REVIEW ARTICLE

Chemotherapy Administration Sequencing:

An Update on the Current Literature
Alanna D. Lehman, PharmD, BCOP; Anna Howard, PharmD, BCOP; Robert Mancini, PharmD, BCOP

BACKGROUND: In response to many questions regarding the sequence of multiple-agent regi-

men administration, in 2011 Mancini and Modlin published a review of the literature for intravenous
chemotherapy approved by the US Food and Drug Administration (FDA) through 2009, to assist
oncology pharmacists and nurses in answering these questions. Since the publication of that
original article, an additional 37 intravenous chemotherapy and monoclonal antibodies have been
approved by the FDA. Of these 37 agents, 18 are FDA approved for use in combination with
another intravenous agent.
OBJECTIVES: To identify FDA-approved intravenous chemotherapy and monoclonal antibodies
since 2010, to review the literature for any preferred sequence recommendations for these agents,
and to update the original chemotherapy sequencing chart with these new intravenous medica-
tions used in combination.
METHODS: First, we collected a list of the newly approved FDA intravenous chemotherapy and
monoclonal antibodies between January 2010 and May 2018 from the CenterWatch website.
Only clinical trials that were conducted in humans and that evaluated the forward and reverse
sequences of drug administration were included. Any agent that was used as a single agent (ie,
monotherapy) was excluded from that list. Then, we used the Lexicomp Solutions’ IV Index and
the Trissel’s IV Compatibility Tool to assess whether the medications were physically compatible
via Y-site co-infusion. In addition, we evaluated base-solution (ie, lactated Ringer’s, normal saline,
and dextrose 5% in water) compatibilities for individual chemotherapy agents. We then evaluated
Lexicomp online for recommended sequence. Finally, we searched PubMed using keywords that
included any combination of the drug name plus “administration,” “sequencing,” or “interactions.”
In addition, we searched PubMed to evaluate for updated information on the earlier chemothera-
pies discussed in the original article, with date limits of January 2010 to May 2018.
RESULTS: A total of 37 intravenous chemotherapy or monoclonal antibodies were approved by
the FDA between January 2010 and May 2018. After eliminating single-agent intravenous drugs,
18 chemotherapies or monoclonal antibodies were approved for use as combination therapy. Of
those, 2 approvals were for biosimilars to bevacizumab and to trastuzumab. Our thorough litera-
ture review yielded no data to suggest any preferred administration sequence based on the ex-
clusion criteria. In addition, our literature review of new studies published from January 2010 to
May 2018 on the previously researched agents yielded no new findings to suggest any update to
the previous recommendations.
CONCLUSION: The 18 intravenous chemotherapy or monoclonal antibodies approved by the
FDA between January 2010 and May 2018 had no studies that discussed the forward and reverse
of the sequencing in terms of safety and efficacy. Overall, when not clearly supported by studies
J Hematol Oncol Pharm.
that assessed safety and efficacy parameters, our recommendation for sequence of administra-
2019;9(4):175-181
tion of combination chemotherapy is to follow the sequence of administration as published in the
drug regimen’s original study. www.JHOPonline.com

KEY WORDS: combination therapy, forward sequencing, intravenous chemotherapy, monoclonal Disclosures at end of text
antibodies, regimen administration sequence, reverse sequencing, sequencing recommendations

M
Dr Lehman is Clinical Oncology Pharmacist, Adult Oncology ultidrug regimens have become a staple in
and Palliative Care, Department of Pharmacy, Duke oncology, thanks to their ability to overcome
University Medical Center, Durham, NC; Dr Howard is Lead multiple areas of treatment resistance by the
Clinical Pharmacist, Oncology, Billings Clinic, Billings, MT; tumor. The use of multidrug regimens facilitates differ-
Dr Mancini is BMT Pharmacy Program Coordinator and ent mechanisms of attack against the tumor.1 This
PGY2 Oncology Residency Program Director, St. Luke’s multidrug regimen method frequently leads to the ques-
Mountain States Tumor Institute, Boise, ID. tion of how to sequence chemotherapies or monoclonal
Copyright © 2019 by Green Hill Healthcare Communications, LLC; protected by U.S. copyright law.
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Vol 9 | No 4 l December 2019 www.JHOPonline.com l Journal of Hematology Oncology Pharmacy 175
 REVIEW ARTICLE
antibodies. This is an important question that is asked
of oncology pharmacists, because of findings that
demonstrate greater toxicity and/or efficacy, depending
on the sequencing of the agents.1-5 A common miscon-
ception in oncology pharmacy is that these agents have
been tested as part of a chemotherapy regimen and are
therefore safe and effective, but this belief has been
disproved by several studies.2-4
The interaction between cisplatin and paclitaxel is
perhaps the most referenced example of this phenome-
non of chemotherapy sequencing affecting toxicity.2
The sequence-specific interaction between cisplatin
and paclitaxel was documented in 1991.3 When cispla-
tin is administered before paclitaxel, there is a signifi-
cant increase in the incidence of neutropenia, which
results from a 25% reduction in paclitaxel clearance. By
contrast, when paclitaxel is used before cisplatin, there
is no such increase in the incidence of neutropenia.3
Another example of this phenomenon has been re-
ported with paclitaxel and cyclophosphamide.4 Pro-
found levels of cytopenias were reported when pacli-
taxel was infused before cyclophosphamide. When
combining chemotherapy in phase 1 and 2 clinical tri-
als, the sequence of these regimens was often not spec-
ified, and as was shown with cisplatin and paclitaxel,
the sequence can have different or increased side effects
for patients.4
When drugs are combined, the rules of pharmacody-
namics and pharmacokinetics still apply. Several che-
motherapy agents are extensively metabolized through
the cytochrome P450 pathway, and many chemothera-
py agents have high degrees of protein binding. When
adding the potential for some chemotherapy-specific
cell-cycle mechanism of action, it is easy to see how
these factors may increase the cytotoxicity, or antago-
nize the mechanism of action, of the second agent.5
These factors can dictate the order of administration,
because of a particular effect or side effect that would­
be encountered, based on the agent’s pharmacokinetic
and pharmacodynamic properties. In addition, a che-
motherapy agent’s compatibility with different diluents
may also affect the chemotherapy regimen’s order of
administration.
A previously published review of literature by
Mancini and Modlin in 2011 helped shed light on the
sequence of the chemotherapy agents approved at that
time and helped answer the many drug information
questions that are asked in a chemotherapy infusion
center.1 Mancini and Modlin compiled available evi-
dence for chemotherapy agents’ sequencing and dilu-
ents compatibility through 2009 and created an easily
readable chart for real-time use in infusion centers or
hospitals.1 However, since then, 18 new intravenous
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176 Journal of Hematology Oncology Pharmacy l www.JHOPonline.com
chemotherapy and monoclonal antibodies have been
approved by the US Food and Drug Administration
(FDA).
The purpose of this current review is to update the
previously published chemotherapy sequencing chart
with the intravenous medications that have been ap-
proved since 2010 by the FDA and are used in combi-
nation. Because of the number of new intravenous
medications that are approved in oncology regularly,
the sequencing of agents is constantly changing and
needs to be reviewed with the updated information. In
addition, this review includes updates on the sequenc-
ing and diluent compatibility of agents previously re-
searched during the literature review for the 2011
publication of the article by Mancini and Modlin.1
Methods
First, we collected from the CenterWatch website
(www.centerwatch.com) a list of the intravenous che-
motherapy and monoclonal antibodies that were ap-
proved by the FDA between January 2010 and May
2018. Any agent that was used as a single agent only
was excluded from the list. Combination therapy was
defined in this current article as FDA-approved regi-
mens only. Then, we compiled a list of agents previous-
ly reviewed by Mancini and Modlin,1 with the current
FDA-approved combination regimens.
To update the 2011 sequencing chart,1 we evaluated
the administration sequence in the original studies in
published regimens, when provided in the study. Any
chemotherapy agent that is not administered on the
same day as another chemotherapy agent per an
FDA-approved regimen was excluded from the chart.
We reviewed Lexicomp (www.lexi.com) as a standard
resource for drug information for the FDA-recommend-
ed sequence specifics in the administration and drug
interaction sections on that website.6 The clinical trial
relating to the FDA approval for each medication and
regimen was reviewed to determine if the authors dis-
cussed the administration sequence.
Next, we conducted a PubMed search using key-
words that included any combination of the drug name
and the various combinations with “administration,”
“sequencing,” or “interactions.” When evaluating for
updated information on the agents listed in the original
article by Mancini and Modlin,1 we searched PubMed
as well, using the same search terms for these agents,
within the date limits of January 2010 to May 2018.
After establishing the literature base, we reviewed the
studies to determine whether they were clinically appli-
cable, defined as clinical trials that were conducted in
humans and that evaluated the forward and reverse se-
quences of drug administration. Review articles were
December 2019 l Vol 9 | No 4
 Chemotherapy Administration Sequencing

Table S
 equencing of Chemotherapy from Original Clinical Trial for Regimens Approved by the FDA,
January 2010-May 2018
Medication FDA-approved regimens Sequence per original clinical trial(s)
Brentuximab vedotin Brentuximab + AVD Brentuximab administered after completion of AVD7
Ipilimumab Ipilimumab + nivolumab Nivolumab administered before ipilimumab14-16,28,29
Irinotecan liposomal Irinotecan liposomal + fluorouracil + leucovorin Irinotecan liposomal administered first, leucovorin second, fluorouracil third8
Necitumumab Necitumumab + cisplatin + gemcitabine Necitumumab administered first, gemcitabine second, cisplatin third9
Olaratumab Olaratumab + doxorubicin Olaratumab first, doxorubicin second10
Pembrolizumab Pembrolizumab + platinum + pemetrexed Pembrolizumab first, then chemotherapy11
Pertuzumab TCHP Pertuzumab and trastuzumab may be used in any order, but taxane should
be administered after pertuzumab and trastuzumab12,17-23
(ddAC/FEC) ➝ (docetaxel/paclitaxel) + pertuzumab
+ trastuzumab
Pertuzumab + trastuzumab + (docetaxel/paclitaxel)
Ramucirumab Ramucirumab + (paclitaxel/docetaxel) Ramucirumab first, then paclitaxel, docetaxel, or FOLFIRI13,24-27,30
Ramucirumab + FOLFIRI
NOTE: Biosimilar medications, subcutaneous or oral regimen combinations, and medications FDA approved as monotherapy only were excluded from this table. Regimens with no
sequencing noted in the original clinical trial or in the manufacturer’s prescribing information were also excluded.
AVD indicates doxorubicin, vinblastine, and dacarbazine; ddAC, dose-dense doxorubicin and cyclophosphamide; FEC, fluorouracil, epirubicin, and cyclophosphamide; FOLFIRI, leucovorin,
fluorouracil, and irinotecan; TCHP, docetaxel, carboplatin, trastuzumab, and pertuzumab.

included if they provided human clinical trial data.
Studies were excluded from the final review if the
agents were not recommended for administration on
the same day, to keep the consistency with same-day
treatment administration at an infusion center. The
prescribing information and the online Lexicomp med-
ication database for each newly approved medication
were evaluated for the sequence of administration rec-
ommendations. If the prescribing information listed a
particular sequence but did not elaborate on the reason
for this sequence, we contacted the drug’s manufacturer
for clarification of the information.
The inclusion and exclusion criteria for this update
were selected to mirror the original sequencing article by
Mancini and Modlin published in 2011.1 If conflicting
data were apparent regarding a sequence after reviewing
the study for inclusion, recommendations were made in
the chart to err on the side of safety. For example, if one
study suggested that a particular sequence was more toxic
and a second study suggested that there was no difference
between the sequences, the recommendation included
on the chart would be that the reverse sequence was less
toxic rather than stating that there was no difference in
the sequence of the agents.
Finally, we used Lexicomp Solutions’ IV Index with
Trissel’s IV Compatibility Tool to assess whether med-
ications were physically compatible via Y-site co-­
infusion. The Trissel tool was used to match the origi-
nal article by Mancini and Modlin who used that tool.
The medications included the chemotherapy and
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Vol 9 | No 4 l December 2019
monoclonal antibodies approved between January 2010
and May 2018 and the agents previously listed by
Mancini and Modlin. In addition, base-solution (ie,
lactated Ringer’s, normal saline, and dextrose 5% in
water) compatibilities for individual chemotherapy
agents were evaluated.
Results
A total of 18 intravenous chemotherapy or mono-
clonal antibodies were approved by the FDA from
January 2010 to May 2018 and were approved for use in
combination with other agents, including 2 agents that
were biosimilars to bevacizumab and trastuzumab. The
literature search we conducted on these 18 agents
yielded 2 articles for evaluation. Both articles were ex-
cluded, because the agents were not administered on
the same day. We also conducted a literature search
from January 2010 to May 2018 on the previously ap-
proved and researched agents included in the 2011
publication, which yielded no new results to suggest
any update to the recommendations.1
The Table lists the sequencing used in the original
clinical trials for 8 of the recently approved medica-
tions that were approved by the FDA for use in combi-
nation therapies.7-30 The original clinical trials pub-
lished on the other 10 agents did not specify a sequence
of administration in FDA-approved regimens.29,31-44
We updated the original compatibility and sequenc-
ing chart (Figure),7,14-44 which was originally published
in 2011,1 to include the FDA-approved intravenous
www.JHOPonline.com l Journal of Hematology Oncology Pharmacy 177
 REVIEW ARTICLE

Figure Updated Chemotherapy Sequencing Chart, May 2018

Second Chemotherapy Agent

Doxorubicin (Liposomal) 33-39

Gemtuzumab ozogamicin 40-42

Cyclophosphamide 44

Irinotecan Liposomal
Bevacizumab- awwb

Brentuximab vedotin

Fluorouracil (5-FU)24
Chemotherapy

14-16,28,29

Mechlorethamine
Bendamustine31

Daratumumab 32
Sequencing Chart

Fludarabine 44
Bevacizumab

Dactinomycin

Daunorubicin

23,25

24,27
Bortezomib32

Dacarbazine

Leucovorin24
Gemcitabine
Doxorubicin
Carboplatin

Ixabepilone
Carmustine

Cytarabine

Ipilimumab
Cetuximab

Melphalan
Bleomycin

Ifosfamide
Docetaxel

Epirubicin

Etoposide

Idarubicin

Irinotecan
Cisplatin
Bendamustine31

Bevacizumab

Bevacizumab-awwb

Bleomycin
Bortezomib32

Brentuximab vedotin

Carboplatin ND ND

Carmustine

Cetuximab
G1, C2 C1, I2
Cisplatin ND ND
PD/T PD
44
Cyclophosphamide
F1,C2
Cytarabine PD

Dacarbazine

Dactinomycin
Daratumumab32

Daunorubicin
Dox 1 LD1-D2 I1, D2
Docetaxel23,25 ND ND
T T
ND ND
T
Dox 1
Doxorubicin ND
T
LD1-D2
Doxorubicin (Liposomal)33-39 T

Epirubicin ND

Etoposide
F1,C2
Fludarabine42 PD
I1, F2 L1, F2
Fluorouracil (5-FU)24 ND ND
PD/T PD
G1, C2
Gemcitabine ND ND ND
PD/T

Gemtuzumab ozogamicin 40-42

Idarubicin
I1, D2
Ifosfamide T

Ipilimumab14-16,28,29
C1, I2 I1, F2
Irinotecan24,27 ND
First Chemotherapy Agent

PD PD/T

Irinotecan Liposomal

Ixabepilone
L1, F2
Leucovorin24 PD

Mechlorethamine

Melphalan

Mesna *
F1, M2 M1, L2
Methotrexate ND
PD PD

Mitomycin

Mitoxantrone

Necitumumab
Nivolumab14-16,28,29

Obinutuzumab31,43

Ofatumumab44

Olaratumab

Oxaliplatin ND
P1. C2 C1, P2 D1, P2 E1, P2 P1. G2
Paclitaxel26,27,30 ND
T T PK/T PK/T
ND
PD/T

Paclitaxel (Abraxane) ND

Panitumumab

Pembrolizumab
P1, G2
Pemetrexed PD/T

Pentostatin

Pertuzumab17-22

Ramucirumab24-27,30

Rituximab

Streptozocin

Temsirolimus
T1, C2 T1, C2 D1, T2
Topotecan ND ND
T T PK/T

Trabectedin33-39

Trastuzumab17-22

Trastuzumab-dkst

Vinblastine

Vincristine
D1, V2 LD1-V2 T
Vinorelbine PK/T

Ziv-aflibercept
Gemtuzumab ozogamicin

*Follow published guidelines

Doxorubicin (Liposomal)

Irinotecan Liposomal
Bevacizumab- awwb

Brentuximab vedotin

Cyclophosphamide

Fluorouracil (5-FU)

SAME DRUG LINE

Mechlorethamine
Bendamustine

THERAPEUTIC DUPLICATION
Daratumumab
Bevacizumab

Dactinomycin

Daunorubicin
Dacarbazine

Gemcitabine
Doxorubicin

Fludarabine
Carboplatin

Ixabepilone
Carmustine
Bortezomib

Y-SITE COMPATIBLE
Leucovorin
Cytarabine

Ipilimumab
Cetuximab

Melphalan
Bleomycin

Ifosfamide
Docetaxel

Epirubicin

Etoposide

Idarubicin

Irinotecan
Cisplatin

Y-SITE INCOMPATIBLE
NOT TESTED

Second Chemotherapy Agent

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178 Journal of Hematology Oncology Pharmacy l www.JHOPonline.com December 2019 l Vol 9 | No 4
 Chemotherapy Administration Sequencing

gent Base Solutions

SEQUENCE

Paclitaxel (Abraxane)

Dextrose 5% Water6
Ramucirumab24-27,30
LEGEND

6
Nivolumab14-16,28,29

31,43

Sodium Chloride6

Lactated Ringers
Trastuzumab-dkst
Mechlorethamine

17-22
Pembrolizumab

Pertuzumab17-22

Trabectedin33-39
26,27,30
Obinutuzumab

44
PD= Pharmacodynamic/Efficacy

Ziv-aflibercept
Panitumumab
Necitumumab

Temsirolimus
Methotrexate

Mitoxantrone

Trastuzumab
Ofatumumab

Streptozocin
Pemetrexed
PK= Pharmacokinetic

Olaratumab

Vinorelbine
Pentostatin

Vinblastine
Melphalan

Oxaliplatin

Topotecan

Vincristine
Mitomycin

Rituximab
Paclitaxel
T= Toxicity
ND= No difference
Mesna

Bendamustine

Bevacizumab

Bevacizumab-awwb

Bleomycin

Bortezomib

Brentuximab
T1, C2
ND ND Carboplatin
T

Avoid PVC DHEP Carmustine

Cetuximab
P1. C2 T1, C2
T T Cisplatin
C1, P2
T Cyclophosphamide

Cytarabine

Dacarbazine

Dactinomycin

Daratumumab

Daunorubicin
D1, T2 D1, V2
PK/T PK/T Avoid PVC DHEP Docetaxel
D1, P2
ND Doxorubicin
PK/T
ND LD1-V2 T
Doxorubicin (Liposomal)
E1, P2
PK/T Epirubicin
<0.4 <0.4 <0.4
ND ND mg/ml mg/ml mg/ml Etoposide

Fludarabine
F1, M2
PD Fluorouracil (5-FU)
P1. G2 P1, G2
PD/T PD/T Gemcitabine

Gemtuzumab ozogamicin

Idarubicin
* Ifosfamide

Ipilimumab
ND Irinotecan

Inrinotecan Liposomal

Avoid PVC DHEP Ixabepilone

M1, L2
PD Leucovorin

Mechlorethamine
For
< 1hr Melphalan

Mesna

Methotrexate

Mitomycin

Mitoxantrone

Necitumumab

Nivolumab

Obinutuzumab

Ofatumumab

Olaratumab
Flush lines Flush lines
with D5W with D5W Oxaliplatin

Avoid PVC DHEP Paclitaxel

Paclitaxel (Abraxane)

Panitumumab

Pembrolizumab

Pemetrexed

Pentostatin

Pertuzumab

Ramucirumab

Rituximab

Streptozocin

Avoid PVC DHEP Temsirolimus

Topotecan

Trabectedin

Trastuzumab

Trastuzumab-dkst

Vinblastine

Vincristine

Vinorelbine

Ziv-aflibercept
BASE LEGEND
Paclitaxel (Abraxane)

Dextrose 5% Water6

6
Trastuzumab-dkst

6
Mechlorethamine

Lactated Ringers
Sodium Chloride

Y-SITE COMPATIBLE
Pembrolizumab
Obinutuzumab

Ziv-aflibercept
Ramucirumab
Panitumumab
Necitumumab

Temsirolimus
Methotrexate

Mitoxantrone

Trastuzumab
Ofatumumab

Streptozocin
Pemetrexed

Pertuzumab

Y-SITE INCOMPATIBLE
Trabectedin
Olaratumab

Vinorelbine
Pentostatin

Vinblastine
Nivolumab
Melphalan

Oxaliplatin

Topotecan

Vincristine
Mitomycin

Rituximab
Paclitaxel

VARIABLE
Mesna

NOT TESTED
gent Base Solutions
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 REVIEW ARTICLE
chemotherapies from January 2010 to May 2018. These
new agents are highlighted in yellow in the chart, in-
cluding Y-site co-infusion compatibility and base-solu-
tion compatibilities. Of the new agents, gemtuzumab
ozogamicin was Y-site compatible with daunorubicin
and cytarabine. In addition, trabectedin is Y-site com-
patible with doxorubicin liposomal. Two of the regi-
mens—obinutuzumab plus bendamustine and ramu-
cirumab plus irinotecan and leucovorin—were
incompatible because of their base-solution require-
ments. A total of 11 of the recently approved agents are
compatible with a single base-solution.
Several of the recently approved medications had
manufacturer recommendations for agent sequencing
when administered on the same day. No information was
included in the prescribing information for those drugs
regarding the reasons for these sequence recommenda-
tions. When contacted, the drug manufacturer represen-
tatives referred to the original clinical trial(s) involved
in the FDA’s approval for sequencing recommendations.
Discussion
The goal of this literature review was to update the
user-friendly reference chart published in 2011 that is
often used by pharmacists and nurses who work in out-
patient infusion centers and on inpatient oncology
floors. As stated in the original article by Mancini and
Modlin, this chart cannot be used for determining the
sequences of chemotherapy agents given over several
days, because that was not the original intent of the
literature search.1
In this current update, no supportive literature was
found regarding the sequencing of the intravenous che-
motherapy agents and monoclonal antibodies that were
approved by the FDA between January 2010 and May
2018, and no new supportive literature was found for the
older agents discussed in the previous publication. While
reviewing the literature for the more recent FDA-ap-
proved agents, the sequence of administration in the
original clinical trial leading to the FDA approval was
present in many of the cases, as noted in the Table.
When using the chemotherapy and monoclonal an-
tibody regimens, as long as the sequence is provided in
the clinical studies related to the FDA approval of the
regimens, institutions should follow the original se-
quence that appears in those articles.
The question posed in the original article by Manci-
ni and Modlin, “Which drug should be administered
first?” still stands today as a common encounter among
oncology pharmacists. With continued growth in on-
cology and an increased number of FDA-approved
agents, this question remains important for pharmacists
to answer.
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180 Journal of Hematology Oncology Pharmacy l www.JHOPonline.com
The original article by Mancini and Modlin did an
excellent job providing a resource that is available in a
timely manner to help find the answer to that question
and avoid the countless hours that can be spent review-
ing the abundance of literature and resources available.
Nevertheless, a need remains for solid head-to-head
evidence regarding the sequences of intravenous che-
motherapy and monoclonal antibody agents in ques-
tion before further conclusions can be made for the new
agents.
Conclusion
The 18 intravenous chemotherapy and monoclonal
antibodies that were recently approved by the FDA
between January 2010 and May 2018 had no studies
discussing forward and reverse sequencing in terms of
safety and efficacy, based on inclusion and exclusion
criteria required by this article. When not clearly sup-
ported by literature that evaluates safety and efficacy,
the recommendation for the sequence of administra-
tion of combination chemotherapies is to follow the
sequence of administration published in the regimen’s
original study. The need for further clinical studies is
paramount to evaluate the optimal sequence for all
combination agents and ultimately to help pharmacists
and nurses answer the common question of which drug
should be administered first.
Author Disclosure Statement
Dr Lehman and Dr Howard have no conflicts of interest
to report. Dr Mancini is on the Speaker’s Bureau for Mil-
lennium Pharmaceuticals.
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