Extracorporeal photopheresis in the management of graft-versus-host disease

Graft-versus-host disease (gvhd) is a common complication after allogeneic stem-cell transplantation (sct) occurring either acutely (agvhd: onset ≤100 days post-transplantation) or chronically (cgvhd: >100 days post-transplantation)1–3. More than half of all patients undergoing allogeneic sct experience gvhd. In the simplest terms, gvhd is a complication in which the infused donor’s immune cells recognize the host patient’s tissues and organs as foreign and begin causing tissue damage. The result is significant morbidity and, for many patients, mortality—either directly or indirectly. ABSTRACT


RATIONALE
Graft-versus-host disease (gvhd) is a common complication after allogeneic stem-cell transplantation (sct) occurring either acutely (agvhd: onset ≤100 days post-transplantation) or chronically (cgvhd: >100 days post-transplantation) [1][2][3] .More than half of all patients undergoing allogeneic sct experience gvhd.In the simplest terms, gvhd is a complication in which the infused donor's immune cells recognize the host patient's tissues and organs as foreign and begin causing tissue damage.The result is significant morbidity and, for many patients, mortality-either directly or indirectly.

Question
Is there a benefit associated with the use of extracorporeal photopheresis (ecp) compared with other treatment options for patients who have received allogeneic stem-cell transplantation (sct) and are experiencing graft-versus-host disease (gvhd), if response rate, survival, or improvement in symptoms are the outcomes of interest?

Perspectives
After allogeneic sct, gvhd is a common complication historically categorized as either acute (agvhd: onset ≤100 days post-transplantation) or chronic (cgvhd: >100 days post-transplantation).Graft-versus-host disease occurs when the donor's immune cells recognize the host patient's tissues and organs as foreign and attack them, causing a multitude of problems, often in liver, gastrointestinal system, and skin.
Photopheresis is one therapy that has emerged since the early 2000s for the management of steroidrefractory gvhd because of its steroid-sparing ability, low associated toxicity, and efficacy in some clinical settings.
The present recommendation report summarizes the available data about photopheresis for the treatment of gvhd and provides recommendations on its use.

Methodology
The medline (Ovid) database was systematically searched for January 1995 to August 2013, and the best available evidence was used to draft recommendations relevant to adult and pediatric patients in Ontario who have received allogeneic sct and are experiencing gvhd.Draft recommendations were first reviewed by clinical and methodology experts before undergoing internal review.Final approval of this practice guideline report was obtained from Primary therapy for agvhd has remained unchanged for 30 years and consists primarily of a calcineurin inhibitor in combination with corticosteroids.Approximately half the affected patients will experience complete resolution of their agvhd with this approach.Patients failing first-line therapy have a poor prognosis, with a 1-year survival of less than 50%.Second-line therapies are varied and are supported mostly by small single-arm trials or cohort studies 4,5 .Many randomized trials of promising therapies for gvhd have been negative or were stopped early because of toxicity or futility.It is well recognized that there is no defined standard second-line therapy for agvhd.Photopheresis in the setting of steroid-dependent and refractory agvhd has demonstrated steroid-sparing effects and clinical responses in limited studies [6][7][8][9][10][11] .
As already indicated, cgvhd is one of the main morbidities and causes of mortality in patients surviving the first few months after allogeneic sct.Like agvhd, cgvhd is treated in the first line with corticosteroids with or without a calcineurin inhibitor 12,13 .Patients with cgvhd have compromised quality of life and lesser survival and a very poor prognosis when front-line therapy for cgvhd fails.As for agvhd, there is no standard second-line therapy for cgvhd.In practice, a variety of therapies for steroid-refractory cgvhd are applied in a trial-and-error approach 14,15 .In addition to having limited efficacy, each of these therapies is either expensive, associated with the potential of moderate-to-severe toxicities, or both.Although research continues on the biology and treatment of cgvhd, no novel therapy currently in trials offers a foreseeable and significant advance over the current state of the art.Photopheresis is a therapy that emerged in the early 2000s for the management of steroid-refractory gvhd because of its steroid-sparing ability, low associated toxicity, and efficacy in some clinical settings 6,[16][17][18][19] .
Photopheresis is currently covered by the Ontario Ministry of Health and Long-Term Care for patients with steroid-refractory gvhd, but the therapy requires patients to travel to Toronto for therapy at the Princess Margaret Cancer Centre, which results in limited access for patients from other regions of the province because of travel and cost.More importantly, this patient population is medically complex, often with compromised functioning, and the travel requirement can be medically unsafe.
The present recommendation report summarizes the available data about photopheresis for the treatment of gvhd and provides recommendations on its use.Relevant articles and abstracts were selected and reviewed by two reviewers (CB, RBR), and the reference lists in those sources were searched for additional trials.Personal files were also searched.

Adult Patients
In the twelve papers on the use of photopheresis in adult patients with gvhd after sct 6,8,9,11,[16][17][18][19]21,22,24,27 , the number of patients reported ranged from 9 (in the case series reported by Lucid et al. 24  the case series reported by Dignan et al. 21 ). The pThe patient diagnoses varied, but the typical population comprised patients with gvhd in whom either steroid treatment 6,9,21 or immunosuppressive therapy 24,27 had failed.Where an ecp device was reported, the only one described was either the uvar or uvar xts system by Therakos (Raritan, NJ, U.S.A.) 6,9,[16][17][18]21,27 .The duration for which patients received ecp treatment varied greatly, from a low of 2 weeks (median not reported) in the prospective cohort study by Greinix et al. 9 to a high of 528 weeks (median: 68 weeks) in the retrospective cohort study by Bisaccia et al. 17 .The most commonly reported outcome was the response rate, followed by survival, treatment-related mortality (trm), safety, quality of life, and the effect of ecp on various measures of gvhd by affected site (Table i).
Quality was assessed according to the criteria described in Section 2, "Methods."See Table i for details of patient selection criteria, ecp treatment given, and outcomes reported.Because the recommendations in the consensus statement 22 are only indirectly related to photopheresis, and because the data on which the recommendations were based are not fully described, the working group decided that adapting the statement was not feasible, and a formal assessment of quality using the agree 2 instrument was therefore not performed.
The rct reported by Flowers et al. 18 did not explicitly describe the method of randomization, but noted that a block method was used in a 1:1 ratio.The trial was reported as being single-blind, but no description of the power and sample size calculation, nor of the length of follow-up, was provided.The statistical analyses used were well described, with continuous variables summarized as medians and ranges, and categorical variables, as totals and percentages.The primary endpoint of total skin score was analyzed using a Wilcoxon rank-sum test, and cumulative response rates [complete (cr) and partial (pr)] were compared using the log-rank test.Withdrawals were well described for both arms, and no losses to follow-up were reported.Therakos provided funding for the trial.
The crossover study reported by Greinix et al. 19 included patients from the rct reported by Flowers et al. 18 that crossed over from the non-ecp arm to the ecp arm, and the resulting sample was well described, as was the intervention that each patient received.All relevant outcomes were reported, including response rates, total skin scores, and change in steroid use.Therakos provided funding for the study.
The prospective cohort study reported by Greinix et al. 9 selected patients based on nonresponse to steroid treatment in a well-described population.The ecp treatment was well described, as were the outcomes of response and survival.A European Commission grant (QLK3-CT-2002-01936 TransEurope) provided funding for the study.
All three of the retrospective cohort studies 8,16,17 located for this review had well-described patient samples representative of a typical patient population.The study by Couriel et al. 8 did not report details of the ecp methods.The study by Apisarnthanarax et al. 16 reported on a series of patients in whom various ecp regimens were used, and those authors therefore did not report the details.By contrast, the study by Bisaccia et al. 17 fully described the single ecp protocol used for all patients.All three studies reported response rates, two reported survival 16,17 , and one also reported median time to response 17 .Therakos supported the study by Apisarnthanarax et al. 16 .The other two studies did not report any source of funding.
The case-series study with historical controls reported by Perfetti et al. 11 had a well-described series of patients, which were representative of the population under study.The ecp regimen was also well reported.Outcomes reported were response rates and survival.This study reported non-industry funding (Association Italiana Ricerca contro il Cancro, carige, Fondazione Ricerca per Trapianto Midollo Osseo).
The four case-series studies located for this review 6,21,24,27 had well-defined groups of patients who were representative of the population of interest; however, Lucid et al. 24 included only patients  with bronchiolitis obliterans, and Dignan et al. 21included only patients with mucocutaneous symptoms of gvhd.All four of the studies included detailed descriptions of the ecp intervention, and all patients received the same regimen.Lucid et al. 24 reported response rates, and Dignan et al. 21reported response rates, survival, and reductions in the dose of immunosuppressant drugs or in use of steroids.Seaton et al. 27 and Greinix et al. 6 both reported on the change in various scores associated with the sites affected by gvhd.No study reported the source of funding.In summary, the quality assessment found that all studies of ecp in the treatment of gvhd in adult patients were of acceptable quality given the nature of their study designs.Table ii presents results for all adult patients.

Pediatric Patients
Among the six papers on the use of photopheresis in pediatric patients with gvhd after sct 7,10,20,23,25,26 , the clinical practice guideline by Kanold et al. 23 also reported case-series data (described in Tables iii and iv).The number of patients included in the studies ranged from 9 in the prospective cohort study reported by Salvaneschi et al. 26 to 77 in the nonrandomized controlled trial reported by Messina et al. 10 .As in the adult patients, the diagnoses in the pediatric patients varied, but the typical population comprised patients with gvhd for whom either steroid treatment 20,25,26 or immunosuppressive therapy 10 had failed.The two studies that reported specifics of the ecp system both used the uvar system by Therakos 10,20 .The reported outcomes varied, but response rate was the most common, followed by survival, trm, reductions in the use of steroids or immunosuppression, infection rates, mycosis, and changes in skin scores (Table iii).
Quality was assessed according to the criteria described in Section 2, "Methods."See Table iii for details of patient selection criteria, ecp treatment given, and outcomes reported.
One clinical practice guideline, reported by Kanold et al. 23 , was obtained.However, this guideline located no supporting evidence, and its recommendations are based solely on expert opinion and a single case series reported by the same authors.Our working group therefore decided that a direct review of the evidence and development of new recommendations would be more appropriate than an attempt to adapt the guideline, and so a formal assessment of quality using the agree 2 instrument was not performed.
In the nonrandomized controlled study reported by Messina et al. 10 , the patient selection criteria were well described, and the resulting cohort was representative of the population of interest, as was the ecp regimen.The reported outcomes were response, survival, and adverse effects.This study was funded by non-industry sources (grants from the Associazione Italiana Ricerca sul Cancro, the Consiglio Nazionale delle Ricerche, the Ministero dell'Universita e della Ricerca Scientifica e Tecnologica, and the Istituto di Ricovero e Cura a Carattere Scientifico).
In the prospective cohort study 26 that was located, the patients were well described and were representative of the population of interest, as was the ecp regimen.The reported outcomes were response and survival.This study was funded through non-industry sources (grants from the Associazione Italiana Ricerca sul Cancro, the Consiglio Nazionale delle Ricerche, the Ministero dell'Universita e della Ricerca Scientifica e Tecnologica, and the Istituto di Ricovero e Cura a Carattere Scientifico).
Of the four case series 7,20,23,25 located, three 7,20,25 included full descriptions of the patients included and the ecp regimen used; the study by Kanold et al. 23 had no description at all of the patients included or the ecp regimen.Outcomes reported in these studies were response rate 7,20,23,25 , survival 7,20,25 , trm 7,20 , progression-free survival 7 , infection 7 , and mycosis 7 .Two studies reported non-industry funding: the study by Perotti et al. 25 reported hospital funding, and the study by Calore et al. 7 reported funding from the Fondazione Citta della Speranza, Associazione Italiana Leucemie e Linfomi.
In summary, the quality assessment found that all the studies of ecp in the treatment of gvhd in pediatric patients were of acceptable quality given the nature of the study designs.

Response
The rct by Flowers et al. 18 detected a statistically significant difference in response rate in favour of ecp over conventional corticosteroid treatment (40% vs. 10%, p = 0.002).Comparing ecp with conventional treatment, the crossover rct reported a similarly significant increase in the overall response rate (26% vs. 8%, p = 0.04) 19 .None of the other comparative studies reported a difference between groups 8,9,16,17 .Noncomparative studies reported response rates ranging from 50% 11,17 to 100% (in liver manifesting agvhd only) 6 .The rct reported by Flowers et al. 18 , which detected a benefit in favour of ecp, remains the best evidence because of the study design.

4.1.2
Treatment-Related Mortality Only the rct by Flowers et al. 18 reported on trm, with no difference being detected.

4.1.3
Overall Survival Only one study, the case series with historical controls reported by Perfetti et al. difference being detected (45% for ecp vs. 44% for control).In the remaining studies, survival ranged from a low of 41% in the study reported by Couriel et al. 8 to a high of 85% in the study reported by Bisaccia et al. 17 (both retrospective cohort studies).

4.1.4
Quality of Life Only the rct by Flowers et al. 18 reported on qualityof-life outcomes, with a significant benefit being detected for ecp treatment compared with conventional treatment (19% for ecp vs. 2.5% for control, p = 0.01).

4.1.5
Other Outcomes The rct by Flowers et al. 18 reported total skin scores; eye, oral, and joint changes associated with gvhd; and adverse events.Significant differences were detected only in eye gvhd, which showed improvement more often with ecp than with conventional treatment (30% for ecp vs. 7% for control, p = 0.04).
The case series by Seaton et al. 27 reported on change from baseline scores after 6 months for cutaneous, hepatic, pulmonary, mucosal, and neuromuscular cgvhd; significant improvements were detected only for cutaneous cgvhd scores [89% at baseline (skin median score: 131) vs. 52% at 6 months (skin median score: 61), p = 0.003].

4.2.1
Response Only one of the pediatric studies, the case series by Calore et al. 7 , reported response outcomes that were comparable for ecp and another treatment option.That study reported response rates for patients who received ecp and patients who remained on steroid treatment.The cr rate was higher in the ecp group (73% vs. 56%, p value not reported), but the pr rate was higher in the group that received steroid treatment (44% vs. 27%, p value not reported).
In the remaining studies, cr rates ranged from a low of 32% 25 to a high of 100% (grade ii only) 20 , and pr rates ranged from a low of 21% 10 to a high of 29% 10,26 in patients with agvhd.For patients with cgvhd, cr rates ranged from a low of 21.7% 25 to highs of 44% 10,26 , and pr rates ranged from a low of 29% 10 to a high of 56% 26 .

4.2.2
Treatment-Related Mortality Two of the studies, the case series by Calore et al. 7 and by Berger et al. 20 , reported trm outcomes.Calore et al. found a trm of 6% in the group that had a good response to steroid treatment; mortality was zero in the ecp group (p value not reported).Berger et al. found an increase in trm as agvhd symptoms worsened (0% in grade ii disease vs. 42% in grade iii-iv disease, p = 0.05); they also found an increase in nonresponders to both treatments (0% in ecp responders vs. 50% in nonresponders to both treatments, p = 0.022).

Overall Survival
Six of the studies reported overall survival outcomes 7,10,20,23,25,26 .Only the study by Calore et al. 7 reported comparable survival rates for ecp and another treatment, with patients who received ecp having a survival rate of 85% and patients who received steroid-based treatment having a survival rate of 57% (p = 0.2).
For agvhd, the study by Messina et al. 10 detected a significant survival benefit in ecp responders compared with nonresponders at a median followup of 5 years (69% vs. 12%, p = 0.001).Perotti et al. 25 reported a 62% survival rate in ecp responders compared with 6.3% in nonresponders at a median follow-up of 23.7 months ( p value not reported).Berger et al. 20 reported a 100% survival rate in patients with grade ii acute disease; the rate was 30% in patients with grade iii or iv disease at a median follow-up of 1.6 years ( p = 0.006).
In patients with cgvhd, Messina et al. 10 reported a survival rate of 96% in ecp responders compared with 58% in nonresponders (median follow-up: 5 years; p = 0.04), and Salvaneschi et al. 26 reported a survival rate of 79% in ecp responders compared with zero in nonresponders (median follow-up: 36 months; p value not reported).The study by Berger et al. 20 reported a survival rate of 100% in patients with limited symptoms, but the rate fell to 28% in patients with extensive symptoms (median follow-up: 2.6 years; p = 0.03).

4.2.4
Quality of Life None of the studies reported quality of life.

4.2.5
Other Outcomes In their case series, Calore et al. 7 presented 2-year progression-free survival, but no difference between the groups was reported (87% for ecp vs. 67% for steroid responders, p value not reported).

REVIEW PROCESS
The clinical lead author wrote the initial recommendations and qualifying statement pertaining to the benefit associated with the use of ecp for patients experiencing gvhd.This report was circulated to the members of the Stem Cell Transplantation working group and discussed during a teleconference.The draft recommendations were then generated.The ensuing recommendation report was presented to the entire Stem Cell Transplantation Steering Committee to ensure the clinical relevance and utility of the recommendations, the absence of obvious defects in the evidence base, and the reasonableness of the recommendations derived through expert opinion.Refined recommendations and a summary of the key evidence were first reviewed by the pebc Assistant Director) to ensure that the guideline development was methodologically rigorous and that the evidence-based recommendations are indeed supported by the evidence in a transparent way.Upon completion of preliminary review and feedback provided by the pebc Assistant Director, the recommendation report was presented to the pebc Scientific Director for final review.
Practice guidelines and recommendation reports developed by the pebc are reviewed and updated as needed.Please visit the Cancer Care Ontario Web site (http://www.cancercare.on.ca) for the full report and subsequent updates.

PRACTICE GUIDELINE
Evidence from a systematic search of the primary literature, consensus of expert opinion, feedback obtained through the review process, and a final approval given by the Stem Cell Transplant Steering Committee and the pebc's Report Approval Panel collectively form the basis of this recommendation report, completed in August 2013.

Target Population
The following recommendations apply to adult and pediatric patients who have received allogeneic transplantation and are experiencing gvhd.

Recommendations
• Extracorporeal photopheresis is an acceptable therapy for the treatment of steroid-dependent or refractory agvhd in adult patients.This recommendation is based on results of three non-comparative studies in adult patients (one prospective single cohort 23 and two case series 6,11 ) and six studies in pediatric patients (one clinical trial 10 , one prospective cohort 26 , and four case series 7,20,23,25 ) that reported response rates ranging from 32% to 100% in favour of ecp.Only one of the pediatric studies reported comparable response rates for patients who received ecp and patients who remained on conventional treatment 7 .
In the opinion of the Expert Panel, although the quality of the data for steroid-refractory agvhd is limited, patients with refractory skin gvhd primarily should be considered for ecp treatment.
• Extracorporeal photopheresis is an effective therapy for the treatment of steroid-dependent or refractory cgvhd in adult and pediatric patients.This recommendation is supported by the evidence obtained from two studies (an rct 18 and a crossover rct 19 ) because, in both studies, a significant increase in the response rate favours ecp over conventional corticosteroid treatment.

Key Evidence
Although the proof for efficacy of ecp is of mixed quality, the weight of the evidence supports that ecp works in certain patients and that, when it works, it can provide clinical improvement.The best data, as summarized earlier, support the use of ecp for steroid-refractory cgvhd that is affecting primarily skin or subcutaneous tissue, lung, and liver 3,8,9,18,19,21,22,24 .The data for steroid-refractory agvhd are more limited, but patients with refractory skin gvhd primarily should also be considered 8,9,23 .Additional factors that favour the use of photopheresis include its steroid-sparing effect and its lack of toxicity.Steroid-sparing is of particular importance, because many patients with cgvhd are older individuals who tolerate corticosteroids poorly.Definitive randomized trial data defining second-line therapy for either agvhd or cgvhd is, for a variety of reasons, many years away (no good candidates, complexity of trials, cost to conduct trials, limited peer funding for such trials, a small market discouraging industry pursuit of the indication).In the interim, the transplant community has, based on practice patterns, identified photopheresis as a valuable component of gvhd management for some patients in whom front-line therapy fails 4,5,8,15 .Appropriate application of photopheresis combined with data collection and reporting will enable ongoing evaluation of this therapy compared with other emerging options for gvhd patients in Ontario.

Qualifying Statement
In Ontario, ecp is currently a covered therapy for patients with steroid-refractory gvhd who meet certain eligibility criteria.

ACKNOWLEDGMENTS
The Stem Cell Transplant Steering Committee, the Advisory Panel on Bone Marrow and Stem Cell Transplantation, and the working group thank the following individuals for their assistance in developing this report: Melissa Brouwers, Sheila McNair, and Hans Messersmith for providing feedback on draft versions; Mark Gichuru for conducting a data audit; and Bruce Histed for copyediting.
Cancer Care Ontario's pebc is sponsored by the Ministry of Health and Long-Term Care through Cancer Care Ontario.The full recommendation report is available on the Cancer Care Ontario Web site, at the pebc Collaborative Projects page: https:// www.cancercare.on.ca/toolbox/qualityguidelines/ other-reports/collaborative-pr-ebs/.

figure 1
figure1 Selection of studies investigating extracorporeal photopheresis in the management of graft-versus-host disease in patients who underwent allogeneic blood or bone marrow transplantation.
pebc's Report Approval Panel (Scientific Director and the e323 Current OnCOlOgy-VOlume 21, number 2, April 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
This recommendation report, produced by the Program in Evidence-Based Care (pebc) and the Stem Cell Transplantation Steering Committee of Cancer Care Ontario was developed through systematic review of the available evidence and interpretation of that evidence by clinical experts.Members of the Committee formed a working group to develop the report.The working group members disclosed any potential conflicts of interest.The pebc is editorially independent of the Ontario Ministry of Health and Long-Term Care.This report was developed as part of the mandate of the Stem Cell Transplantation Steering Committee to provide advice to the Ontario Ministry of Health and Long-Term Care with respect to stemcell transplantation and associated technologies and supportive care interventions.It will be assessed for currency and updated in the future at the request of the Committee.The medline (Ovid) database (1995 through July Week 1, 2012) was searched on July 17, 2012, and the search was updated on August 14, 2013.The search used logic combination of terms: [graft-versus-host disease] AND [stem cell transplantation, OR bone marrow transplantation, OR peripheral blood cell transplantation] AND [photopheresis].

) to 82 (in e312 Current OnCOlOgy-VOlume 21, number 2, April 2014 Copyright
© 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

table i
Study and patient characteristics, adult patientsReference nr Response, first-line treatment with steroids 2 consecutive days (1 cycle) e314 Current OnCOlOgy-VOlume 21, number 2, April 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).)e315 Current OnCOlOgy-VOlume 21, number 2, April 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).a Johnson and Johnson, West Chester, PA, U.S.A. gvhd = graft-versus-host disease (cgvhd: chronic gvhd; agvhd = acute gvhd); boop = bronchiolitis obliterans organizing pneumonia; cop = cryptogenic organizing pneumonia; nr = not reported; bmt = bone marrow transplantation; pbsct = peripheral blood stem-cell transplantation.Current OnCOlOgy-VOlume 21, number 2, April 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

e317 Current OnCOlOgy-VOlume 21, number 2, April 2014
11, compared overall survival between ecp and a control group, with no No data reported for the non-ecp arm at 24 weeks because of the large number of patients in that arm who discontinued the study.
Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).e318Current OnCOlOgy-VOlume 21, number 2, April 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).e319Current OnCOlOgy-VOlume 21, number 2, April 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).e320Current OnCOlOgy-VOlume 21, number 2, April 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).a Johnson and Johnson, West Chester, PA, U.S.A. gvhd = graft-versus-host disease (cgvhd: chronic gvhd; agvhd = acute gvhd); nr = not reported.e321 Current OnCOlOgy-VOlume 21, number 2, April 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

e322 Current OnCOlOgy-VOlume 21, number 2, April 2014
Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).