clinical study gemcitabine, navelbine, and doxorubicin as...

Clinical StudyGemcitabine Navelbine and Doxorubicin as Treatment forPatients with Refractory or Relapsed T-Cell Lymphoma

Zhengzi Qian Zheng Song Huilai Zhang Xianhuo Wang Jing Zhao and Huaqing Wang

Department of Lymphoma Sino-US Center for Lymphoma and Leukemia National Clinical Research Center of CancerKey Laboratory of Cancer Prevention andTherapy Tianjin Medical University Cancer Institute and Hospital TiyuanbeiHuanhuxi Road Hexi District Tianjin 300060 China

Correspondence should be addressed to Huaqing Wang huaqingw163com

Received 25 June 2014 Accepted 16 September 2014

Academic Editor Shiwu Zhang

Copyright copy 2015 Zhengzi Qian et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

T-cell lymphoma (TCL) is resistant to conventional chemotherapy We retrospectively evaluated the therapeutic efficiency andtoxicity of gemcitabine navelbine and doxorubicin (GND) in patients with refractory or relapsed TCL From 2002 to 2012 69patients with refractory or relapsed TCL received GND treatment in our hospital The treatment protocol comprised gemcitabine(800mgm2 group 1 1000mgm2 group 2) on days 1 and 8 navelbine (25mgm2) on day 1 and doxorubicin (20mgm2) on day 1repeated every 3 weeks The overall response rate (ORR) was 652 The median overall survival (OS) was 36 months The 5-yearestimated OS rate was 324 The GND regimen was well tolerated Subgroup analysis demonstrated that the ORR and CR forgroup 1 were similar A longer median OS was observed for group 1 Significant difference in grades 3-4 toxicities was observedbetween groups 1 and 2 (119875 = 0035) Our study indicated that gemcitabine (800mgm2) on days 1 and 8 every 21 days was favorablefor pretreated TCL patients

1 Introduction

T-cell lymphoma (TCL) belongs to a group of malignantclonal hyperplastic diseases that is derived from T lympho-cytes and it is characterized by high heterogeneity stronginvasiveness and a prominent association with Epstein-Barrvirus and human T-lymphotropic virus type 1 infectionsas well as with specific chromosome translocations Thetreatment outcomes of patients with B-cell lymphoma (BCL)have improved due to great advancements in chemotherapycombined with molecular targeted agents such as rituximabHowever due to its highly aggressive features including localtumor invasiveness in early-stage disease the outcomes ofTCL patients are generally worse with poor long-term sur-vival (5-year overall survival (OS) 20ndash30) [1] In additionowing to resistance to conventional chemotherapeutic agentssuch as CHOP (cyclophosphamide doxorubicin vincristineand prednisolone) or CHOP-like regimen which is mediatedby the expression ofmultidrug-resistance proteins a substan-tial proportion of TCL patients develop refractory or relapsed

disease Although high-dose chemotherapy supported byautologous stem cell transplantation (ASCT) offers an advan-tage for some patients the severe toxicities including cardiacand hematological adverse effects limit their widespread useEven the introduction of novel drugs such as L-asparaginasecannot overcome the refractoriness completely Thereforeadditional trials and further studies are needed to developsafe and effective salvage chemotherapy regimens for patientswith refractory or relapsed TCL

Gemcitabine (2101584021015840-difluoro-21015840-deoxycytidine) whichmainly acts on the synthesis phase of the cell cycle byinhibiting DNA synthesis is a pyrimidine antimetabolite Ithas been demonstrated that gemcitabine is one of the mosteffective agents when used either as a monotherapy agent oras part of a combination regimen for patients with relapsedor refractory Hodgkin lymphoma (HL) and non-Hodgkinlymphoma (NHL) [1ndash3] Of particular importance theNational Comprehensive Cancer Network has incorporatedthis nucleoside metabolic inhibitor into its clinical practiceguidelines

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 606752 7 pageshttpdxdoiorg1011552015606752

2 BioMed Research International

Given the encouraging outcomes of previous studies weinvestigated the effectiveness safety and toxicity of gem-citabine navelbine and doxorubicin (GND) combinationchemotherapy in patients with refractory or relapsed TCL

2 Patients and Methods

21 Patients The subjects of this retrospective study arepatients with refractory or relapsed TCL who received GNDtreatment between January 2002 and December 2012 inthe Tianjin Medical University Cancer Hospital Patientswere eligible according to the following criteria histologicalwith immunohistochemical diagnosis of TCL from pro-fessional pathologists according to the Revised European-American Lymphoma classification [4] and available patho-logical reports complete blood counts showing white bloodcell (WBC) counts ge4 times 109L platelet (PLT) counts ge100times 109L neutrophil counts ge15 times 109L and hepatic andrenal function tests demonstrating aspartate aminotrans-ferase and alanine transaminase levels le35UL and serumcreatinine le80120583molL at the beginning of the treatment noabnormalities with electrocardiography (ECG) refractory orrelapsed after conventional therapeutic approaches includingchemotherapy andor radiotherapy and accumulated doseof doxorubicin le 350mgm2 during the previous treatmentExclusion criteria included a history of hepatitis B hepatitisC human immunodeficiency virus uncontrolled infectionor significant cardiac dysfunction or central nervous systemlymphoma at the time of GND administration We collectedthe following clinical characteristics of enrolled patientsretrospectively patient demographics time until relapsehistopathologic subtypes Eastern Cooperative OncologyGroup performance status extent of disease involvementAnn Arbor stage International Prognostic Index serum 1205732microglobulin (1205732-MG) levels lactate dehydrogenase (LDH)levels previous treatment regimens deadline of the follow-upexamination and cause of death

22 Treatment Protocol From our archived clinical recordswe established a cohort of 69 patients who received 2ndash6 cycles(median 4 cycles) of the GND regimen every 3 weeks Alldrugs were diluted in normal saline solution and adminis-tered through the subclavian vein The treatment protocolconsisted of gemcitabine (800mgm2 or 1000mgm2) on days1 and 8 navelbine (25mgm2) on days 1 and 8 and doxoru-bicin (20mgm2) on day 1 In addition 17 patients receivedlocal radiotherapy (36Gy) for lymphoma masses after thecompletion of chemotherapy Prophylactic 5-HT3 receptorantagonist (ramosetron and granisetron) and dexamethasonewere administered routinely 30 minutes before every cycleAll patients were required to undergo a routine examinationincluding physical examination standard blood counts liverand kidney function tests urine routine analysis and ECGon day 1 of each cycle If the results showed no markedabnormalities the subsequent cycle of chemotherapy wascontinued Otherwise patients whose WBC counts were lt4times 109L and neutrophil counts were lt15 times 109L receivedrecombinant human granulocyte colony-stimulating factor

(G-CSF) at a dose of 100 120583gd and patients with PLT countslt100times 109L received thrombopoietin (TPO) at the discretionof the treating physician resulting in a treatment delay for 3ndash7days

23 Response Evaluation All patients underwent a reevalu-ation with complete physical examination laboratory testsand previously positive radiographic examinations such ascomputed tomography (CT) magnetic resonance imagingand positron emission tomography-CT imaging after every2 cycles of the GND regimen The tumor response wasclassified as complete remission (CR) unconfirmed completeremission (CRu) partial remission (PR) stable disease (SD)and progressive disease (PD) according to the InternationalWorkshop criteria for NHL [5] The overall response rate(ORR) consists of CR CRu and PR Adverse effects were alsoobserved and graded from degree 1 to degree 4 according totheNational Cancer Institute CommonTerminology Criteriafor Adverse Events v30 Overall survival (OS) was measuredfrom the first day of GND treatment to the date of death dueto any cause or the date of the last follow-up visit (30 June2013)

24 StatisticalMethod TheSPSS software (Statistical Packagefor Social Science for Windows version 170) for Windowswas used for data analysis Statistical significance was definedat 119875 values lt 005 by using a two-sided significance test Thesurvival rate was estimated and the survival curve was drawnsimultaneouslywith theKaplan-MeiermethodComparisonsbetween response rates were performed by using the Chi-squared test (1205942-test) The median OS is shown with 95confidence interval (CI) limits and estimators for 1- 3- and5-year OS were determined concomitantly To compare thepotential association between variables and prognosis thelog-rank test was performed Variables showing 119875 values lt005 in univariate analyses were candidates for multivariateanalysis which was performed by using the Cox proportionalhazard regression model

3 Results

31 Patient Characteristics The clinical characteristics of 69patients that were retrieved from clinical and pathologi-cal reports are summarized in Table 1 First patients werestratified into 2 groups according to the different doses ofgemcitabine whichwere administered at either 800mgm2 ingroup 1 (119899 = 49) or 1000mgm2 in group 2 (119899 = 20)The timeuntil recurrence from the initial diagnosis was calculatedand a cut-off of 12 months [6] was used to distinguish earlyrelapse (48 patients (37 from group 1 11 from group 2)) fromlate relapse (21 patients (12 from group 1 9 from group 2))Among all patients peripheral TCL-unspecified (PTCL-U)is the most common histopathologic subtype (594) fol-lowed by extranodal natural killerT-cell lymphoma (333)anaplastic large cell lymphoma (44) and subcutaneouspanniculitis-like TCL (29) There was a male preponder-ance (4269) in the cohort and the median age was 59 years

BioMed Research International 3

Table 1 Clinical characteristics and prognostic factors for overall survival (OS) of all patients

Characteristics Number of patients () Univariate MultivariateGroup 1 Group 2 Total 119875 value 119875 value HR 95 CI

Total 49 (71) 20 (29) 69 (100)Recurrent time 0021

Early relapse 37 (755) 11 (55) 48 (696)Late relapse 12 (245) 9 (45) 21 (304)

PathologyPTCL-U 28 (571) 13 (65) 41 (594)NKT 18 (367) 5 (25) 23 (333)Subcutaneous panniculitis-like 2 (41) 0 (0) 2 (29)T-cell lymphomaALCL 1 (21) 2 (10) 3 (44)

SexMale 30 (612) 12 (60) 42 (609)Female 19 (388) 8 (40) 27 (391)

Age yearsMedian (range) 50 (10ndash79) 58 (19ndash80) 59 (10ndash80)le60 20 (408) 9 (45) 29 (420)gt60 29 (592) 11 (55) 40 (580)

B-symptoms 0014Present 27 (551) 10 (50) 37 (536)Absent 22 (449) 10 (50) 32 (464)

Marrow involvement 0000 0042 3816 1049ndash13886Present 9 (184) 5 (25) 14 (203)Absent 40 (816) 15 (75) 55 (797)

Splenomegaly 0010Present 29 (592) 11 (55) 40 (580)Absent 20 (408) 9 (45) 29 (420)

ECOG performance status0-1 19 (388) 8 (40) 27 (391)2 26 (531) 11 (55) 37 (536)ge3 4 (81) 1 (5) 5 (73)

Stage 0004I-II 24 (490) 7 (35) 31 (449)III-IV 25 (510) 13 (65) 38 (551)

IPI0-1 (low-risk group) 19 (388) 2 (10) 21 (304)2-3 (intermediate-risk group) 25 (510) 14 (70) 39 (565)4-5 (high-risk group) 5 (102) 4 (20) 9 (131)

Lymphocyte counts 0005 0000 5305 2100ndash13403ge1 times 109L 36 (735) 16 (80) 52 (754)lt1 times 109L 13 (265) 4 (20) 17 (246)1205732-MG 0001gtUpper limit of normal 26 (531) 13 (65) 39 (565)Normal 23 (469) 7 (35) 30 (435)

LDH 0002 0018 2538 1172ndash5493gtUpper limit of normal 31 (633) 15 (75) 46 (667)Normal 18 (367) 5 (25) 23 (333)

Previous therapeutic regimenRadiotherapy 9 (184) 3 (15) 12 (174)Chemotherapy 29 (592) 13 (65) 42 (609)Chemoradiotherapy 11 (224) 4 (20) 15 (217)

PTCL-U peripheral T-cell lymphoma-unspecified NKT extranodal natural killerT-cell lymphoma ALCL anaplastic large cell lymphoma ECOG EasternCooperative Oncology Group LDH lactate dehydrogenase 1205732-MG serum 1205732microglobulin IPI International Prognostic Index HR hazard ratio and 95CI 95 confidence interval B-symptoms include unexplained fever over 38∘C (1004∘F) for 1-2 weeks unintentional weight loss of gt10 of normal bodyweight over a period of 6 months or less and drenching sweats especially at night IPI scores were calculated by summing the number of risk factors (age gt60 years stage IIIIV involved extranodal sites gt 1 ECOG performance status gt 1 and elevated LDH levels)


Table 2 The clinical results for the two groups

Response Number of patients ()Group 1 (119899 = 49) Group 2 (119899 = 20) Total (119899 = 69)

CR 15 (306) 5 (25) 20 (290)PR 17 (347) 8 (40) 25 (362)ORR (CR + PR) 32 (653) 13 (65) 45 (652)SD 8 (163) 3 (15) 11 (159)PD 9 (184) 4 (20) 13 (189)CR complete response PR partial response ORR overall response rate SD stable disease and PD progressive disease

(range 10ndash80 years) A majority of patients experienced B-symptoms and splenomegaly (536 and 580 resp) Atbaseline 31 patients were classified as stages I-II and 38patients were classified as stages III-IV Remarkably mostpatients showed elevated 1205732-MG levels (565) LDH levels(667) and most frequently elevated lymphocyte counts(754) The previous chemotherapy treatments includedCHOP or CHOP-like regimens (COP CHOEP ECHOPandCHOPT)Hyper-CVAD (cyclophosphamide vincristineAdriamycin and dexamethasone) DICE (dexamethasoneifosfamide carboplatin and etoposide) and ICE (ifosfamidecarboplatin and etoposide) with a median of 3 cycles (range2ndash6 cycles)

32 Response to GND Table 2 demonstrates the clinicalresults of the two groups Overall objective responses to theGND regimen were obvious in 45 out of 69 evaluable patientswith 20 patients achieving CR (290) and 25 patientsachieving PR (362) resulting in an ORR of 652 A totalof 11 and 13 patients responded and developed SD (159)or PD (189) respectively In addition among 20 patientswho achieved CR 3 patients proceeded to receive ASCT and5 patients received biotherapy In subgroup analysis the ORRwas similar between patients fromgroup 1 and group 2 (653versus 650 119875 = 0981) although patients from group 1achieved a higher CR rate than patients from group 2 (306versus 250 119875 = 0641) Higher PR rates were observed inpatients from group 2 versus group 1 (347 versus 400119875 = 0677) There were no statistically significant responserate differences between the two different groups (by using1205942-test)

33 Survival Analysis At the cut-off date of the follow-upexamination (30 June 2013) the median follow-up time was35 years for all patients and 4 years for surviving patients(range 05ndash11 years) The median OS was 36 months (range5ndash67months 95CI 25314ndash46686) among all patientsThemedian OS was higher for patients from group 1 compared topatients from group 2 (37 versus 23months resp) Accordingto the Kaplan-Meier analysis the 1- 3- and 5-year estimatedOS rates for the whole cohort were 717 473 and 324respectively (Figure 1) Estimators for 1-year OS rates weresimilar between groups 1 and 2 (722 versus 703 resp)However we observed significant differences for the 3- and5-year OS rates between patients from groups 1 and 2 (531versus 301 and 365 versus 201 resp (Figure 2))

Time from GND treatment (months)

Prob

abili

ty o

f ove

rall

surv

ival

(OS)

Median OS 36 months (n = 69)

0 20 40 60

00

02

04

06

08

10

Figure 1 The Kaplan-Meier estimate of overall survival (OS) for allpatients

As shown in Table 1 univariate analysis identified 8unfavorable prognostic factors for the 69 enrolled patientsincluding the time until recurrence (119875 = 0021) B-symptoms(119875 = 0014) bone marrow involvement (119875 = 0000)splenomegaly (119875 = 0010) disease stage (119875 = 0004)lymphocyte counts (119875 = 0005) 1205732-MG levels (119875 =0001) and LDH levels (119875 = 0002) Moreover multivariateCox model analysis revealed that bone marrow involvement(119875 = 0042 hazard ratio (HR) 3816 95 CI 1049ndash13886)lymphocyte counts (119875 = 0000 HR 5305 95 CI 2100ndash13403) and LDH levels (119875 = 0018 HR 2538 95CI 1172ndash5493) significantly influenced OS

34 Treatment Toxicities The GND regimen was well tol-erated with grade 3 or greater treatment-emergent adverseevents occurring in less than one-third of all respondingpatients Unexpectedly a significant difference in grade 3to 4 toxicities was present between groups 1 and 2 (163versus 40 119875 = 0035 by using 1205942-test) With regard tohematologic toxicities which were more frequent relativelyamong all patients grade 1 to 2 neutropenia or leukopeniawas reported in 35 patients (507) grade 1 to 2 anemiawas noted in 23 patients (333) and grade 1 to 2 throm-bocytopenia was observed in 18 patients (261) Grade 1to 2 hematologic toxicities for group 2 patients were higher


Table 3 Treatment-emergent adverse events for the two groups

Treatment toxicities Number of patients ()Group 1 (119899 = 49) Group 2 (119899 = 20) Total (119899 = 69)

Grades 1-2Neutropenia or leukopenia 22 (449) 13 (65) 35 (507)Anemia 15 (306) 8 (40) 23 (333)Thrombocytopenia 11 (224) 7 (35) 18 (261)Infection 0 1 (5) 1 (14)Nausea or emesis 25 (510) 9 (45) 34 (493)Fatigue 31 (633) 13 (65) 44 (638)Constipation 19 (388) 10 (50) 29 (422)Others 5 (102) 2 (10) 7 (101)

Grades 3-4Hematologic toxicities 8 (163) 7 (35) 15 (217)Nonhematological toxicities 0 1 (5) 1 (14)

Group 1 (n = 49) median OS 37 monthsGroup 2 (n = 20) median OS 23 months

Prob

abili

ty o

f ove

rall

surv

ival

(OS)

Time from GND treatment (months)0 20 40 60

00

02

04

06

08

10

Figure 2 The Kaplan-Meier estimate of overall survival (OS) forgroups 1 and 2

than those for group 1 patients Table 3 displays the specificproportions for the different groups Although 217 ofpatients (group 1 163 group 2 350) developed grade3 to 4 neutropenia or leukopenia no grade 3 to 4 anemiaor thrombocytopenia was observed By using G-CSF andTPO these hematological toxicities were easily manageableand mostly of short duration (le1 week) Only 1 patient fromgroup 2 had a neutropenia-associated pulmonary infectionand recovered after anti-infective therapy Nonhematologicaltoxicities included nausea emesis fatigue fever headachedecreased appetite constipation and temporary dysfunctionof the liver and kidney most of these were mild and reversedspontaneously No patients presented with severe pulmonarytoxicity catarrh rash dyspnea anaphylaxis edema orperipheral nerve toxicity Treatment related deaths did notoccur Other adverse effects included fever headache andtemporary dysfunction of the liver and kidney

4 Discussion

TCL encompasses a heterogeneous group of diseases alto-gether accounting for less than 15 of all NHLs worldwide Itis known for its aggressive biological behavior low responserate to initial treatment accompanied with a high recurrencerate and poor prognosis even for stage I to II diseasePreviously many advances have been made in the treat-ment of TCL Unfortunately initiatives that just mirroredthe therapies used for BCL have not achieved promisingoutcomes in TCL patients especially in cases with relapsedor refractory disease Because of the disappointing responsesand serious toxicities few options remain for therapeuticapproaches incorporating novel agents such as alemtuzumabbortezomib or L-asparaginase containing regimes [7ndash9] Inaddition there is a paucity of data and consensus from phaseIII trials concerning the treatment of pretreated TCL patients

Gemcitabine a novel nucleoside analogue that is acti-vated by deoxycytidine kinase (dCK) has shown promisingresults in solid tumors such as nonsmall cell lung cancer andin pancreatic and ovarian cancers [10ndash12] Notably recentstudies showed that gemcitabine alone andor gemcitabinecontaining chemotherapies were also efficient in the treat-ment of HL and NHL including heavily pretreated lym-phoma [1ndash3 9] In a phase II study of 44 pretreated patientswith mycosis fungoides or cutaneous peripheral PTCL-Uthis agent presented an attractive treatment option with asurprisingly high RR of 705 [13] Furthermore Marchi etal reported RR of 75 with gemcitabine monotherapy ina phase II study of 32 previously untreated cutaneous TCLpatients with 22 of patients achieving CR [14] Bergman etal explored the possible mechanisms in vitro and found thatgemcitabine acts against various human malignant cells witha multidrug resistance (MDR) phenotype by circumventingMDR [15] MDR associated with cross-resistance to somenatural toxin-related compounds is characterized by theoverexpression of drug efflux pumps such as P-glycoproteinand MDR-associated proteins 1ndash3 which may be a result ofincreased dCK activity and reduced deoxycytidine deami-nase activity [16] Therefore MDR cells often presented with


accumulated gemcitabine metabolism and sensitivity Thismechanism was related to the incorporation of gemcitabineinto DNA and RNA which in turn led to DNA damage [15]

According to previous studies the effectiveness of gemc-itabine is demonstrated with satisfactory response rates andacceptable toxicities However there are very limited dataavailable describing the efficacy and safety of gemcitabinecombined with navelbine and specifically about doxorubicinas treatment for patients with refractory or relapsed TCL Inthis report we retrospectively analyzed a cohort of 69 patientswith a range of pretreated TCL histology who had receivedthe gemcitabine-containing regimen GND

The ORR was 652 including 290 of patients whoachievedCR and a significant survival benefit (medianOS 36months) Our observations are encouraging and comparableto other published salvage regimens such as ICE [17] andDHAP [18] Even though those intensive regimens couldachieve an ORR of 60ndash70 [17 18] significant toxicitiesespecially serious complications related tomyelosuppressionaffected patientsrsquo survival In contrast mild bone marrowtoxicity with GND was another significant advantage overother regimens as only 15 patients (217) developed grade3 to 4 neutropenia or leukopeniaThe incidence of grade 3 or4 nonhematological toxicity was low and severe pulmonarytoxicity associated with gemcitabine [19] was not observedIn addition these promising results were observed in acohort of refractory or relapsed patients many of which werecharacterized according to poor prognostic features such asearly relapse [6] stages III-IV disease elevated LDH and 1205732-MG levels and elevated lymphocyte counts [20 21]

The different outcomes may be due to the schedule ordose intensity of our study compared to historical reportsGrade 3 to 4 myelosuppression related toxicity as docu-mented in the Royal Marsden Hospital experience [22] forCALGB 59804 was common (grade 3 to 4 neutropenia 62and 63 separately) [3] In addition it is well established thatnavelbine and doxorubicin which act on different parts ofthe cell cycle play an important role in the management ofmalignant lymphomas especially in the first-line treatmentThus the GND regimen did not contain alkylating agentssuch as ifosfamide and cyclophosphamide which couldincrease the risk of secondary malignancies in patients withNHL [23]

In the further subgroups in which gemcitabine was givenat different doses the OS and treatment-associated adverseevents particularly grade 3 to 4 toxicities (163 versus 40in groups 1 and 2 resp 119875 = 0035) were significantlydifferent despite similar ORRs (653 versus 65 in groups1 and 2 resp 119875 = 0981) The outcome of our study indicatesthat gemcitabine at 800mgm2 on days 1 and 8 schedulerepeated every 21 days was favorable for pretreated TCLpatients

5 Conclusion

In summary our retrospective analysis showed that the GNDtreatment regimenwas effective andwell tolerated by patientswith refractory or relapsed TCL When interpreting the

outcome of our study the limited number of cases shouldbe kept inmindTherefore further prospective investigationsthat involve a larger number of patients will be helpful toconfirm the advantages of the GND regime and elucidate itsclinical significance intensively

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] P L Zinzani F Venturini V Stefoni et al ldquoGemcitabine assingle agent in pretreated T-cell lymphoma patients evaluationof the long-term outcomerdquoAnnals of Oncology vol 21 no 4 pp860ndash863 2009

[2] B Bai H-Q Huang Q-Q Cai et al ldquoPromising long-termoutcome of gemcitabine vinorelbine liposomal doxorubicin(GVD) in 14-day schedule as salvage regimen for patients withpreviously heavily treated Hodgkinrsquos lymphoma and aggressivenon-Hodgkinrsquos lymphomardquo Medical Oncology vol 30 no 1 p350 2013

[3] N L Bartlett D Niedzwiecki J L Johnson et al ldquoGemcitabinevinorelbine and pegylated liposomal doxorubicin (GVD) asalvage regimen in relapsed Hodgkinrsquos lymphoma CALGB59804rdquo Annals of Oncology vol 18 no 6 pp 1071ndash1079 2007

[4] S A Pileri L Leoncini and B Falini ldquoRevised European-American lymphoma classificationrdquo Current Opinion in Oncol-ogy vol 7 no 5 pp 401ndash407 1995

[5] B D Cheson B Pfistner M E Juweid et al ldquoRevised responsecriteria for malignant lymphomardquo Journal of Clinical Oncologyvol 25 no 5 pp 579ndash586 2007

[6] C Guglielmi F Gomez T Philip et al ldquoTime to relapse hasprognostic value in patients with aggressive lymphoma enrolledonto the parma trialrdquo Journal of Clinical Oncology vol 16 no 10pp 3264ndash3269 1998

[7] S J Kim K Kim Y Park et al ldquoDose modification of alem-tuzumab in combination with dexamethasone cytarabine andcisplatin in patients with relapsed or refractory peripheral T-celllymphoma analysis of efficacy and toxicityrdquo Investigational NewDrugs vol 30 no 1 pp 368ndash375 2012

[8] J Lee C Suh H J Kang et al ldquoPhase I study of proteasomeinhibitor bortezomib plus CHOP in patients with advancedaggressive T-cell or NKT-cell lymphomardquo Annals of Oncologyvol 19 no 12 pp 2079ndash2083 2008

[9] H K Ahn S J Kim D W Hwang et al ldquoGemcitabine aloneandor containing chemotherapy is efficient in refractory orrelapsed NKT-cell lymphomardquo Investigational New Drugs vol31 no 2 pp 469ndash472 2013

[10] C Manegold B Bergman A Chemaissani et al ldquoSingle-agent gemeitabine versus cisplatln-etoposlde early results of arandomised phase II study in locally advanced or metastaticnon-small-cell lung cancerrdquo Annals of Oncology vol 8 no 6pp 525ndash529 1997

[11] H A Burris III M J Moore J Andersen et al ldquoImprovementsin survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer arandomized trialrdquo Journal of Clinical Oncology vol 15 no 6pp 2403ndash2413 1997


[12] P G Rose K Mossbruger N Fusco M Smrekar S Eatonand M Rodriguez ldquoGemcitabine reverses cisplatin resistancedemonstration of activity in platinum- and multidrug-resistantovarian and peritoneal carcinomardquo Gynecologic Oncology vol88 no 1 pp 17ndash21 2003

[13] P L Zinzani G Baliva M Magagnoli et al ldquoGemcitabinetreatment in pretreated cutaneous T-cell lymphoma experiencein 44 patientsrdquo Journal of Clinical Oncology vol 18 no 13 pp2603ndash2606 2000

[14] E Marchi L Alinari M Tani et al ldquoGemcitabine as frontlinetreatment for cutaneous T-cell lymphoma phase II study of 32patientsrdquo Cancer vol 104 no 11 pp 2437ndash2441 2005

[15] A M Bergman H M Pinedo I Talianidis et al ldquoIncreasedsensitivity to gemcitabine of P-glycoprotein and multidrugresistance-associated protein-overexpressing human cancer celllinesrdquo British Journal of Cancer vol 88 no 12 pp 1963ndash19702003

[16] A M Bergman B Munch-Petersen P B Jensen et al ldquoCol-lateral sensitivity to gemcitabine (2101584021015840-difluorodeoxycytidine)and cytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell linesrdquoBiochemical Pharmacology vol 61 no 11 pp 1401ndash1408 2001

[17] CHMoskowitz J R Bertino J R Glassman et al ldquoIfosfamidecarboplatin and etoposide a highly effective cytoreductionand peripheral-blood progenitor-cell mobilization regimen fortransplant-eligible patients with non-Hodgkinrsquos lymphomardquoJournal of Clinical Oncology vol 17 no 12 pp 3776ndash3785 1999

[18] W S Velasquez F Cabanillas P Salvador et al ldquoEffectivesalvagae therapy for lymphoma with cisplatin in combinationwith high-dose ara-C and dexamethasone (DHAP)rdquo Blood vol71 no 1 pp 117ndash122 1988

[19] F Barlesi C Doddoli C Gimenez L Greillier G Lima andJ-P Kleisbauer ldquoAcute pulmonary toxicity due to gemcitabinea role for asbestos exposurerdquo Revue des Maladies Respiratoiresvol 20 no 2 part 1 pp 201ndash206 2003

[20] J J Castillo DMorales P Quinones E Cotrina C Desposorioand B Beltran ldquoLymphopenia as a prognostic factor in patientswith peripheral T-cell lymphoma unspecifiedrdquo Leukemia andLymphoma vol 51 no 10 pp 1822ndash1828 2010

[21] M P Escalon N S Liu Y Yang et al ldquoPrognostic factors andtreatment of patients with T-cell non-Hodgkin lymphoma theM D Anderson Cancer Center experiencerdquo Cancer vol 103no 10 pp 2091ndash2098 2005

[22] H-T Arkenau G Chong D Cunningham et al ldquoGemcitabinecisplatin and methylprednisolone for the treatment of patientswith peripheral T-cell lymphoma the Royal Marsden Hospitalexperiencerdquo Haematologica vol 92 no 2 pp 271ndash272 2007

[23] Y Xu H Wang S Zhou et al ldquoRisk of second malignant neo-plasms after cyclophosphamide-based chemotherapy with orwithout radiotherapy for non-Hodgkin lymphomardquo Leukemiaand Lymphoma vol 54 no 7 pp 1396ndash1404 2013

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Given the encouraging outcomes of previous studies weinvestigated the effectiveness safety and toxicity of gem-citabine navelbine and doxorubicin (GND) combinationchemotherapy in patients with refractory or relapsed TCL

2 Patients and Methods

21 Patients The subjects of this retrospective study arepatients with refractory or relapsed TCL who received GNDtreatment between January 2002 and December 2012 inthe Tianjin Medical University Cancer Hospital Patientswere eligible according to the following criteria histologicalwith immunohistochemical diagnosis of TCL from pro-fessional pathologists according to the Revised European-American Lymphoma classification [4] and available patho-logical reports complete blood counts showing white bloodcell (WBC) counts ge4 times 109L platelet (PLT) counts ge100times 109L neutrophil counts ge15 times 109L and hepatic andrenal function tests demonstrating aspartate aminotrans-ferase and alanine transaminase levels le35UL and serumcreatinine le80120583molL at the beginning of the treatment noabnormalities with electrocardiography (ECG) refractory orrelapsed after conventional therapeutic approaches includingchemotherapy andor radiotherapy and accumulated doseof doxorubicin le 350mgm2 during the previous treatmentExclusion criteria included a history of hepatitis B hepatitisC human immunodeficiency virus uncontrolled infectionor significant cardiac dysfunction or central nervous systemlymphoma at the time of GND administration We collectedthe following clinical characteristics of enrolled patientsretrospectively patient demographics time until relapsehistopathologic subtypes Eastern Cooperative OncologyGroup performance status extent of disease involvementAnn Arbor stage International Prognostic Index serum 1205732microglobulin (1205732-MG) levels lactate dehydrogenase (LDH)levels previous treatment regimens deadline of the follow-upexamination and cause of death

22 Treatment Protocol From our archived clinical recordswe established a cohort of 69 patients who received 2ndash6 cycles(median 4 cycles) of the GND regimen every 3 weeks Alldrugs were diluted in normal saline solution and adminis-tered through the subclavian vein The treatment protocolconsisted of gemcitabine (800mgm2 or 1000mgm2) on days1 and 8 navelbine (25mgm2) on days 1 and 8 and doxoru-bicin (20mgm2) on day 1 In addition 17 patients receivedlocal radiotherapy (36Gy) for lymphoma masses after thecompletion of chemotherapy Prophylactic 5-HT3 receptorantagonist (ramosetron and granisetron) and dexamethasonewere administered routinely 30 minutes before every cycleAll patients were required to undergo a routine examinationincluding physical examination standard blood counts liverand kidney function tests urine routine analysis and ECGon day 1 of each cycle If the results showed no markedabnormalities the subsequent cycle of chemotherapy wascontinued Otherwise patients whose WBC counts were lt4times 109L and neutrophil counts were lt15 times 109L receivedrecombinant human granulocyte colony-stimulating factor

(G-CSF) at a dose of 100 120583gd and patients with PLT countslt100times 109L received thrombopoietin (TPO) at the discretionof the treating physician resulting in a treatment delay for 3ndash7days

23 Response Evaluation All patients underwent a reevalu-ation with complete physical examination laboratory testsand previously positive radiographic examinations such ascomputed tomography (CT) magnetic resonance imagingand positron emission tomography-CT imaging after every2 cycles of the GND regimen The tumor response wasclassified as complete remission (CR) unconfirmed completeremission (CRu) partial remission (PR) stable disease (SD)and progressive disease (PD) according to the InternationalWorkshop criteria for NHL [5] The overall response rate(ORR) consists of CR CRu and PR Adverse effects were alsoobserved and graded from degree 1 to degree 4 according totheNational Cancer Institute CommonTerminology Criteriafor Adverse Events v30 Overall survival (OS) was measuredfrom the first day of GND treatment to the date of death dueto any cause or the date of the last follow-up visit (30 June2013)

24 StatisticalMethod TheSPSS software (Statistical Packagefor Social Science for Windows version 170) for Windowswas used for data analysis Statistical significance was definedat 119875 values lt 005 by using a two-sided significance test Thesurvival rate was estimated and the survival curve was drawnsimultaneouslywith theKaplan-MeiermethodComparisonsbetween response rates were performed by using the Chi-squared test (1205942-test) The median OS is shown with 95confidence interval (CI) limits and estimators for 1- 3- and5-year OS were determined concomitantly To compare thepotential association between variables and prognosis thelog-rank test was performed Variables showing 119875 values lt005 in univariate analyses were candidates for multivariateanalysis which was performed by using the Cox proportionalhazard regression model

3 Results

31 Patient Characteristics The clinical characteristics of 69patients that were retrieved from clinical and pathologi-cal reports are summarized in Table 1 First patients werestratified into 2 groups according to the different doses ofgemcitabine whichwere administered at either 800mgm2 ingroup 1 (119899 = 49) or 1000mgm2 in group 2 (119899 = 20)The timeuntil recurrence from the initial diagnosis was calculatedand a cut-off of 12 months [6] was used to distinguish earlyrelapse (48 patients (37 from group 1 11 from group 2)) fromlate relapse (21 patients (12 from group 1 9 from group 2))Among all patients peripheral TCL-unspecified (PTCL-U)is the most common histopathologic subtype (594) fol-lowed by extranodal natural killerT-cell lymphoma (333)anaplastic large cell lymphoma (44) and subcutaneouspanniculitis-like TCL (29) There was a male preponder-ance (4269) in the cohort and the median age was 59 years







SexMale 30 (612) 12 (60) 42 (609)Female 19 (388) 8 (40) 27 (391)






Stage 0004I-II 24 (490) 7 (35) 31 (449)III-IV 25 (510) 13 (65) 38 (551)














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