML 1 79 44 DeathHeart failure 1 75 17 Death

Abbreviation: AML, acute myelogenous leukemia.

0

C u m u l a

t i v e

I n c

i d e n c e

o f C N S R e c u r r e n c e


0.50

0.45

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

12 3624 6048 8472 96

Fig 4. Cumulative incidence of CNS recurrence (solid gold line) and cumula-tive mortality without CNS involvement (dashed blue line); 5-year CNScumulative incidence, 5.9% (95% CI, 0% to 12%). Vertical bar represents95% CI.

Table 2. Summary of Acute Hematologic and Nonhematologic Toxicities

Acute Toxicity

Grade

0 1-2 3-4No. % No. % No. %

Hematologic, total 36 68 2 4 5 28Anemia 48 90 3 6 2 4Neutropenia 38 72 1 2 14 26Thrombocytopenia 49 92 0 4 8

Neurologic 39 74 7 13 7 13Cardiac 50 94 2 4 1 2GI 42 79 10 19 1 2Infection 48 90 3 6 2 4Fever of unknown origin 50 94 2 4 1 2Cutaneous 49 92 3 6 1 2





6/7

and OS of 78% and 66%, respectively, but both without an apparentcurve plateau. Moreover, the risk of CNS relapse was still high(16%). 29,30 A comparison of these results with those of the IELSG-10study may suggest that there could be some benet from theadditionof rituximab. However, a longerfollow-upis neededto clarify theroleof rituximab in PTL treatment.

The incidence of CNS relapses in both brain parenchyma and

meninges is more common in PTL than in other aggressive lympho-mas. This complication is usually observed during the rst 2 years of follow-up in nodal DLBCL,31 whereas late CNS relapses have beenreported inPTL. 1,6-10 InthepreviousIELSGseries,5-and10-yearrisksof CNS relapse of 20% and 35% were observed.1 In this study, thecumulativeincidenceofCNSrelapseat 5 years wasonly6%. However,in the absence of a comparison group without CNS prophylaxis, wecannot ascribe these results to the introduction of CNS prophylaxis.Thebest strategyfor preventing CNS relapse is still a matter of debate.The value of prophylactic intrathecal chemotherapy is controversialbecause CNS relapses occur more frequently in brain parenchymathan in meninges and also in patients who have received intrathecalchemotherapy. 9,14,16 However, PTL patients are usually elderly andmany of them may not tolerate aggressive CNS prophylaxis such assystemic high-dose methotrexate or cytarabine chemotherapy regi-mens. The CNS prophylaxis chosen in our studyfour doses of IT-MTXis easy to administer with good compliance and low toxicity despite the advanced age of the patients, and it was feasible in 94% of the patients. Nevertheless, in our study, despite CNS prophylaxis,three patients experienced CNS disease, and one of them had paren-chymal disease. This underlines the necessity of further studies toproperly dene the best strategy forCNS prophylaxis in patientswithPTL. For instance, the use of drugs with a higher CNS bioavailability,such as intrathecal liposomal cytarabine and/or the addition of sys-temic intermediate-dose methotrexate, may play a role in preventing

CNS relapses. A new prospective study(IELSG-30) conducted by theIELSG is ongoing to test this hypothesis.

In conclusion, this study showed that R-CHOP21 combinedwith CNS and testicular prophylaxis is feasible in patients youngerthan age 80 years with PTL. However, the long-term benet of thisstrategy should be conrmed with a longer follow-up in a larger seriesofpatients. The resultsofthis studymight beconsideredasa referencefor future studies on this rare lymphoma.

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a nancial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; thoserelationships marked with a C were compensated. For a detailed

description of the disclosure categories, or for more information about ASCOs conict of interest policy, please refer to the Author DisclosureDeclaration and the Disclosures of Potential Conicts of Interest section inInformation for Contributors.Employment or Leadership Position: None Consultant or Advisory Role: Umberto Vitolo, Roche Italy (C); Armando Lopez-Guillermo,Roche (C) Stock Ownership: None Honoraria: None ResearchFunding: None Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Umberto Vitolo, Mary K. Gospodarowicz,Franco Cavalli, Andreas H. Sarris, Emanuele ZuccaAdministrative support: Franco Cavalli, Emanuele Zucca

Provision of study materials or patients: Umberto Vitolo, AnnalisaChiappella, Andres J.M. Ferreri, Maurizio Martelli, Monica Balzarotti,Chiara Bottelli, Annarita Conconi, Henry Gomez, ArmandoLopez-Guillermo, Giovanni Martinelli, Francesco Merli, DomenicoNovero, Lorella Orsucci, Vincenzo Pavone, Umberto Ricardi, SergioStorti, Emanuele ZuccaCollection and assembly of data: Umberto Vitolo, Annalisa Chiappella,Ileana Baldi, Emanuele ZuccaData analysis and interpretation: Umberto Vitolo, Annalisa Chiappella,Andres J.M. Ferreri, Ileana Baldi, Umberto Ricardi, Mary K.Gospodarowicz, Franco Cavalli, Andreas H. Sarris, Emanuele ZuccaManuscript writing: Umberto Vitolo, Annalisa Chiappella, Andres J.M.Ferreri, Maurizio Martelli, Ileana Baldi, Monica Balzarotti, ChiaraBottelli, Annarita Conconi, Henry Gomez, Armando Lopez-Guillermo,Giovanni Martinelli, Francesco Merli, Domenico Novero, LorellaOrsucci, Vincenzo Pavone, Umberto Ricardi, Sergio Storti, Mary K.Gospodarowicz, Franco Cavalli, Andreas H. Sarris, Emanuele ZuccaFinal approval of manuscript: Umberto Vitolo, Annalisa Chiappella,Andres J.M. Ferreri, Maurizio Martelli, Ileana Baldi, Monica Balzarotti,Chiara Bottelli, Annarita Conconi, Henry Gomez, ArmandoLopez-Guillermo, Giovanni Martinelli, Francesco Merli, DomenicoNovero, Lorella Orsucci, Vincenzo Pavone, Umberto Ricardi, SergioStorti, Mary K. Gospodarowicz, Franco Cavalli, Andreas H. Sarris,Emanuele Zucca

REFERENCES

1. Zucca E, Conconi A, Mughal TI, et al: Patternsof outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by theInternational Extranodal Lymphoma Study Group.J Clin Oncol 21:20-27, 2003

2. Shahab N, Doll DC: Testicular lymphoma.Semin Oncol 26:259-269, 1999

3. Mller MB, dAmore F, Christensen BE:Testicular lymphoma: A population-based studyof incidence, clinicopathological correlations andprognosisThe Danish Lymphoma Study Group,LYFO. Eur J Cancer 30A:1760-1764, 1994

4. Gundrum JD, Mathiason MA, Moore DB, etal: Primary testicular diffuse large b-cell lympho-ma: A population-based study on the incidence,natural history, and survival comparison with pri-mary nodal counterpart before and after the intro-

duction of rituximab. J Clin Oncol 27:5227-5232,2009

5. Booman M, Douwes J, Glas AM, et al: Pri-mary testicular diffuse large B-cell lymphomas haveactivated B-cell-like subtype characteristics. J Pathol210:163-171, 2006

6. Seymour JF, Solomon B, Wolf MM, et al:Primary large-cell non-Hodgkins lymphoma of thetestis: A retrospective analysis of patterns of failureand prognostic factors. Clin Lymphoma 2:109-115,2001

7. Fonseca R, Habermann TM, Colgan JP, et al:Testicular lymphoma is associated with a high inci-dence of extranodal recurrence. Cancer 88:154-161,2000

8. Crellin AM, Hudson BV, Bennett MH, et al:Non-Hodgkins lymphoma of the testis. RadiotherOncol 27:99-106, 1993

9. Ferry JA, Harris NL, Young RH, et al: Malig-nant lymphoma of the testis, epididymis, and sper-

matic cord: A clinicopathologic study of 69 caseswith immunophenotypic analysis. Am J Surg Pathol18:376-390, 1994

10. Tondini C, Ferreri AJ, Siracusano L, et al:Diffuse large-cell lymphoma of the testis. J ClinOncol 17:2854-2858, 1999

11. Touroutoglou N, Dimopoulos MA, Younes A,et al: Testicular lymphoma: Late relapses and pooroutcome despite doxorubicin-based therapy. J ClinOncol 13:1361-1367, 1995

12. Doll DC, Weiss RB: Malignant lymphoma ofthe testis. Am J Med 81:515-524, 1986

13. Coifer B, Lepage E, Briere J, et al: CHOPchemotherapy plus rituximab compared with CHOPalone in elderly patients with diffuse large-B-celllymphoma. N Engl J Med 346:235-242, 2002

14. Pfreundschuh M, Trumper L, Osterborg A, etal: CHOP-like chemotherapy plus rituximab versusCHOP-like chemotherapy alone in young patientswith good-prognosis diffuse large-B-cell lymphoma:

Vitolo et al




7/7

A randomised controlled trial by the MabThera Inter-national Trial (MInT) Group. Lancet Oncol 7:379-391,2006

15. Pfreundschuh M, Schubert J, Ziepert M, et al:Six versus eight cycles of bi-weekly CHOP-14 withor without rituximab in elderly patients with aggres-sive CD20 B-cell lymphomas: A randomised con-trolled trial (RICOVER-60). Lancet Oncol 9:105-116,2008

16. Gatter KC, Warnke RA: Diffuse large B-celllymphoma, in Jaffe ES, Harris NL, Stein H, et al (eds):World Health Organization Classication of Tumours.Pathology and Genetics of Tumours of Haematopoi-etic and Lymphoid Tissues. Lyon, France, IARC Press,2001, pp 171-174

17. Cheson BD, Horning SJ, Coifer B, et al:Report of an international workshop to standardizeresponse criteria for non-Hodgkins lymphomas: NCISponsored International Working Group. J Clin On-col 17:1244, 1999

18. Cheson BD, Pstner B, Juweid ME, et al:Revised response criteria for malignant lymphoma.J Clin Oncol 25:579-586, 2007

19. Kaplan EL, Meier P: Nonparametric estima-tion from incomplete observations. J Am Stat Assoc

53:457-481, 1958

20. Kim HT: Cumulative incidence in competingrisks data and competing risks regression analysis.Clin Cancer Res 13:559-565, 2007

21. Vitolo U, Ferreri AJ, Zucca E: Primary testicu-lar lymphoma. Crit Rev Oncol Hematol 65:183-189,2008

22. Linassier C, Desablens B, Lefrancq T, et al:Stage I-IIE primary non-Hodgkins lymphoma of thetestis: Results of a prospective trial by the GOELAMSStudy Group. Clin Lymphoma 3:167-172, 2002

23. Larouche JF, Berger F, Chassagne-Cle mentC, et al: Lymphoma recurrence 5 years or laterfollowing diffuse large B-cell lymphoma: Clinicalcharacteristics and outcome. J Clin Oncol 28:2094-2100, 2010

24. Zelenetz A, Abramson JS, Advani RH, et al:NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkins lymphomas. J Natl Compr Canc Netw8:288-334, 2010

25. Pfreundschuh M: How I treat elderly patientswith diffuse large B-cell lymphoma. Blood 116:5103-5110, 2010

26. Sehn LH, Donaldson J, Chhanabhai M, et al:Introduction of combined CHOP plus rituximab ther-apy dramatically improved outcome of diffuse largeB-cell lymphoma in British Columbia. J Clin Oncol

23:5027-5033, 2005

27. Feugier P, Virion JM, Tilly H, et al: Incidenceand risk factors for central nervous system occur-rence in elderly patients with diffuse large-B-celllymphoma: Inuence of rituximab. Ann Oncol 15:129-133, 2004

28. BoehmeV, Schmitz N,Zeynalova S, et al: CNSevents in elderly patients with aggressive lym-phoma treated with modern chemotherapy (CHOP-14) with or without rituximab: An analysis of patients

treated in the RICOVER-60 trial of the GermanHigh-Grade Non-Hodgkin Lymphoma Study Group(DSHNHL). Blood 113:3896-3902, 2009

29. Sarris AH, Vitolo U, Zucca E, et al: Prospectivemanagement of primary testicular lymphoma (PTL)with doxorubicin-based chemotherapy, prophylacticintrathecal (IT) methotrexate and radiotherapy (RT),but without rituximab: Results from IELSG. Blood108, 2006 (abstr 2454)

30. Mazloom A, Fowler N, Iyengar P, et al: Pri-mary testicular diffuse large B-cell lymphoma, M.D.Anderson Cancer Center experience. Blood 114,2009 (abstr 2697)

31. van Besien K, Gisselbrecht C, PfreundschuhM, et al: Secondary lymphomas of the central ner-vous system: Risk, prophylaxis and treatment. Leuk

Lymphoma 49:52-58, 2008

Acknowledgment We thank Pasqualina De Masi,Elena Porro, andCristina Morinini for their contribution to data collection and management andthe nurses

and doctors for their expert care of the patients enrolledonto the study.Supported by unrestrictedGrant No. ICP OCS-02062-03-2007 from the Swiss Cancer League and by an unrestricted grant from Ministerodella Salute, Dipartimento dellInnovazione-Direzione Generale Ricerca Scientica e Tecnologica (Progetto di Ricerca Finalizzata Bando

2008, u.p.b. 3.1.2.10, scientic research, chapter 3398).




Documents

linfoma testicular