Pan Arab Journal of Oncology - Arab Medical Association Against ...

Pan Arab Journal of OncologyISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 6; issue 1 | March 2013The wish for healing has always been half of health.Lucius Annaeus SenecaOriginal Articles• Nasopharyngeal Carcinoma: Plasma EBVDNA concentration & FDG PET• Hepatocellular carcinoma & 3DCRT• Prostate Carcinoma: 3DCRT vs. IMRT• Large volume seminoma: an institutionexperience

NewÆvinflunineThe 1 st and only registered chemotherapyafter failure of a platinum-containing regimenin advanced or metastatic TCCUPierre Fabre Oncology Middle East - Riad El Solh - P.O.Box 11 - 2131 Beirut - Lebanon Fax : 00 961 1 98 98 42Full Prescribing information is available upon request

editorial board

amaac Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

international advisory board

ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 3 | September 09ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 3; issue 4 | December 10ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 5; issue 1 | March 2012but don’t wait to catch it from others.Be a carrier.Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 1; issue 2 | June 08ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 3 | December 09ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 4; issue 1 | March 2011ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 5; issue 2 | June 2012Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 1; issue 3 | September 08ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 3; issue 1 | March 10ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 4; issue 2 | June 2011ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 5; issue 2 | September 2012Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 1 | January 09ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 3; issue 2 | June 10ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 4; issue 3 | September 2011ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 5; issue 4 | December 2012Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 2 | April 09ISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 3; issue 3 | October 10Hope begins in the dark, the stubborn hope that if you just showup and try to do the right thing, the dawn will come. You wait andwatch and work: You don’t give up.Anne LamottISSN: 2070-254XOfficial Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 4; issue 4 | December 2011ISSN: 2070-254Xspecial thanks Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

Thank you for all contributors, authors and reviewers of PAJOGerard Abadjian, MDHamdi Abdel Azim, MDWafaa Abdel-Hadi, MDA. Abdelkefi, MDAbdel Rahman M., MDFatma Aboulkasem, MDOmalkhair Abulkhair, MDMohsen Abdel Mohsen, MDArabi Abdessamad, MDNoha Abdou, MDMiguel Aboud, MDPhilippe Aftimos, MDSalim Adib, MDB. Allani, MDBekadja Mohamed Amine, MDElie Attieh, MDFadwa Attiga, MDAhmad Awada, MDAmal Baccar, MDJean-Marc Bachaud, MDThouraya Baroudi, MDAli Bazerbachi, MDAmel Ben Ammar Elgaaied, MDKhaled Ben Rhomdhane, MDAlain Bernard, MDGhislaine Bernard, MDNizar Bitar, MDH. Boussen, MDKarim Chahed, MDGeorges Chahine, MDAnouar Chaieb, MDNicolas Chemali, MDLotfi Cherni, MDLotfi Chouchane, MDElizabeth Cohen, MDMichel Daher, MDGéraldine Dalmasso, MDKamal El-Dein Hamed Mohamed, MDDalia Darwish, MDJean-Pierre Droz, MDTayssir Eyada, MDAhmad El-Ezzawy, MDFadi Farhat, MDNivine Gado, MDMarwan Ghosn, MDHeba Gouda, MDE. Gouider, MDAmin Haddad, MDMohammad El-Hajj, MDKhaled Halahlah, MDBechr Hamrita, MDGregory Hangard, MDColette Hanna, MDMohamed A Hassan, MDHassan A. Hatoum, MDJohan Hoebeke, MDHesham El Hossieny, MDAhmad Husari, MDNoha Ibrahim, MDElias Jabbour, MDSima Jeha, MDMaria Kabbage, MDFadi El Karak, MDJoseph Kattan, MDM. Kefi, MDJamal Khader, MDHussein Khaled, MDSami Khatib, MDAnne Laprie, MDRobert Launois, MDKatell Le Lay, MDChristelle Lemaitre-Guillier, MDRami Mahfouz, MDNazar Makki, MDCarole Massabeau, MDAndre Megarbane, MDBrahimi Mohamed, MDMohsen Mokhtar, MDWalid Moukaddem, MDJonathan Moyal, MDElie Nasr, MDFadi Nasr, MDGhazi Nsouli, MDBen Othman, MDZaher Otrock, MDMartine Piccart, MDShadi Qasem, MDSilvia Al Rabadi, MDKarim Rashid, MDSami Remadi, MDKamel Rouissi, MDRaya Saab, MDEbtessam Saad El Deen, MDLaurence Ehret-Sabatier, MDGamal Saied, MDNagi El-Saghir, MDIbrahim Saikali, MDKhaled El-Saleh, MDZiad Salem, MDLobna Sedky, MDAli Shamseddine, MDAhmad Shehadeh, MDSana Al-Sukhun, MDIyad Sultan, MDAli Taher, MDPaul-Henri Torbey, MDWafa Troudi, MDVirginie Vandenberghe, MDAlain Vergnenegre, MDLaure Vieillevigne, MDBesma Yacoubi-Loueslati, MDMahmoud Yassein, MDRiad Younes, MDwww.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 5

letter to the editor

notes

original article

to presence of positive family history of breast cancer using the log-rank test.Multivariate analysis using Cox proportional hazards models was then used todetermine independent variables affecting DFS. SPSS program (version 17.0)was used for all analyses, and a two sided p-value less than 0.05 was consideredstatistically significant.ResultsBetween 1999 and 2008, 2387 women were identified in our database, with 606cases (25.4%) having positive family history (+veFH). More than half of cases(326 cases) have the disease in their 1 st degree relatives while the rest (260 cases)have history of breast cancer in their 2 nd or 3 rd degree relatives.The median age of the whole cohort was 49 years (19 – 88 years) and it wassimilar in both groups +veFH and –veFH. Although patients younger than 35years at presentation represented 6.6% among the former group compared to10.1% among the latter; yet this difference was reversed in age group 36-40years (14.6% versus 11.2%) resulting in similar percentage if we used age 40 asthe cutoff (21.2% versus 21.3%). [Table 1]Regarding TNM stage at presentation, 10.8% of +veFH patients presentedadvanced stage (T 3or T 4), 55.3% with lymph node involvement and 5% withmetastatic disease compared to 14.8%, 60.4% and 9.4% among the –veFHgroup respectively and this difference was statistically significant for T and M(p=0.034, 0.001) while N showed borderline significance (p=0.053).The percentage of patients presenting with bilateral disease, high grade tumorsor lobular histological subtype was similar among both groups. Regardingimmunohistochemistry, there was also no difference between the groupsregarding both Hormone receptors positivity and Her2 overexpression. Detailedpatients’ clinicopathological characteristics at diagnosis of breast cancer aresummarized in Table 1.At a median follow up period of 35 months, median disease free survival (DFS)for the whole cohort was 63.5 months. Patients with +veFH had median DFSof 66.4 months compared to 63.3 months for –veFH patients which was notstatistically significant (p=0.927). [Figure 1]Using univariate analysis for the data of the whole cohort, +veFH was not afactor affecting DFS; however the following variables were associated withshorter DFS: age less than 35 years, advanced T stage, lymph node involvement,ER negativity and Her2 overexpression. [Table 2]Multivariate analysis confirmed independent effect of Tumor, nodal stageand ER status on DFS while age and Her2 expression did not show statisticalsignificance. [Table 3]DiscussionThis study showed that tumours detected in Egyptian women with a familyhistory of breast cancer were smaller, less likely to be node positive and lesslikely to be metastatic than those with no family history.Although it was reported that women with +veFH of breast cancer not onlyhave higher risk of developing this cancer, but their risk increases at a youngerage.[10,11] This was not shown in our study where the median age was similarbetween both groups.Comparing our study to the large Sweden population-based study which includedmore than 17000 cases with a median follow up period of 36 months, 13% ofpatients had 1 st degree relative with breast and/or ovarian cancers [12] which issimilar to our study (326/2387).In our study, women with +veFH presented with relatively smaller tumours. Thisobservation was also reported by Nomizu et al [2] and Cao et al.[11] A possibleexplanation may be that individuals with +veFH prefer to undergo regularscreening of breasts and present with a small tumour size at initial diagnosis.In the Sweden study, no information about the stage of breast cancer at diagnosiswas indicated, yet the authors supposed that breast cancer arising in women witha genetic predisposition might have a different, presumably more aggressive,biologic behaviour than sporadic cancer with a nongenetic aetiology.[12] Aswe had the baseline clinicopathological characteristics of patients with familyhistory in our database; those with +veFH did not show difference in hormonalor Her2 overexpression status denoting aggressive biological behavior, and thesefindings were also demonstrated in other studies.[11]Our study confirms the results of other population based studies both Europeanand American that the presence of +veFH is not a poor prognostic factor perse with no negative impact on Disease Free survival; [5,13-14] Yet it raisesthe awareness of the individual for rapidly seeking medical advice in case ofaccidental finding of a breast lump as well as self motivation for screeningmammography in spite of the absence of a national screening program incountries like Egypt.In conclusion, due to the lack of genetic counseling in Egypt, family historystill represents an important risk factor because it raises public health awarenesstowards earlier diagnosis. As disease free and overall survival in patients withhereditary cancer does not differ significantly from survival in sporadic patients,this makes every effort done to detect breast cancer at an earlier stage worthwhile.AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OFINTEREST The authors indicated no potential conflicts of interest.References1. Kishk NA. Breast cancer in relation to some reproductive factors. J EgyptPublic Health Assoc. 74: 547-66, 1999.2. Nomizu T, Tsuchiya A, Kanno M, et al. Clinicopathological features ofhereditary breast cancer. Breast Cancer 4: 239-242, 1997.3. Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologiccharacteristics of patients with BRCA-positive and BRCA-negative breastcancer. J Clin Oncol 26: 4282-4288, 2008.4. Hamann U and Sinn HP. Survival and tumor characteristics of Germanhereditary breast cancer patients. Breast Cancer Res Treat 59: 185-192,2000.5. Slattery ML, Berry TD and Kerber RA. Is survival among womendiagnosed with breast cancer influenced by family history of breast cancer?Epidemiology 4: 543-548, 1993.6. Easton DF. Familial risks of Breast cancer. Breast cancer res 4: 179-81,2002.7. Thompson D, Easton D. The genetic epidemiology of breast cancer genes. JMammary Gland Biol Neoplasia 9: 221-36, 2004.8. Nadine Jalkh, Jinane Nassar-Slaba, Eliane Chouery et al. Prevalanceof BRCA1 and BRCA2 mutations in familial breast cancer patients inLebanon. Hereditary Cancer in Clinical Practice 10:7, 2012.9. Dite GS, Jenkins MA, Southey MC, et al. Familial risks, early-onset breastcancer, and BRCA1 and BRCA2 germline mutations. J Natl Cancer Inst95: 448-57, 2003.10. Claus EB, Risch N, Thompson WD. Genetic analysis of breast cancer inthe cancer and steroid hormone study. Am J Hum Genet 48, 232-242, 1991.www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 9

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

notes

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013rectum in the PTV and thus conforms the dose to the target volume and achievesa higher level of rectum sparing. This increases the scope for dose escalation.However this is commonly associated with areas of under-dosage in the targetvolume 2The accurate outlining of the target volumes, margins, rectum and bladder iscrucial in prostate IMRT. Reduction in the margin without immobilisation of thepatient may lead to under-dosing of the target volume 3 .Prostate motion could cause more than 5mm shift in the anterior direction.This can affect the target coverage and expose a greater volume of rectum tohigh doses resulting in high incidence of rectal bleeding. Problems relating tounacceptable dose to the rectum limit escalation of the prostate dose more thanproblems affecting the bladder 4- 6The probability of tumour control and normal tissue complications afterradiation therapy are dose dependent. The tolerance dose of critical structuresis also dependent on the volume of irradiated normal tissues within the PTV. 5,7,8MethodsCT studies of ten randomly selected patients with low risk prostate cancer fromfuture hand oncology centre (age ranges 51-78, mean 69 years) planned andcalculated with 15 MV photon beam on CMS treatment planning system (Xio,Germany) using the data for the 15MV photon beam of Primus linear accelerator(Siemens, Germany). The CT scan slices were spaced 5mm from the sacroiliacjoint to the lesser trochanter. All patients scanned in a supine position with acomfortably full bladder.Various volumes of interest were defined: CTV (prostate and seminal vesicle),PTV2 (prostate+1.0cm margin) and PTV1 (CTV+1.0cm margin) were outlined.Organs at risk (OAR) including rectum, bladder and femoral heads were outlined.Bladder and rectum were defined by contouring the whole organ including thecontents.www.amaac.org

The average of the volume of bladder, rectum, PTV1 & PTV2 was calculated(range, 77cc-294cc, mean, 160cc), (range, 21cc-123cc, mean, 63cc), (range,66cc-655.5cc, mean, 237cc) and (range, 48cc-414cc, mean, 147cc) respectively.femoral head DVPs, and body max dose were also compared using WilcoxonSigned-Ranks test of SPSS (version 18). A P value of less than 0.05 was takenas statistically significant.3DCRT and inverse planned IMRT plans were planned. 3DCRT carried out in2 phases. In phase 1 & Phase 2, 5 fields at gantry angle 0 0 , 57 0 , 90 0 , 270 0 &296 0 were used to irradiate PTV1 & PTV2 respectively. In phase 1, the beamswere adjusted to conform to PTV1 using MLCs and in phase 2, the MLCs weremodified to conform the beams to PTV2 and to shield the rectum.Results3DCRT and inverse planned IMRT plans produced for 78Gy were compared forten patients (Tables 1-3).A total dose of 78Gy was prescribed to the isocentre following the ICRUdefinition for normalisation point 9 . In the first phase of 3DCRT treatment, adose of 54Gy was delivered to PTV1. In the second phase of the treatment anadditional dose of 24Gy was delivered to PTV2.Inverse planned IMRT was carried out using step-and-shoot technique with 7non-opposing fields at gantry angle 0 o, 50 o, 108 0 , 153 o , 204 0 , 255 0 & 305 o with 10intensity levels and 50-87 segments.The tolerance doses for rectum and bladder were; for the rectum the aim was tokeep the dose to 66%, 50%, 25% and 10% of the volume (D 66%, D 50%, D 25%andD 10%) to be less than 45Gy, 55Gy, 65Gy and 70Gy respectively. Regarding thedose to the bladder, the aim was to keep the dose to 50%, 33% and 20% of thebladder volume (D 50%, D 33%, and D 20%) to be less than 60Gy, 60-65Gy and 65Gyrespectively 10,11 . The treatment also aimed to keep the rectal volume receiving50Gy & 70Gy (V 50Gy& V 70Gy) below 60-65% and 25-30% respectively 12 . Forboth plans, the rectum volume receiving 25Gy, 55Gy, 60Gy, 65Gy, 75Gy and80Gy (V 25Gy, V 55GyV 60GyV 65Gy,V 75Gyand V 80Gy) and bladder volume receiving50Gy, 60Gy, 65Gy & 70Gy, 75Gy and 80Gy (V 50Gy, V 60GyV 65GyV 70Gy,V 75GyandV 80Gy) were compared. The tolerance of femoral head was taken to be less than45Gy maximum point dose.To optimize the IMRT plan, the dose constraint was 78Gy for PTV2 and 54Gyfor PTV1. For rectum; the dose of 60Gy & 35Gy was specified to 17% & 35% ofthe rectum volume and no volume should receive more than 66Gy. For bladder,the dose of 45Gy & 34Gy was specified to 25% & 50% of its volume and novolume should receive more than 60Gy. For femoral heads, 30Gy was specifiedto 9% of the volume and no volume should receive more than 35Gy.Both plans were compared for PTV1 & PTV2 dose coverage & homogeneity,sparing of rectum, bladder and femoral heads and the maximum body dose. Toassess the differences in PTV1 & PTV2 dose coverage, dose distribution andDVPs (the minimum dose, dose to 95% of the volume (D 95%) and the maximumpoint dose of the PTV1 & PTV2) were used. Dose homogeneity within PTV1 &PTV2 was calculated as max dose /min dose. To evaluate the differences in thesparing of the rectum, bladder and femoral heads between the two techniques,their DVPs were used.Table 1 gives the statistical analysis for PTV2 & PTV1 DVPs comparing3DCRT and IMRT plans. It shows that the PTV1 coverage (PTV1 D 95%) wasnot significantly different in both plans (p=0.678) with the maximum dosesignificantly higher with CR plans (p=0.007). On the other hand, the PTV2coverage (PTV2 D 95%) and the PTV2 maximum doses were significantly higherwith IMRT plans (p=0.028 & 0.005). It also shows that the average minimumdose of PTV1 & PTV2 for both plans was comparable (p=0.386 &0.386).The dose homogeneity within PTV1 was comparable in both plans (average,1.45 for CR compared to 1.58 for IMRT, p=0.093) while within PTV2, it wassignificantly better for CR (average 1.07 compared to 1.14 for IMRT plans,p=0.005).Table 2 & 3 gives the statistical analysis for rectum, bladder and femoral headsDVPs comparing 3DCRT and IMRT plans (figure 1). Table 2 shows that there isa significant reduction of the most of rectum DVPs with IMRT plans (Howeverthis reduction was not significantly different in both plans for D 66%, D 50%, D 10%,V 25Gy&V 50Gy). This reduction increased in the range of 50Gy to 75Gy. So IMRTachieves better rectum sparing.Table 2 shows that there is a significant reduction (31% & 33% ) of the averageof the maximum point dose of right and left femoral heads, with IMRT planscompared with 3DCRT (P=0.005)Table 3 also shows that there is a reduction of bladder DVPs with IMRTplans except for BD 50%, which was higher with IMRT and BV 50Gywhich wascomparable in both plans. This reduction increased in the range of 50Gy-80Gyand IMRT achieves better sparing of the bladder. However this reduction was notsignificantly different for both plans.Body maximum dose, IMRT plans shows a significant reduction (11%) comparedto 3DCRT (average 70 Gy compared to 79 Gy for 3DCRT) (p=0.005).This study had approval of Institutional Review Board as a retrospective one inwhich confidentially of records was considered.Statistical analysisThe DVPs for both plans were statistically analysed for any significant differencein dose coverage and homogeneity within PTV1 & PTV2. Rectum, bladder andAwww.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 13

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

notes

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013The treatment of metastatic colorectal cancer (mCRC) has changed dramaticallyfrom the 1980s, when only fluorouracil (5-FU) was available for treatment andthe median survival was at best 12 months, to a time when mCRC is consideredmore of a chronic disease in which the median survival is now reported in excessof 2 years [1].Newer approaches to CRC therapy have focused on targeting cellular signaling,including the epidermal growth factor and vascular endothelial growth factor(VEGF) pathways. Establishing a blood supply (angiogenesis) is critical totumor growth and progression, as evidenced by local increases in vasculardensity that precede the rapid growth of transplanted tumors [2]. There areseveral VEGF family members that have differential effects on angiogenesis[3]. Bevacizumab, a humanized variant of an anti-VEGF monoclonal antibody[4], has been approved by the U.S. Food and Drug Administration (FDA) as anantiangiogenic cancer therapy in the treatment of colorectal, lung, and breastcancers [5,6].In addition to its direct antiangiogenic effects, bevacizumab may also improvethe delivery of chemotherapy by altering tumor vasculature and decreasing theelevated interstitial pressure in tumors [7,8].Irinotecan (CPT-11) received US Food and Drug Administration (FDA)approval in 2002. Irinotecan inhibits the topoisomerase 1 enzyme. Normally,topoisomerase 1 catalyzes DNA breakage, repair, and rejoining of DNA strands,all necessary for DNA replication. Irinotecan-induced inhibition stabilizes thesebreaks, leaving fragmented DNA and resulting in cell death [9].The combined analysis of the data from two prospective phase III randomized,controlled, multicenter, multinational clinical trials in patients with previouslyuntreated metastatic colorectal cancer served as the basis for U.S. and Europeanapproval of irinotecan/ 5-FU/LV for this indication, showed median survivalsof 15.9 months versus 13.3 months, higher response rates, 36%-42% lower riskof tumor progression and a 20%-23% lower risk of death with the irinotecancombination than with 5-FU/LV alone [10].www.amaac.org

In patients with mCRC, the addition of bevacizumab to chemotherapy has beenshown to improve survival [11]. In phases 1 and 2 trials of the treatment ofcolorectal cancer, the addition of bevacizumab to commonly used chemotherapyregimens increased the response rate, the median time to disease progression,the median duration of survival and was generally well tolerated and didnot demonstrate dose-limiting toxicity or interactions with commonly usedchemotherapy regimens [12-14].In a large, phase III, randomized, doubleblind, placebo-controlled clinical trialconducted by Hurwitz et al, on patients with previously untreated mCRC, theaddition of bevacizumab to irinotecan/fluourouracil/leucovorin increasedsurvival from 15.6 months to 20.3 months, (HR = 0.66; P < .001). The 1-yearsurvival rates were 63.4% and 74.3%, in favor of the bevacizumab arm.Similarly, PFS, response rate, and duration of response were all improved [15].Bevacizumab was also shown to produce similar benefits in OS, PFS, and RRwhen combined with fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) inthe second-line setting [16].The goal of this trial was to investigate the safety and efficacy of bevacizumabas a novel antiangiogenic therapy when added to first-line irinotecan-basedchemotherapy FOLFIRI in patients with mCRC. The primary end points wereprogression free survival and tumor response rate. Secondary end points wereoverall survival, duration of response and safety.Patients and MethodsPatient CharacteristicsPatients age ≥18 and < 70 years with histologically confirmed mCRC, withbidimensionally measurable disease, an Eastern Cooperative Oncology Group(ECOG) performance status of 0-2 and a life expectancy of more than threemonths. Adequate hematologic, hepatic, and renal function (including urinaryexcretion of no more than 500 mg of protein per day) was also required.Exclusion criteriaIncluded prior chemotherapy or biologic therapy for metastatic disease (adjuvantor radiosensitizing use of fluoropyrimidines with or without leucovorin morethan 12 months before study entry was permitted), radiotherapy or surgery formCRC was permitted if completed ≥4 weeks before study treatment, clinicallysignificant cardiovascular disease, clinically detectable ascites, pregnancy orlactation, use of full-dose anticoagulants or thrombolytics; serious nonhealingwound, ulcer, or bone fracture; clinically significant bleeding diathesis orcoagulopathy; proteinuria >500 mg/24 hours and known CNS metastases.Treatment PlanThe 24 eligible patients were treated with the combination of FOLFIRI (irinotecan 200 mg/m 2 on Day 1 + 5-fluorouracil (5-FU) 400 mg/m 2 + folinicacid 400 mg/m 2 on day 1 followed by 5-FU 2400 mg/m 2 via 46-h infusion) +bevacizumab 5 mg/kg on day 1, every 2 weeks. Treatment with the same dosesof bevacizumab and FOLFIRI was repeated every 2 weeks until the occurrenceof grade 3 or 4 toxicity or tumor progression.Patient evaluationsBaseline evaluations included a medical history, physical examinations,vital signs, performance status determination, complete blood count withdifferential and platelet counts, blood coagulation variables, serum chemistryprofile and urine protein analysis tests. All the patients had a contrast-enhancedpelviabdominal and chest CT scans, magnetic resonance imaging (MRI) of thebrain to exclude brain metastasis, before starting the treatment. After the baselineevaluation, tumor status was assessed every 6 weeks for the first 24 weeks ofthe study and then every 12 weeks for the remainder of therapy. All completeand partial responses required confirmation at least four weeks after they werefirst noted.Toxicities were evaluated during each cycle and graded according to the NationalCancer Institute Common Toxicity Criteria (NCI-CTC) [17], version 3.0.Treatment Response EvaluationRadiographic response was measured by comparing each patient’s baseline CTscans imaging performed before the initiation of therapy and serial CT scansimaging performed every 6 weeks after starting therapy. Imaging responsecriteria were defined as follows: partial response (PR) was determined if thecontrasted images showed a greater than 50% decrease in the area of enhancementprovided that the patient was stable or improved clinically. Complete response(CR), was determined by the resolution of all measurable abnormalities on thecontrast images for any patient who also was stable and improved clinically.Progressive disease (PD), an increase in the degree of enhancement by at least25%, appearance of a new lesion, or deterioration in the patient’s clinical statusthat was thought to be related to tumor progression. The patient was deemed tobe stable if the criteria for a partial or complete response or tumor progressionwere not met.Survival analysisThe collected data was revised, coded, tabulated and introduced to a PC usingStatistical package for Social Science (SPSS 15.0.1 for windows; SPSS Inc,Chicago, IL, 2001). Data was presented and suitable analysis was done accordingto the type of data obtained for each parameter.-Kaplan-Meier Survival Analysis [18]: a descriptive procedure for examiningthe distribution of time-to-event variables. Overall Survival was measured fromthe date of entry into the study until death from any cause or last follow-up.Progression free survival was measured from the date of entry into the studyuntil date of first evidence of disease progression.-Log rank test examine the equality of survival times across groups. P value:level of significant; P>0.05: Non significant (NS), P< 0.05: Significant (S),P

original article

In a phase III study conducted by Hurwitz et al, on 813 patients with previouslyuntreated metastatic colorectal cancer, they randomly assigned 402 to receiveirinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg/kg,every two weeks) and 411 to receive IFL plus placebo. A higher and impressivesurvival benefit was seen. This combination increased median survival from15.6 months to 20.3 months, corresponding to a 34% reduction in the hazard ofdeath (P=0.0001). Similar increases occurred in progression-free survival (6.2v 10.6 months; hazard ratio, 0.54; P=0.0001), response rate (34.8% v 44.8%;P=0.0036), and duration of response (7.1 v 10.4 months; hazard ratio, 0.62;P =0.0014). The 1-year survival rates were 63.4% and 74.3%, in favor of thebevacizumab arm [1].Fig 4: Comparative OS between responders and non responders amongstudy patients.Treatment toxicityThe twenty four patients received 4-10 doses of treatment (median 8). Overalltoxicity was acceptable, none of the patients discontinued treatment or had dosereduction because of side effects or poor compliance. There were no grade3/4 hematologic toxicities. Importantly, we did not observe any thromboticcomplications, bowel perforation or severe bleeding other than epistaxis in1 (4.17%) patient. Two cases (8.33%) of transient grade 3 non-hematologictoxicities (severe fatigue) were reported. Three patients (12.5%) developedhypertension and they were ultimately controlled with antihypertensivemedication, and no patient required removal from study or dose reduction forthis toxicity. Treatment-Related toxicities are summarized in Table (3).Table 3: Treatment-Related toxicities among study patients population.Adverse Effect Grade 1 Grade 2 Grade 3 Grade 4Anemia 2Neutropenia 3Thrompocytopenia - 3 - -Epistaxis - - 1 -Hypertension - 3 -Fatigue 2 2Diarrhea 2 3 - -Nausea/Vomiting 3 2 - -DiscussionIn April 2004, following US Food and Drug Administration approval ofbevacizumab (Bev), the BICC-C a phase III trial was amended to compareFOLFIRI with bevacizumab (FOLFIRI_Bev) with mIFL with bevacizumab(mIFL_Bev), 117 patients were randomly assigned to either FOLFIRI_bevacizumab (Bev; n=57) or mIFL_Bev (n=60). With a median follow-up of34.4 months, overall survival was significantly greater for patients who receivedFOLFIRI_Bev (median 28.0 months) when compared with mIFL_Bev (median,19.2 months; P =0.037; HR for death _ 1.79; 95% CI, 1.12 to 2.88). Theproportion of patients alive at 1-year was 87% for the FOLFIRI_Bev treatedgroup and 61% for mIFL_Bev. They demonstrated that FOLFIRI_Bev conferreda significant survival benefit when compared with mIFL_bevacizumab [22].Consistent with the previous higher results, two prospective observationalcohorts of patients in whom populations were treated with chemotherapy atthe physician’s discretion (irinotecan-, oxaliplatin-, 5-FU–, or capecitabinebased)in combination with bevacizumab, in order to monitor the safety profileof bevacizumab. Each study registered over 1,900 patients starting in 2004,with multinational (First BEAT [Bevacizumab Expanded Access Trial]) andUS-based (BriTE [Bevacizumab Regimens: Investigation of Treatment Effectsand Safety]) populations [23,24]. The First BEAT investigators reported anOS of 22.7 months and PFS of 10.8 months [23] whereas the BRiTE studydemonstrated an OS of 27.1 months and PFS of 10.1 months [25].At the same time, three small studies of bevacizumab plus 5-FU/LV were allnegative but with trends showing improvements in PFS and OS. Median OSincreased from 14.6 to 17.9 months (P=0.0081), while PFS increased from5.6 to 8.8 months (P=0.0001) [26]. This was a particularly important study toassess any potential benefit of bevacizumab for patients who are not suitablefor irinotecan or oxaliplatin treatment, demonstrating a role for bevacizumabwithout adding significant toxicity.In the past 20 years, great advances have been made in the treatment of advancedcolorectal cancer, increasing survival from 6 months to over 2 years. However,among patients diagnosed with mCRC, the 5-year survival rate is, on average,only 8% [19].The results of several trials add to a growing body of data demonstrating thatbevacizumab, a humanized monoclonal antibody against VEGF, providesimportant clinical benefit when added to first-line chemotherapy for the treatmentof mCRC. When compared with FU/LV alone, the addition of bevacizumabprolonged median survival by 3.7-4.7 months, progression-free survival by 3.7months, and response duration by 2.4 months, and increased the response rateby 11% [20, 21] .In the current study, it was found that the addition of bevacizumab in a dose of5 mg/kg to first-line chemotherapy FOLFIRI resulted in an objective responserate (CR+PR) of 37.5% as 2 patients (8.33%) out of the 24 patients achievedcomplete response while 7 patients (29.17%) achieved a partial response andresulted in a median PFS and OS of 7 months and 20 months, respectively,with a median duration of response of 8.2 months. The responding patients hadan improved OS and PFS compared with the non responding patients (P=0.01).We reported a slightly inferior survival outcome and objective response rate thanthat reported in BICC-C trial, Hurwitz et al. study, First BEAT and BRiTE study,and this was attributed to factors that resulted in this inferior outcome such asinclusion of more than half of our study population with 2-3 metastatic sites,www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 21

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

21. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trialof fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations inpatients with previously untreated metastatic colorectal cancer. J Clin Oncol2004;22:23-30.22. Salama JK, Mell LK, Schomas DA, et al: Concurrent chemotherapy andintensity-modulated radiation therapy for anal canal cancer patients: Amulticenter experience. J Clin Oncol 25:4581-4586, 2007.23. Berry SR, Van Cutsem E, Kretzschmar A, et al: Final efficacy results forbevacizumab plus standard first-line chemotherapies in patients withmetastatic colorectal cancer: First BEAT (abstract 4025). J Clin Oncol26(15S):184s, 2008.24. Hedrick E, Kozloff M, Hainsworth J, et al: Safety of bevacizumab pluschemo-therapy as first-line treatment of patients with metastatic colorectalcancer: updated results from a large observational registry in the US(BRiTE) (abstract 3536). J Clin Oncol24(18S):155s,2006.25. Kozloff M, Hainsworth J, Badarinath S, et al: Survival of patientswith metastatic CRC treated with bevacizumab in combination withchemotherapy: results from the BRiTE registry (abstract 375). Presentedat the 2007 Gastrointestinal Cancers Symp-osium; Orlando, Fla; January19-21, 2007.26. Kabbinavar FF, Hambleton J, Mass RD, et al: Combined analysis of efficacy:The addition of bevacizumab to fluorouracil/leucovorin improves survivalfor patients with metastatic colorectal cancer. J Clin Oncol 23:3706-3712,2005.27. Fuchs CS, Marshall J, Mitchell E, et al: Randomized, controlled trial ofirinotecan plus infusional, bolus, or oral fluoropyrimidines in first-linetreatment of metastatic colorectal cancer: results from the BICC-C study. JClin Oncol 25:4779-4786, 2007.28. Purdie DM, Berlin JD, Flynn PJ, et al: The safety of long-term bevacizumabuse: Results from the BRiTE observational cohort study (OCS) (abstract4103). J Clin Oncol 26(15S):203s, 2008.www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 23

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

MethodsFrom January 2010 till April 2012 thirty patients with locally advanced nonmetastatic HCC unfit for trans arterial chemoembolization (TACE), werereferred to the Alexandria Clinical Oncology Department for 3DCRT to thehepatic mass and portal vein thrombus (if present). CT simulation was performedin supine position with 2-3mm slice thickness. Then the CT data were transferredto treatment planning system (Precise Elekta) where required structures werecontoured. They include GTV (high CT value area in early phase contrastenhancedCT image), CTV (1cm margin around the GTV) & PTV (0.5cm &1.5cm margin to the CTV in axial and craniocaudal axes) respectively.Whole liver, healthy liver (total liver volume minus PTV), kidneys and spinalcord were also contoured. The volume & length of PTV, volume of whole andhealthy liver and the ratio of the volume of PTV to whole liver volume werecalculated.All CT scans were planned with 6MV photon beam in 10 patients and 15 MVin 20 patients. This is according to the depth of the tumor from the surface 3 .For each patient, optimum plan was carried out using different number (2-5)and directions of photon fields to encompass the PTV and to well spare nearbyOARs. MLCs were used for all cases to shape the beam and to spare OARs aspossible.For all plans, isodose distributions and DVHs were generated. The optimumplan was evaluated by PTV dose coverage (minimum and maximum dose),conformity and inhomogeneity within PTV and sparing of OARs. OARs sparingwas assessed using the mean dose for whole liver (28-30Gy), healthy liver (23-26 Gy) and kidneys (20-23Gy for one kidney) and the maximum point dose ofspinal cord (≤ 45 Gy). 3,8 .This study had approval of Institutional Review Board as a retrospective one inwhich confidentially of records was considered.Statistical analysisFor all plans, data were recorded, compared and analyzed statistically usingexcel sheet 2003 & linear regression models by SPSS software, version 18.Performance statusSite012right lobeleft lobeNumber (%)518 (60)716 (53)14Portal vein thrombosis 20 (66.6)Alpha fetoprotein level elevationabove normalSize of the mass< 5 cm5-10 cm> 10 cm28 (93)5817 (56.6)Hepatitis C positivity 18 (60)Hepatitis B Positivity 5 (16.6)Okuda stage 16IIIIII718 (60)5The number of beams that achieved the optimum plan was two, three, fourand five beams in 1, 17, 6 & 6 patients respectively. The most common beamarrangements were three fields (right anterior oblique, right posterior oblique andright lateral) for right lobe tumors and four to five fields (right anterior oblique,right posterior oblique/ posterior, right lateral and left anterior oblique) for leftlobe tumors. In 4 cases the tumor was present in build up so a bolus of 1-1.5 cmwas used to improve target coverage. Different doses were prescribed; 50Gyin 12 patients, then as far as the dose to OARs did not exceed the tolerance thedose was escalated to 54Gy in 3 patients and to 60Gy in 14 patients. In one casethe dose reduced to 45 Gy to avoid exceeding the tolerance dose of spinal cord.Dose distributionResultsClinico-pathologic data of 30 HCC patients are shown in table 1.AgeSexmeanrangemalefemaleTable 1: Clinico-pathologic dataNumber (%)57.1 years40-75 years26 (86.6)4For all patients, the optimum plan was achieved; the average of min dose was95%, the average of dose gradient within PTV was 13% and also, the 95% dosewash matched well the PTV shape (figure 1 (a & b) and figure 2).Regarding the dose to OARs, all DVPs were within their tolerance. The averageof mean dose to right, left kidney, whole and healthy liver was 29%, 4%, 58%and 48% respectively while the average of spinal cord max. point dose was 32%.The average of body max dose was 109%. Table2 shows the numeric findingsfrom the DVH analysis of the PTVs and OARs.www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 25

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013Table 4: Summary of significant negative correlations between differentanatomic factors and number of beams. R, R 2 and P values are shown.No of beamsRR 2P valuePTVVolume-0.6370.38

Table 5 and figure 3 summarize the significant correlation between differentanatomic factors and number of beams with each DVP. It also shows theproportion of variation in each DVP due to the variation in each anatomic factoror number of beam (R 2 ). For example; the variation in the volume of PTVaccounted for 59% of the variation in body max dose.Table 5: The correlation between different anatomic factors and number ofbeams with each DVP. R, R 2 and P values are shown.DVPsPTV Max doseRR 2P valueDose gradientRR 2P valueRt kidney mean doseRR 2P valueLt kidney mean doseRR 2P valueWhole liver mean doseRR 2P valueHealthy liver mean doseRR 2P valueSC. max doseRR 2P valueBody max doseRR 2P valuePTVVolume0.6540.42

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013No ofbeamsPTVVolumePTV Length PTV Length positionHealthyliverVolume0.82,

This work presents a detailed study for the effect of patient anatomy on the dosedistributions for 3DCRT plans in cases with HCC. With the knowledge of thefavourable and unfavourable anatomic parameters for each DVP, it is possible topredict the results regarding the target coverage and OAR dose distribution. Thiswork will also help to determine the optimum number and direction of beamsfor different tumour site and size. It shows us whether it will be of benefit to usemultiple beams or not for specific patient geometries.ConclusionAs for IMRT, the dose distribution of 3DCRT plan is strongly dependent notonly on the geometrical relationship between target and critical organs but alsoon number of beams used. The size of the effect varies with all factors together.References1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379:1245-55.2. Ik Jae Lee and Jinsil Seong. The Optimal Selection of RadiotherapyTreatment for Hepatocellular Carcinoma. Gut and Liver 2012 ; (2): 139-483. Yu-Cheng Kuo, Ying-Ming Chiu, Wen-Pin Shih, Hsiao-Wei Yu, Chia-WenChen, Pei-Fong Wong, Wei-Chan Lin, and Jeng-Jong Hwang. Volumetricintensity-modulated Arc (RapidArc) therapy for primary hepatocellularcarcinoma: comparison with intensity-modulated radiotherapy and 3-Dconformal radiotherapy. Radiat Oncol. 2011; 6: 76.4. R. CABRERA & D. R. NELSON Review article: the management ofhepatocellular carcinoma. Aliment Pharmacol Ther 2010; 31:461–76.5. Judith Meza-Junco a, Aldo J. Montano-Loza b, David M. Liu c,d, MichaelB. Sawyer a, Vincent G. Bain b, Locoregional radiological treatment forhepatocellular carcinoma; Which, when and how? / Cancer TreatmentReviews 2012; 38 : 54–626. Carlo Greco, Gianpiero Catalano, Alfio Di Grazia, and Roberto Orecchia.Radiotherapy of Liver Malignancies. From Whole Liver Irradiation toStereotactic Hypofractionated Radiotherapy. Tumori 2004; 90: 73-9.7. Dawson LA, Normolle D, Balter JM, McGinn CJ, Lawrence TS, Ten HakenRK. Analysis of radiation-induced liver disease using the Lyman NTCPmodel. Int J Radiat Oncol Biol Phys 2002; 53:810–21.8. Li Zhang, Mian Xi, Xiao-Wu Deng, Qiao-Qiao Li, Xiao-Yan Huang andMeng-Zhong Liu. Four-dimensional CT-based evaluation of volumetricmodulated arc therapy for abdominal lymph node metastasis fromhepatocellular carcinoma. Journal of Radiation Research 2012; 01: 1–89. ICRU report 62. Prescribing, recording, and reporting photon beam therapy.(Suppl. to ICRU report 50): Bethesda, MD: The International Commissionon Radiation Units and Measurements, Nov. 1999.10. Wong JW, Sharpe MB, Jaffray DA, Kini VR, Robertson JM, Stromberg JS,Martinez AA: The use of active breathing control (ABC) to reduce marginfor breathing motion. Int J Radiat Oncol Biol Phys1999; 44: 911-19.11. Dawson LA, Brock KK, Kazanjian S, Fitch D, McGinn CJ, Lawrence TS,Ten Haken RK, Balter J: The reproducibility of organ position using activebreathing control (ABC) during liver radiotherapy. Int J Radiat Oncol BiolPhys 2001; 51:1410-21.12. Helal, A.M., Przeslak, A.J., Sundar, S., & Perkins, A.C. (2006). The effectof target volume / OAR geometry on the dose distribution within rectumand bladder for IMRT treatment of prostate cancer. (Poster) in NCRI cancerconference; 8 th –11 th October 2006; Birmingham. UK.13. Helal A.M, Przeslak, A.J., Morgan, DAL & Perkins, A.C. (2007). Theeffect of patient geometry on the dose distributions for IMRT plans of headand neck cancer. (Poster) in 4 th Radiation Oncology Conference; 19 th –21 stMarch 2007; Edinburgh, UK.14. Helal, A.M., Przeslak, A.J., Sundar, S., & Perkins, A.C. (2007). Patientgeometry and applicability of class solution for optimised IntensityModulated Radiotherapy dose distributions for prostate cancer. (Poster) inprostate cancer symposium; 22 nd –24 th February; Florida, USA15. Helal A M. (2007). The Effect of Patient Anatomy on Optimized IntensityModulated Radiotherapy Dose Distributions for Head and Neck and ProstateCancer. PHD Thesis. Nottingham University.UK16. A Grieco, M Pompili, G Caminiti, L Miele, M Covino, B Alfei, G LRapaccini and G. Gasbarrini. Prognostic factors for survival in patientswith early-intermediate hepatocellular carcinoma undergoing non-surgicaltherapy: comparison of Okuda, CLIP, and BCLC staging systems in a singleItalian centre. Gut 2005;54:411-1817. Petra, A. Intensity modulated radiotherapy treatment planning with OMP/TMS for head and neck carcinomas in the ARTSCAN study. Master ofScience thesis 2004. Lund University.UK18. Kessler, M.L, Mcshan, D.A., Epelman, M.A., Vineberg, K.A., Eisbruch,A., Lawrence, T.S & Fraass, B.A. Costlets: A generalised approach to costfunction for automated optimization of IMRT treatment plans. Optimisationand engineering 2005; 6: 421-48.19. Beavis, A. W. Is tomotherapy the future of IMRT? Br J Radiol 2004; 77:285 95.20. ZHANG Li, XI Mian, SUN Wen-zhao, LIANG Jian, HUANG Xiao-yan,LIU Meng-zhong. Dosimetric Comparison of 3DCRT, Static IMRT, andVMAT for Hepatocellular Carcinoma. Journal of sun yat Sen University2012; 33 (3): 402-621. Asselen, B.V., Dehnad, H., Raaijmakers, C.P., Roesink, J.M., Lagendijk, J.J.,Terhaard, C.H. The dose to the parotid glands with IMRT for oropharyngealtumours: The effect of reduction of positioning margins. Radiother Oncol2002; 64:197–204.22. Hsiung, C.Y., Yorke, E.D., Chui, C.S., Hunt, M.A., Ling, C.C., Huang,E.Y., Wang, C.J., Chen, H.C., Yeh, S.A., Hsu, H.C. & Amols, H.I. Intensitymodulated radiotherapy versus conventional three dimensional conformalradiotherapy for boost or salvage treatment of nasopharyngeal carcinoma.Int J Radiat Oncol Biol Phys 2002; 53: 638-47.23. Hsiung, C.Y., Hunt, M.A., Yorke, E.D., Chui, C.S., Hu, J., Xiong, J.P.,Ling, C.C., Lo, S.K., Wang, C.J., Huang, E.Y. & Amolsm, H.I. Intensitymodulatedradiotherapy as the boost or salvage treatment of nasopharyngealcarcinoma: The appropriate parameters in the inverse planning and theeffects of patient’s anatomic factors on the planning results. RadiotherOncol 2005; 77:53-7.24. Astreinidou, E., Dehnad, H., Terhaard, C.H. & Raaijmakers, C.P. Level IInodes and radiation induced xerostomia. Int J Radiat Oncol Biol Phys 2004;58: 124-31.25. Hunt, M.A., Hsiung, C.Y., Spirou, S.V., Chui, C.S., Amols, H.I. & Ling,C.C. Evaluation of concave dose distributions created using an inverseplanning system. Int J Radiat Oncol Biol Phys 2002; 54: 953-62.26. Samuelsson, A. & Johansson, K.A. Intensity modulated radiotherapytreatment planning for dynamic multileaf collimator delivery: influence ofdifferent parameters on dose distribution. Radiother Oncol 2003; 66: 19-28.www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 29

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013of all germ cell tumours and is increasing in incidence. The peak incidenceoccurs between thirty and forty years of age (2).For treatment purposes, two broad categories are recognized: pure seminoma,and all others, which together are termed nonseminomatous germ-cell tumors(NSGCT). Seminoma, 80% of which are diagnosed at stage I, is highly sensitiveto both radiotherapy and chemotherapy and, therefore, unlike many malignantneoplasms, cure is an expected outcome in the majority of cases, even withmetastatic disease at presentation. Its prognosis is generally good, but thetreatment-induced morbidity must not be underestimated (3).For higher stages of seminoma there is international consensus on treatmentwith multiple courses of cisplatinum based combination chemotherapy (4, 5).As patients with advanced seminoma are infrequent there are no randomizedstudies comparing different kinds of cisplatinum-based chemotherapy. However,these patients were often included in protocols for low risk testicular cancerirrespective of histology. Results from these studies have shown that 4 cycles ofEP (Etoposide and Cisplatinum) are as effective as other cisplatinum regimens(6). No studies support the use of single agent carboplatin chemotherapy inadvanced disease (7, 8). According to the Modified after the Royal MarsdenHospital staging system; large volume disease is clinical stage (CS) IIC-D,IIIC-D, IVC-D, L1-L2 and very large volume disease is CS IV0-D, L3-L4;extralymphatic extrapulmonary metastases (bone, liver, brain), table1 (9).Materials and MethodsDuring the period between September 2007 and April 2012 the records of 10patients with large volume seminoma were retrospectively reviewed. Dataextracted included age, date of diagnosis, histopathology, baseline tumor markers(ßHCG, LDH), primary site, baseline clinical stage, baseline risk stratification,first line chemotherapy regimen, number of cycles, type of toxicity, overallresponse, date of relapse, second line treatment and current status. Tumors werestaged according to the Modified after the Royal Marsden Hospital stagingsystem and patients were stratified according to the International Germ CellCollaborative Consensus Classification Group (IGCCCCG), table 2 and 3.www.amaac.org

ResultsTable 4 provides a summary of patient characteristics such as age, stage, treatment,follow-up, and overall survival. Total of 10 patients were reviewed. Median ageat diagnosis was 32 years (17-49). Median follow up was 32 months (4-54).Baseline staging work up included CT chest, abdomen and pelvis in 9 patientsand the remaining 1 had both CT and PET-CT as baseline imaging work up.The primary site of disease was testicular in 8 patients, 3 of them diagnosed withundescended testis with clinical stages IIB, IIC, and IID, and the remaining 5patients with clinical stages IIB, IIB, IIC, IID, and IVC, L1. Primary mediastinalin 2 patients with clinical stages IIIC and IIID. Nine patients had classicalseminoma and 1 patient had spermatocytic seminoma. Baseline serum BHCGwas high in 3 patients and baseline serum LDH was high in 3 patients as well.All patients were good risk according to IGCCCG.Nine patients treated with PEB (Cisplatin, Etoposide and Bleomycin) regimen,5 patients received 4 cycles of PEB and 4 patients treated with 3 cycles. Onepatient treated with 3 cycles of EP (Etoposide and Cisplatin) regimen withoutBleomycin due to lung pathology. All patients achieved complete response.Two patients with primary mediastinal disease received consolidation mediastinalirradiation with a total radiation dose of 3600 cGrey, 1 patient with undescendedtestis received para-aortic nodal irradiation.One patient relapsed in the mediastinum and retroperitoneal lymph nodes onfollow up PET-CT and was salvaged with second line chemotherapy, in the formof 2 cycles of VIP (Vinblastine, Ifosfamide and Cisplatin) regimen followed bypara-aortic nodal irradiation.All patients completed their planned cycles of chemotherapy. Seven patients hadno major toxicities, 3 patients had febrile neutropenia and needed admission intothe hospital and 1 patient had ototoxicity in the form of tinnitus. One patient hadgrade IV hematologic toxicity with the second line chemotherapy regimen. . Atthe last follow-up evaluation, all patients are alive and disease-free.DiscussionTesticular cancers, 95% of which are germ-cell tumors (GCT), are the mostcommon solid malignancies affecting males between the ages of 15 and 35 years,although it accounts for only about 1% of all cancers in men. In 2010 it caused anestimated 350 deaths with 8480 new cases diagnosed in the United States alone(10). Its prevalence is one of the world’s highest, and is still increasing (11).Nevertheless its origin remains poorly understood, although some environmentalor genetic risk factors are suspected (3). Little is known about etiological riskfactors for the development of testicular tumours. Ten percent of the patientshave had a history of cryptorchidism. Some epidemiological studies show asignificantly increased percentage of pure seminoma as compared to germ celltumours of other histologies in men with undescended testis (12). Other riskfactors are hypotrophic testicle and infertility (13).Most of the studies on advanced germinal cancer include both seminomaand nonseminomatous tumors (14). As there is no bad prognostic subtype foradvanced pure seminomas, most of the centers tend to treat them in the same wayas the bad prognostic subtypes of nonseminoma. The current standard treatmentconsists of 3-4 cycles of BEP or EP chemotherapy regimens (15). There are norandomized studies on patients with stage IIB disease comparing radiotherapyand chemotherapy. The reported relapse rate with radiotherapy varies between9–24%. All available data are based on small series of patients. The relapsesafter radiotherapy are predominately located outside the retroperitoneum. Evenif the risk factors for subclinical disseminated disease in stage IIB disease areunknown it is reasonable to believe that tumour volume is of importance. Bothradiotherapy and chemotherapy are viable alternatives (16). For higher stages ofseminoma there is international consensus on treatment with multiple coursesof cisplatinum based combination chemotherapy (5). In the International GermCell Consensus Classification (table3), a prognostic factor-based classificationsystem for metastatic germ cell cancers, metastatic seminoma is classified asgood or intermediate prognosis. No seminoma patients are classified as poor risk.Adverse prognostic factors are non-pulmonary visceral metastases, especiallyliver or brain. Also, presence of supra clavicular nodes and raised LDH (>twotimes the upper limit of normal) added negative prognostic information (17).Seminomatous tumours are often characterized by slow clinical regression ratefollowing chemotherapy. Residual tumour mostly consists of fibrotic or necrotictissue. In post-chemotherapy seminoma residuals, a positive PET is highlypredictive for the presence of viable tumour especially when using a ≥3 cmcut-off. A negative PET scan is excellent for the exclusion of disease in lesions≥ 3 cm. PET can contribute to the management of residual seminoma lesions,especially in terms of avoiding unnecessary additional treatment for patientswith non-regressing lesions ≥ 3 cm (18).By the late 1980s, investigators realized that certain clinical and tumor featurescould predict the likelihood of patient response to standard chemotherapyregimens. Several algorithms were developed to stratify patients into “good”or “poor” prognostic groups and were incorporated into clinical trials in orderto test treatment strategies in specific patient populations. Differences betweenthe algorithms made it difficult to compare trial results. The International GermCell Cancer Collaborative Group (IGCCCG) was formed, and a universalclassification scheme was developed.2 In this stratification system, patients areseparated into good-, intermediate-, and poor-prognostic groups according topredicted outcome to cisplatin-combination chemotherapy, based on histology,primary site, sites of metastasis, and serum tumor marker elevation (19).Seminoma can be divided into three pathologic categories: classical,spermatocytic, and seminoma with syncytiocytotrophoblastic cells. Thespermatocytic type is rare, occurs in older men, and may have a better prognosis.The classical and the syncytiocytotrophoblastic types of seminoma behavesimilarly, although the syncytiocytotrophoblastic subtype is associated withincreased serum ß-HCG levels. Occasionally, seminoma may contain numerousmitotic figures. When three or more mitotic figures are identified per high powerfield throughout the tumor, it is designated as seminoma with high mitotic indexor anaplastic seminoma (20).Cisplatin dose-intensified chemotherapy does not seem to be superior to standardBEP or radiotherapy (21). Post therapeutic follow-up modalities consist of afour-week post chemotherapy thoraco-abdomino-pelvic CT scan (22). Thesubsequent management depends on the size of the residual mass. If the latteris less than 3 cm in diameter, a simple surveillance in advised. If it is larger,a PET-CT exam is recommended. If the latter remains positive, a definitiveconfirmation by biopsy is necessary. If the PET-CT is negative, surveillance maybe sufficient (23). In the presence of active residual tumoral tissue, radiotherapyor chemotherapy remains the treatment of choice (23).In the case of relapse after chemotherapy, and if it occurs less than three monthsafter one chemotherapy cycle, the disease is still considered to be sensitive toa platinum-based chemotherapy salvage treatment (24). The chemosensitivitypersists even after the second or third chemotherapy cycles. Cisplatin is thefundamental drug that must be part of any salvage chemotherapy (25). The mostused first line salvage protocols are the VIP (cisplatin, etoposide, and ifosfamide),TIP (paclitaxel, ifosfamide, cisplatin) or VeIP (vinblastine, ifosfamide, cisplatin)schedules. In fact, relapse after a platinum-based chemotherapy is very rare, andabout 50% of them are cured by salvage chemotherapy (26).www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 31

original article 2 cm> 3 – ≤ 20 metastases, no metastases >2 cm≤ 20 metastases, > 2 cm>20 metastasesLiver metastasesBrain metastasesBone metastasesTable 3: International Germ Cell Collaborative Consensus ClassificationPrognostic riskgroupsSeminomaNon-seminomaGood PrognosisgroupIntermediateprognosis groupPoor prognosisgroup90% of seminomasAll of the followingcriteria:Any primary siteNo non-pulmonaryvisceral metastasesNormal AFPAny ß-HCGAny LDH5-year survival 86%10% of seminomasAny of the followingcriteria:Any primary siteNon-pulmonary visceralmetastasesNormal AFPAny ß-HCGAny LDH5-year survival 72%No patients classified aspoor prognosis56% of non-seminomasAll of the followingcriteria:Testis/retroperitonealprimaryNo non-pulmonaryvisceral metastasesAFP 10 x n5-year survival 48%Table 2: Medical Research Council groupingsGroupDefinitionSmall volume disease CS Mk+, IIA-B, III0-A-B, L1-2Large volume diseaseVery large volume diseaseCS IIC-D, IIIC-D, IVC-D, L1-L2CS IV0-D, L3-L4; extralymphaticextrapulmonal metastases (Bone, liver, brain)32 > Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013AFP = alpha-fetoprotein; ß-HCG = beta-human chorionic gonadotropin;LDH = lactate dehydrogenase.Table 4: Patients' characteristicsPatients' characteristicsNumber of patientsAge in years:MedianRangeClinical stage:CS IIBCS IICCS IIDCS IIIACS IIICCS IIIDCS IVC,L13217-49Undescended testis 3Primary mediastinal disease 2Primary testicular disease 8PEB regimens:4 cycles3 cycles322011154www.amaac.org

EP regimen 1Number of relapses 1Second line chemotherapy 1Salvage radiotherapy 1AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OFINTEREST The authors indicated no potential conflicts of interest.References1. Huyghe E, Matsuda T, Thonneau P. Increasing incidence of testicular cancerworldwide: a review. J Urol 2003;170(1):5-11.2. Powles TB, Bhardwa J, Shamash J, et al. The changing presentation of germcell tumours of testis between 1983 and 2002. BJU Int 2005;95(9);1197-2000.3. Khan O, Protheroe A: Testis Cancer. Postgrad Med J 2007, 83(984):624-32.4. Schmoll HJ, Souchon R, Krege S, et al ; European Germ Cell CancerConsensus Group. European consensus on diagnosis and treatment of germcell cancer: a report of the European Germ Cell Cancer Consensus Group(EGCCCG). Ann Oncol 2004;15(9):1377-99.5. Albers P, Albrecht W, Algaba F, et al. Guidelines on testicular cancer.European Urology 2005;48:885-94.6. Mencel PJ, Motzer RJ, Mazumdar M et al. Advanced seminoma: treatmentresults, survival and prognostic factors in 142 patients. J Clin Oncol1994;12(1):120-6.7. Horwich A, Oliver RT, Wilkinson PM, Mead GM & 7 others. MRCTesticular Tumour Working Party. A medical research council randomizedtrial of single agent carboplatin versus etoposide and cisplatin for advancedmetastatic seminoma. MRC Testicular Working Party. Br J Cancer 2000;83(12):1623-9.8. Bokemeyer C, Kollmannsberger C, Stennin S, Hartmann JT & 8 others.Metastatic seminoma treated with either single agent carboplatin or cisplatinbasedcombinationchemotherapy: a pooled analysis of two randomizedstudies. Br J Cancer 2004; 91(4):683-7.9. PECKHAM, M.J. (1981a). Investigation' and staging: General aspects andstaging classification. In: The Management of Testicular Tumours, (Ed.Peckham) London: Edward Arnold p.89.10. Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin2010, 60(5):277-300.11. Levi F, Te VC, Randimbison L, La Vecchia C: Trends in testicular cancerincidence in Vaud, Switzerland. Eur J Cancer Prev 2003, 12(4):347-9.12. Taran I, Elder JS. Results of orchiopexy for the undescended testis.World JUrol 2006 in press.13. Raman JD, Nobert CF & Goldstein M. Increased incidence of testicularcancer in men presenting with infertility and abnormal semen analaysis. JUrol 2005;174(5):1819-2214. Nichols CR, Catalano PJ, Crawford ED, Vogelzang NJ, Einhorn LH, LoehrerPJ: Randomized comparison of cisplatin and etoposide and either bleomycinor ifosfamide in treatment of advanced disseminated germ cell tumors: anEastern Cooperative Oncology Group, Southwest Oncology Group, andCancer and Leukemia Group B Study. J Clin Oncol 1998, 16(4):1287-93.15. National Comprehensive Cancer Network clinical practice guidelines inoncology testicular cancer V:1; 2011. [http://www.nccn.org/professionals/physician_gls/f_guidelines.asp].16. Chung PW, Gospodarowicz MK, Panzarella T, et al. Stage II testicularseminoma: patterns of recurrence and outcome of treatment. Eur Urol2004;45(6):754-59.17. Gholam D, Fizazi K, Terrier-Lacombe M-J. Advanced seminoma – treatmentresults and prognostic factors for survival after first line, cisplatin-basedchemotherapy and for patients with recurrent disease. A single-institutionexperience in 145 patients. Cancer 2003;98:745-52.18. Becherer A, De Santis M, Karanikas G, Szabo M & 6 others. FDG PETis superior to CT in the prediction of viable tumour in post-chemotherapyseminoma residuals. Eur J Radiol 2005; 54(2): 284-8.19. InternationalGerm Cell Cancer Collaborative Group. International GermCell Consensus Classification: a prognostic factor-based staging system formetastatic germ cell cancers. J Clin Oncol. 1997;15(2): 594-603.20. Bobba VS, Mittal BB, Hoover SV, Kepka A: Classical and anaplasticseminoma: difference in survival. Radiology 1988, 167(3):849-52.21. Giannis M, Aristotelis B, Vassiliki K, Ioannis A, Konstantinos S, NikolaosA, Georgios P, Georgios P, Pantelis P, Meletios-Athanasios D: Cisplatinbasedchemotherapy for advanced seminoma: report of 52 cases treated intwo institutions. J Cancer Res Clin Oncol 2009, 135(11):1495-500.22. Mottet N, Culine S, Iborra F, Avances C, Bastide C, Lesourd A, Michel F,Rigaud J: Testicular tumors. Prog Urol 2007, 17(6):1035-45.23. Krege S, Beyer J, Souchon R, Albers P, Albrecht W, Algaba F, BambergM, Bodrogi I, Bokemeyer C, Cavallin-Ståhl E, Classen J, Clemm C, Cohn-Cedermark G, Culine S, Daugaard G, De Mulder PH, De Santis M, de WitM, de Wit R, Derigs HG, Dieckmann KP, Dieing A, Droz JP, Fenner M,Fizazi K, Flechon A, Fosså SD, del Muro XG, Gauler T, Geczi L, et al:European consensus conference on diagnosis and treatment of germ cellcancer: a report of the second meeting of the European Germ Cell CancerConsensus group (EGCCCG): part II:. Eur Urol 2008, 53(3):497-513.24. Schmoll HJ, Jordan K, Huddart R, Pes MP, Horwich A, Fizazi K, Kataja V,ESMO Guidelines Working Group: Testicular seminoma: ESMO ClinicalPractice Guidelines for diagnosis, treatment and follow-up. Ann Oncol2010, 21(5):140-6.25. Culine S, Abs L, Terrier-Lacombe MJ, Théodore C, Wibault P, Droz JP:Cisplatin-based chemotherapy in advanced seminoma: the Institut GustaveRoussy experience. Eur J Cancer 1998, 34(3):353-8.26. Vuky J, Tickoo SK, Sheinfeld J, Bacik J, Amsterdam A, Mazumdar M,Reuter V, Bajorin DF, Bosl GJ, Motzer RJ: Salvage chemotherapy forpatients with advanced pure seminoma. J Clin Oncol 2002, 20(1):297-301.www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 33

original article 50%was observed in 83% pts and 66% achieved complete biochemical response. Inthe FDG-avid tumor pts, the median SUV at baseline was 12 (range 10.5 - 17.4).Post TPF metabolic response was observed in 100% and was complete in 33%.All patients with complete biochemical response had also a complete metabolicresponse by PET. At 2-year loco-regional progression free rate is 95% and 2 yearoverall survival rate is 84%. No recurrence was seen in complete (biochemical/ metabolic) responders.Conclusion: A negative post induction FDG-PET and complete biochemicalresponse after TPF are of significant value in LA-NPC and are useful determinantto predict outcome.IntroductionNasopharyngeal carcinoma is an endemic carcinoma associated with Epstein-Barr virus (EBV) infection. Radiotherapy is the primary treatment, but studies34 > Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013have supported the use of combined radiotherapy and chemotherapy foradvanced cases. 1-4Incorporation of chemotherapy with standard RT has improved the therapeuticoutcome of patients with locoregionally advanced NPC. This is supported bya meta-analysis of six randomized trials suggesting that when compared withRT alone, the addition of chemotherapy in any sequence increases disease-freesurvival by 35% at 2 to 4 years and overall survival by 20% at 3 to 4 years. Akey question remains regarding the optimal sequencing of chemotherapy andradiotherapy. Many published randomized trials of concurrent chemoradiotherapyhave demonstrated a progression-free (PFS) and/or overall survival (OS) benefitover radiotherapy alone. 5-6The recognition of the importance of Epstein-Barr virus (EBV) in thepathogenesis of NPC has stimulated a growing interest in EBV-based biomarkersfor patients with this malignancy. 6EBV is present in cells from almost every primary and metastatic nasopharyngealcarcinoma, regardless of the degree of tumor differentiation or the geographicorigin of the patient. 7Although initial studies based on qualitative measurement systems showedthat plasma EBV DNA has a sensitivity of only 59–75% for diagnosis of NPC,its sensitivity in quantitative assays was as high as 90%. Such a diagnosticsensitivity appears to be at least as good as that of IgA-VCA. Of further interestis the observation that plasma EBV DNA was found to be rarely detectable inpatients who had complete eradication of cancer. 8-12The early restaging by a single whole-body FDG-PET scan after the first orsecond course of induction chemotherapy is useful in detecting response toinduction chemotherapy and in predicting therapy outcome for locoregionallyadvanced NPC patients. The non-major-responders may benefit from early PETrestaging by switching to an alternative treatment to avoid the unnecessary sideeffect of chemotherapy or by fine-tuning the subsequent treatment modalities. 13The relationships between different 18F-FDG PET functional parameters andEBV DNA load has been described before in very few studies. 14In our study, we assessed the association of 18F-FDG PET functional parametersand EBV DNA load post induction chemotherapy for our patients withNasopharyngeal Carcinoma (NPC).www.amaac.org

Material and MethodsTwenty patients with locally advanced nasopharyngeal carcinoma with nodistant metastasis who presented to the Oncology Centre at King Fahd SpecialistHospital, Dammam in Saudi Arabia were enrolled in this study during theperiod between July 2007 and April 2012. All patients received two cycles ofTPF induction chemotherapy: Docetaxel: 75 mg/ m2, Cisplatin: 75 mg /m2 andcontinuous infusion of 5-Fluorouracil: 750 mg/ m2 for 96 hours followed 3-4weeks later by concurrent weekly Cisplatin ( 40 mg/ m2) and IMRT (GTV:70Gy over 35 fractions). All patients had a non-metastatic disease as provedby doing chest and abdominal CT scan, PET/CT scan and bone scan (whenindicated).Patient Monitoring and Follow upBefore treatment, patients underwent a complete history and physicalexamination, including evaluation of performance status, assessment for thepresence of concurrent co-morbid conditions with estimation of body weight,height, vital signs and measurement of palpable or visual lesions. Laboratorystudies included a complete blood count (CBC) with white blood cell differentialcount, biochemistry profile, kidney function test, liver function tests, hepatitismarkers, random blood sugar and Epstein-Barr virus (EBV) DNA plasma levelinitially and post induction chemotherapy. Radiological examinations, includingCT head and neck, chest, abdomen and pelvis, were required before startingtreatment, at the end of induction chemotherapy, post concurrent chemoradiationand then periodically. Isotopic bone scan was not done routinely. FDG PET/CTwas done at presentation and post induction chemotherapy. Patients should havedental clearance before initiation of radiation therapy.Chemotherapy protocolNeoadjuvant chemotherapy consisted of two cycles of TPF regimen: Docetaxel(75 mg/m 2 administered intravenously [IV] over 1 hour), Cisplatin (75 mg/m 2 administered intravenously [IV] over 1 hour) and continuous infusion of5-Fluorouracil (750 mg/ m 2 CI for 96 hours) given on days 1 and 21. During RT,cisplatin at a dose of 40 mg/m 2 IV infusion was administered weekly throughoutradiation, given at approximately 60 minutes before receiving radiotherapy.Radiation therapy techniqueIntensity Modulated Radiation Therapy (IMRT) using Simultaneous IntegratedBoost (SIB) was used in treating patients, three planning target volumes (PTVs)were created: PTV 70 Gy to the primary and involved nodes, PTV 60 Gy tothe rest of nasopharynx, the oropharynx, posterior two thirds of the anteriormaxillary sinuses and to non involved upper neck nodes, and finally PTV 54 Gyto non involved lower neck nodes.Quantification of EBV DNA loadPlasma EBV DNA was measured by real-time quantitative PCR. DNA wasextracted from plasma samples. Circulating EBV DNA concentrations weremeasured by a real-time quantitative PCR system that amplified a DNA segmentin the BamHI-W fragment region of the EBV genome. Results were expressedas DNA copies/ ml of plasma. The lower limit of reliable quantification was 5copies/ assay, although occasionally 1 copy/assay was also detectable (the lattercorresponding to 12 copies of EBV DNA/ ml of plasma).Imaging with FDG PET/CTAll patients required to be fasting for at least 6 hours before 18F-FDG PET/CT.Imaging was performed with a PET/CT system consisting of a PET scanner andCT scanner. Before acquisition of PET images, helical CT was performed fromthe head to the proximal thigh. Emission scans from the head to the proximalthigh were acquired at 50–70 minutes after injection of 370 MBq of 18F-FDG.PET images were reconstructed with CT used for attenuation correction. Themaximum standard uptake values (SUVmax) were obtained by drawing theregions of interest over the most intense slice of the primary tumor within thenasopharynx and the neck lymph nodes.ResultsFrom July 2007 to April 2012, twenty patients referred to Oncology Centreat King Fahd Specialist Hospital, Dammam in Saudi Arabia were enrolled inthis study. This study was approved by the institutional review board of thehospital. We have previously reported the toxicity of induction chemotherapyand concurrent chemoraiotherapy.The overall response rate to induction chemotherapy reached 90% with completeremission (CR) and partial remission (PR) rates of 30% and 60% respectively.Six weeks post concurrent chemoradiation therapy, 85% and 10% of patientswere in complete remission and partial remission respectively, (Table 1).Base line EBV-DNA ranged between 1,184 - 43,000 copies/ ml with a median of11,300. Post induction chemotherapy with TPF 66% and 34% achieved completeand partial biochemical response, respectively. Reduction of EBV-DNA copiesby more than 50% was seen in 83% of patients, (Table 2, 3).For PET/CT the maximum standard uptake values (SUV) was seen in the primarytumor. SUV values ranged between 10.5 - 17.4 with a median of 12. Metabolicresponse was defined as a decrease in maximum SUV of 35% or more. All thepatients showed metabolic responses which was variable. Complete and partialmetabolic responses were seen in 33% and 67% of patients, respectively, (Table2, 4).All patients with complete biochemical response showed also completemetabolic response.At 2 years loco-regional progression free survival was 95%. Overall survivalrate at 2 years was 84%. No recurrences were seen in complete biochemical andmetabolic responders. At last follow up seventeen patients (85%) were alive andfree of disease.DISCUSSIONPlasma EBV-DNA load is different from other peripheral blood markers in thatit measures the tumor derived EBV genomic material rather than an antibodyresponse to genomic or peptide components of the EBV. The use of real timePCR to detect EBV-DNA in plasma had been shown to be both sensitive (96%)and specific (93%). 11Many studies had confirmed the role of EBV-DNA as a prognostic marker innasopharyngeal carcinoma. 15-16 Other trials had confirmed that the plasma levelof EBV-DNA was undetectable in patients who had complete remission of theircancers. 12In our study, the baseline median concentration of plasma EBV-DNA was 11,300copies/ ml. We have to take into consideration that the study population includedonly patients with locally advanced disease. Post induction chemotherapy 83%of patients showed >50% reduction of plasma EBV-DNA copies.Currently, conventional imaging tools like CT and MRI are routinely used instaging NPC patients. A fused integrated morphological and functional imagingmodality of positron emission tomography / computed tomography (PET/CT) isanother possible useful new tool to be utilized in the assessment of NPC patientslike in other oncological patients. 17Yen et al demonstrated that there is a significant correlation between the presencewww.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 35

neck cancer. Mol Imaging Biol 2003;5:257-270.14. Kai-Ping Chang, Ngan-Ming Tsang, Chun-Ta Liao, Cheng-Lung Hsu,Ming-Jui Chung, Chuan-Wei Lo, Sheng-Chieh Chan, Shu-Hang Ng, Hung-Ming Wang, and Tzu-Chen Yen. Prognostic Significance of 18F-FDG PETParameters and Plasma Epstein-Barr Virus DNA Load in Patients withNasopharyngeal Carcinoma. J Nucl Med 2012; 53:21–28.15. Tan EL, Selvaratnam G, Kananathan R, Sam CK. Quantification of Epstein-Barr virus DNA load, interleukin-6, interleukin-10, transforming growthfactor-beta1and stem cell factor in plasma of patients with nasopharyngealcarcinoma. BMC Cancer. 2006;6:227.16. Hui EP, Sung FL, Yu BK, et al. Plasma osteopontin, hypoxia, and responseto radiotherapy in nasopharyngeal cancer. Clin Cancer Res. 2008;14:7080–7087.17. Feinmesser R, Miyazaki I, Cheung R, Freeman JL, Noyek AM, Dosch HM.Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissueobtained by fine-needle aspiration. N Engl J Med 1992; 326: 17-21.18. Yen RF, Hong RL, Tzen KY, Pan MH, Chen TH. Wholebody 18F-FDGPET in recurrent or metastatic nasopharyngeal carcinoma. J Nucl Med2005;46:770-774.19. Allal AS, Slosman DO, Kebdani T, Allaoua M, Lehmann W, DulguerovP. Prediction of outcome in head-and-neck cancer patients using thestandardized uptake value of 2- [18F]fluoro-2-deoxy-D-glucose. Int J RadiatOncol Biol Phys 2004;59:1295-1300.20. Mäkitie AA, Reis PP, Irish J, Zhang T, Chin SF, Chen X, Marriott C, KellerA, Perez-Ordonez B, Kamel-Reid S, Siu LL: Correlation of Epstein-Barrvirus DNA in cell-free plasma, functional imaging and clinical course inlocally advanced nasopharyngeal cancer: a pilot study. Head Neck. 2004Sep;26(9):815-22.21. Chan A. T.C., B. B.Y. Ma, Y.M. D. Lo, et al: Phase II Study of NeoadjuvantCarboplatin and Paclitaxel Followed by Radiotherapy and ConcurrentCisplatin in Patients With Locoregionally Advanced NasopharyngealCarcinoma: Therapeutic Monitoring With Plasma Epstein-Barr Virus DNA,J. Clin. Oncol 2004; August 1; 22(15): 3053 - 3060.22. Paccagnella. A, A. Buffoli, H. Koussis, A. Gava, T. Franceschi, G. Gardani,F. Valduga, F. Gaion, D. Dondi, M. G. Ghi: Concomitant chemoradiotherapy(CT/RT) vs neoadjuvant chemotherapy with docetaxel/cispaltin/5-fluorouracil (TPF) followed by CT/RT in locally advanced head and neckcancer. Final results of a phase II randomized study. J Clin Oncol 26: 2008(May 20 suppl; abstr 6000).23. M. Yamouni, Y. Beldjilali, K. A. Benhadji, H. Khellafi, F. Betkaoui, Y. Kaid,L. Benchlef, F. Z. Daim, S. Toubal, A. Boukerche, A. Abdelaoui, L. Djellali:A phase II trial of induction chemotherapy with cisplatin, docetaxel, andcapecitabine followed by concurrent cisplatin-radiotherapy in advancednasopharyngeal carcinoma. Department of Oncology, University Hospitalof Oran, Oran, Algeria; Department of Medical Oncology, UniversityHospital of Oran, Oran, Algeria; Department of Radiotherapy, UniversityHospital of Oran, Oran, Algeria. J Clin Oncol 29: 2011 (suppl; abstr 5543).www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 37

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013be invisible by routine imaging and thus can be missed in patients who receivea conservative treatment without sentinel lymph-node technique. The choice ofthe loco-regional treatment when an IMLN is discovered either preoperatively orduring surgery is not a consensus because of the rarity of these cases.In this study, we will present the epidemiological, anatomical and pathologicalaspects of IMLN through four case-reports and a literature research.MethodsWe report four cases of primary breast cancer having IMLNs discovered eitherby imaging methods or incidentally on pathology, treated at Salah Azaiz Institute.The clinical and pathological characteristics of the primary tumor were recorded.For each patient, clinical stage at presentation was classified according to the2002 American Joint Committee on Cancer Staging System. Primary tumortreatment features were also recorded: type of surgical treatment, neoadjuvantor adjuvant systemic therapy use, radiation-therapy use and treatment outcome.ResultsThe mean age at the time of initial diagnosis was 59 years (range from 41 to 70).The mean primary tumor size was 26 mm (range from 25 to 30 mm); 3 were T2tumors, and one was T4d tumor. Tumors were invasive ductal carcinoma in threecases and the fourth was invasive lobular carcinoma. The pathological gradeof the primary tumor was grade 3 in 3 cases and grade 2 in one case. Hormonereceptor status was available for 3 patients and was positive in once. IMLNs wereseen on mammography and ultrasonography in three cases and were incidentallydiscovered on histopathologic assessment in one case. The IMLN was located inthe superior and external quadrant in 3 cases and in the inferior internal quadrantin the other case. Tumors were located in the same quadrant as IMLN in threecases. None of the patients had a sentinel lymph node biopsy. Three patientshad metastasis within the IMLN and with capsula infraction in one case. Ofthe 3 patients with IMLN metastasis, 2 had additional disease in the axillarynodes (3N+ /17N and 9N+/6R+/16) while 1 patient had an isolated metastasisin IMLN with no axillary node involvement and the fourth patient was axillarywww.amaac.org

and IMLN negative. Three patients had mastectomy while one patient had breastconservation surgery (IMLN negative). All patients had adjuvant chemotherapyand radiotherapy. One patient had endocrine therapy. One patient lost fromfollow-up. The three others were disease free after a median follow up of 48months (range from 12 to 84) (Table1).Table 1: Patient characteristicsCase 1 Case 2 Case 3 Case 4Age 65 61 70 41Quadrant of IMLN IIQ SEQ SEQ SEQQuadrant of the tumor SIQ SEQ SEQ SEQMammography & US - + + +TNM T2 N0 M0 T2 N1 M0 T2 N0 M0 T4d N1 M0Type of surgery Radical Conservative Radical RadicalHistological typepSize (mm)SBRIMLN statusAxillary statusHormone receptorsChemotherapyRadiotherapyHormonal therapyDIC2538N+8N-UnknownYes50GyNoDIC303N-19N--Yes64GyNoLIC3021N+/1R+*3N++Yes50GyYesDIC30 & 1531N+9N+-Yes*64GyNoUS: untrasonography; DCI: invasive ductal carcinoma; LIC: lobular invasivecarcinoma; SEQ: superior and external quadrant; SIQ: superior and medialquadrant; IIQ: inferior and medial quadrant; pSizse: pathological size; 1N+/1R+:a positive IMLN with capsular rupture; Yes*: this patient had chemotherapybefore surgeryDiscussionBy definition, IMLNs are completely surrounded by breast tissue, and must bedistinguished from low–laying axillary lymph nodes of level one of Berg. The7th edition of the American Joint Committee on Cancer staging system does notconsider IMLNs in breast cancer classification [3].According to the literature, IMLNs are reported in 1% to 50% of breast cancerpatients [2, 4-9]. The highest rates of IMLN were recorded by pathologists [2].They were metastatic in 24% in Pugliese et al. study and in 27.2% in Intra et al.study [1,10].The first to publish their results were Egan and McSweeney (initially in1983 then updated in 1984) [6]. They performed a histological evaluation ofmastectomy specimens sectioned into 5 mm-thick sections with a specificallydesigned protocol to identify IMLN. They found a 26% incidence of IMLNs.Jadusingh detected IMLN in only 7 of 682 specimens (1%) [4]. More recently,Shen et al. reported IMLN involvement in 28% of 130 cases associated witha primary breast malignancy [7]. Guth et al. identified 64 (31%) specimenswith IMLNs where 20 were involved, and 44 were negative [11]. Schmidt etal. reported their dissection of cadaver breasts where 7.5% had IMLNs. Halfof these nodes were not shown by mammography [12]. Stomper et al. whoexamined 1500 mammograms, found evidence of IMLNs in 13% [13]. IMLNswith benign features are present in approximately 5% of all patients undergoingmammography according to Gordon and Gilks [14].The presence of IMLNs may not always be described by the reporting radiologist.Benign IMLN on mammography are typically described as a small nonpalpablemass less than 10 mm in diameter, well circumscribed, more or less lobulatedand characterized by a radiolucent center and a hilar notch, which represents fatin the hilum of the node. On ultrasonographic examination, the mass appearsas a solid ovoid node, isoechoic or slightly hypoechoic and an echogenic arearepresenting the hilar fat may be visible.Deviations or changes during follow-up from the typical characteristic of benignIMLN, such as enlargement (> 1cm) with loss of the lucent centre and hilarnotch, usually indicate involvement with metastatic disease as reported byGunhan-Bilgen et al. [15]. The sensitivity of mammography or ultrasonographyin the detection of IMLN metastasis is low: 3 cases in our study were reportedas normal [15]. In Hogan et al. study, only 10% of IMLNs were identified onpre-operative imaging and four of them (19%) were described as abnormal [8].MRI may be useful in diagnosing small IMLN metastasis with 93% sensitivityand 89% specificity using size-based criteria (defining > 5 mm as positive)according to Kinoshita et al. [16]. However, MRI is very expensive comparedwith mammography and ultrasonography.IMLN with abnormal radiologic features can be detected but differentiatingmalignant from benign, such as inflammation or hyperplasia, is impossible byimaging methods only. Therefore, any changes in radiological aspect of IMLNshould be considered and a core biopsy using guide wire localization or fineneedle aspiration has to be performed [17].In the absence of systematic research of IMLN by imaging methods, their realfrequency and their anatomical aspects are not well established. IMLN can besolitary or multiple, unilateral or bilateral. It is more frequently located in theupper outer quadrants which correlate with our cases [6, 12]. However, theymay be located in all quadrants of the breast. According to Upponi et al. halfof positive IMLN were located in the same quadrant as the primary tumor [17].Egan and McSweeny found that IMLNs were located in all quadrants of thebreast but were more likely to be positive in the same quadrant as the tumor[6]. IMLN was located in the same quadrant of the tumor in 3 of our cases andsituated in a different quadrant than the tumor in one case. IMLN was involvedin the latter case.Some authors found that 72% to 81% of patients who had IMLN metastasis alsohad axillary lymph node involvement [7-9, 11]. Therefore, on the basis of thestrong association of axillary metastases and positive IMLN, when a metastaticIMLN is encountered complete axillary lymph node dissection is recommended.The impact of the IMLN sentinel technique is controversial. IMLN was detectedby sentinel technique in several studies [1, 7, 11, 18-21]. However the significanceof this node remains unclear. Some authors consider it as in transit node in theclassical lymphatic drainage of the mammary gland [19]. Others do not agreewith this hypothesis and mandate an axillary-sentinel node to assess the axillarynodestatus [1, 18, 20 ,21]. In our cases no patient had axillary invasion with anegative IMLN which is in favor of the first hypothesis. However, we cannotmake any conclusion because of the small number of our cases.Metastatic disease to the IMLN may significantly affect prognosis and it isan independent predictor of poor outcome in patients with breast carcinomaaccording to Shen et al. [7]. Guth et al. concluded that IMLN metastases area marker for disease severity and that it may influence the choice of adjuvanttherapy [11]. The benefit of systemic adjuvant therapy is difficult to assess.Nevertheless, IMLN need to be considered.In cases of breast conservation surgery, a positive IMLN does not mandate amastectomy as long as both the primary tumor and the IMLN can be resectedwith an adequate cosmetic result [22]. It shouldn’t be considered as a multifocaldisease. One of our cases, who had a small tumor at diagnosis, received a radicalsurgery because of a high number of ILMN which were all involved. For patientsundergoing planned mastectomy, the pathologist have to be warned.www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 39

original article Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

notes

news from the arab world Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 43

news from the arab world Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

MissionE a s t e r n P r o v i n c eK i n g d o m o f S a u d i A r a b i aFight Cancer on all fronts through all possible direct and indirect channels& by all means.ActivitiesDATEFebruary 4, 2013February 6, 2013February 27 - 28, 2013March 13, 2013March 21, 2013April 3 & 4 , 2013April 02, 2013April 18, 2013April 25, 2013May 8, 2013September 15, 2013October 2013November 20, 2013ACTIVITIESLung Cancer Symposium “ International Cancer Day”Breast Cancer Symposium for Primary care physicians2 More Minutes Saved My Life CampaignUpdates on Multiple Myeloma Symposium1 day Mini Symposium “Updates in Colorectal Cancer”(International Colorectal Cancer Month)Breast Cancer Symposium for Primary care physicians2 More Minutes Saved My Life CampaignASCO – GFFCC ConferenceHepatobiliary Pancreatic Cancer ConferenceBreast Cancer Symposium for Primary care physicians2 More Minutes Saved My Life CampaignBreast Cancer Symposium for Primary care physicians2 More Minutes Saved My Life CampaignPharmacology Oncology SymposiumAdvanced Management of Breast CancerLatest Improvement of Lymphoma Management(International Lymphoma Day)th“5 Sharqiyah Wardiyah”Breast Cancer CampaignSick Children’s DayLOCATIONSheraton Hotel, DammamBishaSheraton Hotel, DammamSheraton Hotel, DammamMadinahKing Fahd Medical City, RiyadhJeddahMakkahSheraton Hotel, DammamPlaza Conference Center, AramcoPlaza Conference Center, AramcoEastern ProvinceSunset Beach Resortwww.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 45

cancer awareness calendar Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

objectives & scope of the PAJO

instructions for the authors Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013AbstractAbstracts are limited to 250 words and must appear after the titlepage. Abstracts must be formatted according to the followingheadings: (1) Purpose, (2) Patients and methods (or materials andmethods, similar heading), (3) Results, and (4) Conclusion. Authorsmay use design instead of Patients and methods in abstracts ofReview Articles. Comments and Controversies, Editorials andCorrespondence do not require abstracts.TextThe body of the manuscript should be written as concisely aspossible and must not exceed the manuscript category wordlimits described herein. All pages of a submission should benumbered and double-spaced. Helvetica and Arial at 12pt sizeare the recommended fonts for all text (see Figures section foracceptable fonts for figures). The Journal adheres to the styleguidelines set forth by the International Committee of MedicalJournal Editors.ReferencesReferences must be listed and numbered after the body text in theorder in which they are cited in the text. They should be doublespacedand should appear under the heading “REFERENCES.”Abbreviations of medical periodicals should conform to thoseused in the latest edition of Index Medicus and on MEDLINE.The «List of Journals Indexed in Index Medicus» includes thelatest abbreviations. Inclusive page numbers must be cited inthe reference. When a reference is for an abstract or supplement,it must be identified as such in parentheses at the end of thereference. Abstract and supplement numbers should be provided,if applicable. When a reference is a personal communication,unpublished data, a manuscript in preparation, or a manuscriptsubmitted but not in press, it should be included in parentheses inthe body of the text, and not cited in the reference list. Publishedmanuscripts and manuscripts that have been accepted and arepending publication should be cited in the reference list.Reference Styleº Journal article with one, two, or three authors1. Dolan ME, Pegg AE: O6-Benzylguanine and its role inchemotherapy. Clin Cancer Res 8:837-847, 1997º Journal article with more than three authors2. Knox S, Hoppe RT, Maloney D, et al: Treatment of cutaneousT-cell lymphoma with chimeric anti-CD4 monoclonal antibody.Blood 87:893-899, 1996º Journal article in press (manuscript has been accepted forpublication)3. Scadden DT, Schenkein DP, Bernstein Z, et al: Combinedimmunotoxin and chemotherapy for AIDS-related non-Hodgkin’slymphoma. Cancer (in press)º Supplement4. Brusamolino E, Orlandi E, Morra E, et al: Analysis of long-termwww.amaac.org

esults and prognostic factors among 138 patients with advancedHodgkin’s disease treated with the alternating MOPP/ABVDchemotherapy. Ann Oncol 5:S53-S57, 1994 (suppl 2)º Book with a single author5. Woodruff R: Symptom Control in Advanced Cancer. Victoria,Australia, Asperula Pty Ltd, 1997, pp 65-69º Book with multiple authors6. Iverson C, Flanagin A, Fontanarosa PB, et al: American MedicalAssociation Manual of Style (ed 9). Baltimore, MD, Williams &Wilkins, 1998º Chapter in a multiauthored book with editors7. Seykora JT, Elder DE: Common acquired nevi and dysplasticnevi as precursor lesions and risk markers of melanoma, inKirkwood JM (ed): Molecular Diagnosis and Treatment ofMelanoma. New York, NY, Marcel Dekker, 1998, pp 55-86º Abstract8. Bardia A, Wang AH, Hartmann LC, et al: Physical activity andrisk of postmenopausal breast cancer defined by hormone receptorstatus and histology: A large prospective cohort study with 18years of follow up. J Clin Oncol 24:49s, 2006 (suppl; abstr 1002)9. Kaplan EH, Jones CM, Berger MS: A phase II, open-label,multicenter study of GW572016 in patients with trastuzumabrefractory metastatic breast cancer. Proc Am Soc Clin Oncol22:245, 2003 (abstr 981)º Conference/meeting presentation10. Dupont E, Riviere M, Latreille J, et al: Neovastat: Aninhibitor of angiogenesis with anti-cancer activity. Presented atthe American Association of Cancer Research Special Conferenceon Angiogenesis and Cancer, Orlando, FL, January 24-28, 1998º Internet resource11. Health Care Financing Administration: Bureau of datamanagement and strategy from the 100% MEDPAR inpatienthospital fiscal year 1994: All inpatients by diagnosis related groups,6/95 update. http://www.hcfa.gov/a1194drg.txtº Digital Object Identifier (DOI)12. Small EJ, Smith MR, Seaman JJ, et al: Combined analysisof two multicenter, randomized, placebo-controlled studies ofpamidronate disodium for the palliation of bone pain in men withmetastatic prostate cancer. J Clin Oncol 10.1200/JCO.2003.05.147FiguresFigures must be cited in the order they appear in the text usingArabic numerals. Figures should be submitted in a seperatedocumen. Figure legends are required for all article types. Figurelegends must not exceed 55 words per figure and should be writtenbelow the figure.Images may be embedded in word or Power Point files.TablesTables must be cited in the order in which they appear in thetext using Arabic numerals. The table’s legend may include anypertinent notes and must include definitions of all abbreviationsand acronyms that have been used in the table. Tables submittedwith multiple parts will be renumbered. Tables should be submittedin a seperate document. Legends must not exceed 55 words pertable and should be written above the figure.Appendices/AcknowledgmentsAppendices and acknowledgments will appear in the print versionof the article.Language: Appropriate use of the English language is encouragedfor publication in the Journal.5. Post-acceptance InformationCopyright FormCorresponding authors must provide unique e-mail addressfor each contributing author at manuscript submission. Uponacceptance of the manuscript, each author will receive an e-mailinvitation to sign a statement confirming that the manuscriptcontains no material for which publication would violate anycopyright or other personal or proprietary right of any person orentity. Manuscripts will not be published until each author hascompleted the form.Page ProofsCorresponding author will receive proofs and must carefullyreview them for data and typesetting errors. Corrections to proofsmust be returned by e-mail, fax, or mail within 1 week. Thecorresponding author is responsible for collecting and submittingall author corrections into a single submission. Publication maybe delayed if proofs are not returned by the publisher’s deadline.The Editor-in-Chief must approve all major alterations, whichmay delay publication of the manuscript.º Government Announcement/Publication13. Miller BA, Ries CAG, Hankey BF, et al (eds): Cancer StatisticsReview: 1973-1989. Bethesda, MD, National Cancer Institute,NIH publication No. 92-2789, 1992º ASCO Educational Book14. Benson AB 3rd: Present and future role of prognostic andpredictive markers for patients with colorectal cancer. Am SocClin Oncol Ed Book 187-190, 2006www.amaac.org Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013 < 49

subscription Pan Arab Journal of Oncology | vol 6; issue 1 | March 2013www.amaac.org

Give them the energyto keep up with lifeAranesp ® offers convenient and tailored treatmentas the only ESA licensed for QW and Q3W 1-3Aranesp ® (darbepoetin alfa) SureClick Brief Prescribing Information. Please refer to theSummary of Product Characteristics before prescribing Aranesp ® . Pharmaceutical Form:Solution for injection presented in prefilled pens containing 150, 300, and 500 micrograms ofdarbepoetin alfa, for single-dose use only. Indication: Treatment of symptomatic anaemia in adultcancer patients with non-myeloid malignancies receiving chemotherapy. Dosage andAdministration: Cancer patients: Aranesp ® should be administered by the subcutaneous route topatients with anaemia (e.g. haemoglobin concentration ≤10 g/dL (6.2 mmol/l)) in order to increasehaemoglobin to not greater than 12 g/dL (7.5 mmol/l). Anaemia symptoms and sequelae may varywith age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’sclinical course and condition is necessary. Due to intra-patient variability, occasional individualhaemoglobin values for a patient above and below the desired haemoglobin level may beobserved. Haemoglobin variability should be addressed through dose management, withconsideration for the haemoglobin target range of 10 g/dL (6.2 mmol/l) to 12 g/dL (7.5 mmol/l). Asustained haemoglobin level of greater than 12 g/dL (7.5 mmol/l) should be avoided; guidance forappropriate dose adjustments for when haemoglobin values exceeding 12 g/dL (7.5 mmol/l) areobserved are described below. The recommended initial dose is 500 μg (6.75 μg/kg) given onceevery three weeks, or once weekly dosing can be given at 2.25 μg/kg body weight. If the clinicalresponse of the patient (fatigue, haemoglobin response) is inadequate after nine weeks, furthertherapy may not be effective. Aranesp ® therapy should be discontinued approximately four weeksafter the end of chemotherapy. Once the therapeutic objective for an individual patient has beenachieved, the dose should be reduced by 25 to 50% in order to ensure that the lowest approveddose of Aranesp ® is used to maintain haemoglobin at a level that controls the symptoms ofanaemia. Appropriate dose titration between 500 μg, 300 μg, and 150 μg should be considered.Patients should be monitored closely, if the haemoglobin exceeds 12 g/dL (7.5 mmol/l), the doseshould be reduced by approximately 25 to 50%. Treatment with Aranesp ® should be temporarilydiscontinued if haemoglobin levels exceed 13 g/dL (8.1 mmol/l). Therapy should be reinitiated atapproximately 25% lower than the previous dose after haemoglobin levels fall to 12 g/dL (7.5mmol/l) or below. If the rise in haemoglobin is greater than 2 g/dL (1.25 mmol/l) in 4 weeks, thedose should be reduced by 25 to 50%. Contraindications: Hypersensitivity to darbepoetin alfa,r-HuEPO or any of the excipients. Poorly controlled hypertension. Special Warnings andPrecautions: General: blood pressure should be monitored in all patients, particularly duringinitiation of Aranesp ® therapy. If blood pressure is difficult to control by initiation of appropriatemeasures, the haemoglobin may be reduced by decreasing or withholding the dose of Aranesp ® .Iron status should be evaluated for all patients prior to and during treatment and supplementaryiron therapy may be necessary. Non-response to therapy with Aranesp ® should prompt a searchfor causative factors. Deficiencies of iron, folic acid or vitamin B12 reduce the effectiveness oferythropoiesis-stimulating agents and should therefore be corrected. Intercurrent infections,inflammatory or traumatic episodes, occult blood loss, haemolysis, severe aluminium toxicity,underlying haematologic diseases, or bone marrow fibrosis may also compromise theerythropoietic response. A reticulocyte count should be considered as part of the evaluation. Iftypical causes of non-response are excluded, and the patient has reticulocytopenia, anexamination of the bone marrow should be considered. If the bone marrow is consistent withPRCA, testing for anti-erythropoietin antibodies should be performed. Pure red cell aplasia causedby neutralising anti-erythropoietin antibodies has been reported in association with erythropoiesisstimulatingagents (ESAs), including darbepoetin alfa. This has been predominantly reported inpatients with CRF treated subcutaneously. Cases have also been reported in patients with hepatitisC treated with interferon and ribavirin, when epoetins are used concomitantly (ESAs are notindicated for use in this patient population). These antibodies have been shown to cross-react withall erythropoietic proteins, and patients suspected or confirmed to have neutralising antibodies toerythropoietin should not be switched to darbepoetin alfa. Active liver disease was an exclusioncriteria in all studies of Aranesp ® , therefore no data are available from patients with impaired liverfunction. Since the liver is thought to be the principal route of elimination of Aranesp ® andr-HuEPO, Aranesp ® should be used with caution in patients with liver disease. Aranesp ® shouldalso be used with caution in those patients with sickle cell anaemia or epilepsy. Convulsions havebeen reported in patients receiving Aranesp ® . Misuse of Aranesp ® by healthy persons may lead toan excessive increase in packed cell volume. This may be associated with life-threateningcomplications of the cardiovascular system. The needle cover of the pre-filled syringe contains drynatural rubber (a derivative of latex), which may cause allergic reactions. In patients with chronicrenal failure, maintenance haemoglobin concentration should not exceed the upper limit of thetarget haemoglobin concentration. In clinical studies, an increased risk of death, seriouscardiovascular events and vascular access thrombosis was observed when ESAs wereadministered to target a haemoglobin of greater than 12 g/dL (7.5 mmol/l). Controlled clinical trialshave not shown significant benefits attributable to the administration of epoetins whenhaemoglobin concentration is increased beyond the level necessary to control symptoms ofanaemia and to avoid blood transfusion. Cancer patients: Effect on tumour growth. Epoetins aregrowth factors that primarily stimulate red blood cell production. Erythropoietin receptors may beexpressed on the surface of a variety of tumour cells. As with all growth factors, there is a concernthat epoetins could stimulate the growth of tumours. In several controlled studies, epoetins havenot been shown to improve overall survival or decrease the risk of tumour progression in patientswith anaemia associated with cancer. In controlled clinical studies, use of Aranesp ® and otherESAs have shown: shortened time to tumour progression in patients with advanced head and neckcancer receiving radiation therapy when administered to target a haemoglobin of greater than 14g/dL (8.7 mmol/l) (ESAs are not indicated for use in this patient population); shortened overallsurvival and increased deaths attributed to disease progression at 4 months in patients withmetastatic breast cancer receiving chemotherapy when administered to target a haemoglobin of12-14 g/dL (7.5-8.7 mmol/l); increased risk of death when administered to target a haemoglobinof 12 g/dL (7.5 mmol/l) in patients with active malignant disease receiving neither chemotherapynor radiation therapy (ESAs are not indicated for use in this patient population). In view of theabove, in some clinical situations blood transfusion should be the preferred treatment for themanagement of anaemia in patients with cancer. The decision to administer recombinanterythropoietins should be based on a benefit-risk assessment with the participation of theindividual patient, which should take into account the specific clinical context. Factors that shouldbe considered in this assessment should include the type of tumour and its stage; the degree ofanaemia; life-expectancy; the environment in which the patient is being treated; and patientpreference. In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobinvalue exceeds 12 g/dL (7.5 mmol/l), the dosage adaptation described in the Posology and Methodof Administration section should be closely respected, in order to minimise the potential risk ofthromboembolic events. Platelet counts and haemoglobin level should also be monitored at regularintervals. Pregnancy and Lactation: No adequate experience in human pregnancy and lactation.Exercise caution when prescribing Aranesp ® to pregnant women. Do not administer to women whoare breastfeeding. When Aranesp ® therapy is absolutely indicated, breastfeeding must bediscontinued. Undesirable Effects: General: There have been reports of serious allergic reactionsincluding anaphylactic reaction, angioedema, allergic bronchospasm, skin rash and urticariaassociated with darbepoetin alfa. Clinical Trial Experience - Cancer patients: Adverse reactionswere determined based on pooled data from seven randomised, double-blind, placebo-controlledstudies of Aranesp ® with a total of 2112 patients (Aranesp ® 1200, placebo 912). Patients withsolid tumours (e.g., lung, breast, colon, ovarian cancers) and lymphoid malignancies (e.g.,lymphoma, multiple myeloma) were enrolled in the clinical studies. Incidence of undesirableeffects considered related to treatment with Aranesp ® from controlled clinical studies: Verycommon (≥1/10) Oedema; Common (≥1/100 to