Short-term intra-arterial infusion chemotherapy for head and neck cancer patients maintaining quality of life

Abstract

Purpose: Head and neck cancer treatment achieves good locoregional tumor control rates while causing severe side effects.
Therapy with chemotherapeutic drugs administered intravenously is limited because either the concentrations at the tumor
site are too low or the total dosages are too high. The evaluation of a technique for short-term intra-arterial infusion chemotherapy
is described herein.
Methods: In a retrospective study, we reviewed the medical records of 97 patients with head and neck cancers who received
short-term intra-arterial infusion chemotherapy (62 patients previously untreated, 35 patients with prior radiotherapy). All
patients refused further radiotherapy. Response rates, overall survival and adverse effects were the study endpoints. The
blood supply of the tumors was controlled with indigocarmine blue infusion and staining of the tumor region.
Results: Complete or partial response was found in 67%, 52% and 63% of previously untreated patients and in 25%, 30% and
29%, respectively, of previously irradiated patients for staging groups I–III, IVA and IVB/C. Patients with T3/T4 tumors who
were previously irradiated showed a median overall survival of 9 months, and those without pretreatment showed a median
overall survival of 22.5 months. None of the patients required tube feeding. No new case of dysphagia, xerostomia, or functional
speech and hearing loss was reported. Pain and clinical symptoms were reduced for all patient groups. Indigocarmine
staining showed reduced tumor blood supply in previously irradiated regions but good blood supply in untreated regions.
Conclusions: Short-term intra-arterial infusion chemotherapy achieves promising response rates and lacks severe adverse
effects.

Full text

Vol.:(0123456789)
1 3
Journal of Cancer Research and Clinical Oncology (2019) 145:261–268
https://doi.org/10.1007/s00432-018-2784-4
ORIGINAL ARTICLE – CLINICAL ONCOLOGY
Short-term intra-arterial infusion chemotherapy forhead andneck
cancer patients maintaining quality oflife
KarlR.Aigner1 · EmirSelak1 · KorneliaAigner1
Received: 28 September 2018 / Accepted: 27 October 2018 / Published online: 31 October 2018
© The Author(s) 2018
Abstract
Purpose Head and neck cancer treatment achieves good locoregional tumor control rates while causing severe side effects.
Therapy with chemotherapeutic drugs administered intravenously is limited because either the concentrations at the tumor
site are too low or the total dosages are too high. The evaluation of a technique for short-term intra-arterial infusion chemo-
therapy is described herein.
Methods In a retrospective study, we reviewed the medical records of 97 patients with head and neck cancers who received
short-term intra-arterial infusion chemotherapy (62 patients previously untreated, 35 patients with prior radiotherapy). All
patients refused further radiotherapy. Response rates, overall survival and adverse effects were the study endpoints. The
blood supply of the tumors was controlled with indigocarmine blue infusion and staining of the tumor region.
Results Complete or partial response was found in 67%, 52% and 63% of previously untreated patients and in 25%, 30% and
29%, respectively, of previously irradiated patients for staging groups I–III, IVA and IVB/C. Patients with T3/T4 tumors who
were previously irradiated showed a median overall survival of 9 months, and those without pretreatment showed a median
overall survival of 22.5 months. None of the patients required tube feeding. No new case of dysphagia, xerostomia, or func-
tional speech and hearing loss was reported. Pain and clinical symptoms were reduced for all patient groups. Indigocarmine
staining showed reduced tumor blood supply in previously irradiated regions but good blood supply in untreated regions.
Conclusions Short-term intra-arterial infusion chemotherapy achieves promising response rates and lacks severe adverse
effects.
Keywords Head and neck cancer· Intra-arterial chemotherapy· Quality of life· Regional chemotherapy
Introduction
Current treatment options, adverse effects
andsuicide rates
The standard head and neck cancer therapies, high-dose radi-
ation accompanied by intravenous cisplatin chemotherapy,
lead to satisfying tumor control rates but are often limited
because of aggravating adverse effects. Dysphagia, tracheos-
tomy, mucositis, weight loss, functional speech and hearing
loss often result from radiotherapy(Achim etal. 2017). The
suicide risk for head and neck (HN) cancer patients is greater
than for other cancer incidences and is increased in patients
treated with radiation alone compared to those treated with
surgery alone (Green and Griffiths 2014; Anguiano etal.
2012; Misono etal. 2008; Osazuwa-Peters etal. 2016).
The reasons for the increased suicide rates in HN cancer
patients are poor quality of life due to the therapy’s side
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s0043 2-018-2784-4) contains
supplementary material, which is available to authorized users.
* Karl R. Aigner
info@medias-klinikum.de; info@prof-aigner.de
http://www.medias-klinikum.de/
Emir Selak
e.selak@medias-klinikum.de
http://www.medias-klinikum.de/
Kornelia Aigner
Kornelia.aigner@medias-klinikum.de
http://www.medias-klinikum.de/
1 Department ofSurgical Oncology, Medias Klinikum
Burghausen, Krankenhausstr. 3a, 84489Burghausen,
Germany
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262 Journal of Cancer Research and Clinical Oncology (2019) 145:261–268
1 3
effects (Park etal. 2016; Briscoe and Webb 2016; Ringash
etal. 2015; Zecha etal. 2016). Radiation’s side effects derive
from damage to healthy tissue including the facial nerves,
and systemic chemotherapy’s side effects mainly derive from
cisplatin toxicity.
The control of tumors that positively test for human papil-
loma virus (HPV) seem to be achieved more easily and is,
therefore, under investigation for a more gentle treatment,
such as intensity-modulated radiotherapy (IMRT) or tran-
soral robot surgery (TORS), without primary chemoradia-
tion (Marta etal. 2014). Only R0 resections give hope for a
possible omission of radiochemotherapy.
However, the problem of severe side effects not only
remains but increases while tumor control improves in
general. A shift in the patient cohort to more HPV-related
tumors with a better prognosis may lead to a more gentle
treatment with less radiotherapy. For the younger genera-
tion, there is an even more urgent need for treatment without
life-threatening or sociopsychologically problematic adverse
effects (Ringash 2015; Rathod etal. 2015). Irradiation for
HNC accounts for good locoregional tumor control rates but
is also the main reason for severe side effects and patients’
discomfort. Chemotherapy administered intravenously is
limited mainly because of its nephrotoxicity. An efficacious
concentration at the tumor site would require a non-tolerable
systemic dosage. We, therefore, investigated the feasibility
and response rates of intra-arterial infusion chemotherapy
and observed drug concentrations in the tumor-supplying
artery as well as the tumor-draining vein.
Chemotherapy application methods
The standard application method for chemotherapeutic
drugs is intravenous infusion. The infusion time ranges from
30min to several hours. The drug is distributed in the whole-
body blood volume, and the drug concentration at the tumor
site is similar to that in the rest of the body.
An alternative application method is intra-arterial (i.a.)
infusion, where the drug is administered via an angiocatheter
or an implanted port catheter that allows infusion into the
tumor-supplying artery and, in the case of head and neck
cancer, the carotid artery. Different techniques of infusion
result in different drug exposure times and concentrations
reached at the tumor site. An i.a. bolus injection, usually
applied with very high cisplatin dosages (100mg/m2),
reaches high local concentrations during a brief infusion
time of less than 1min, which are decreased by thiosulfate
(Robbins etal. 2010; Kovacs etal. 2012). An i.a. short-term
infusion differs from a bolus injection in terms of dosage
(maximum 55mg/m2) and infusion time (5–12min). Drug
exposure rates for these three applications differ from each
other, as i.a. bolus injection yields very high drug concen-
trations (55,000ng/ml) in less than one minute, and i.a.
short-term infusion yields relatively high drug concentra-
tions (25,000ng/ml) in approximately 12min. The advan-
tages of intra-arterial chemotherapy for head and neck can-
cer treatment include increased drug concentration at the
tumor site with decreased systemic drug levels in the rest
of the body. Decisive results of i.a. chemotherapy concern-
ing locoregional and distant tumor control and possible side
effects have remained unavailable mainly for two reasons.
First, the combination with radiation does not give a clear
picture of which effect (tumor control or adverse) is derived
from radiation and which is derived from chemotherapy.
Quality of life studies comparing i.a. chemoradiotherapy
versus intravenous (i.v.) chemoradiotherapy are affected by
radiation as the main source of adverse effects. Second, the
exact technique of i.a. infusion is crucial for the outcome,
and former studies have not always been optimal in terms of
catheter position, concentration, and time of chemo exposure
(Robbins etal. 2010; Kovacs etal. 2012; Rasch etal. 2010).
Methods
Patient description
This is a retrospective observational cohort study. We
reviewed the medical records of 97 patients with head and
neck cancers who received short-term intra-arterial chemo-
therapy within 1992–2017. Observation time was minimum
10months, with a median of 34months.
Inclusion criteria were nasopharyngeal (n = 8),
hypopharyngeal (n = 19), and oropharyngeal (n = 70) car-
cinoma. All patients who received short-term intra-arterial
chemotherapy had either refused treatment with systemic
chemotherapy and radiotherapy at any time (n = 62) or
received prior treatment (n = 35). Investigations were per-
formed in compliance with the principles of good clinical
practice outlined in the Declaration of Helsinki and federal
guidelines, and had approval by the Medias Institutional
Review Committee. Informed consent was obtained from
each participant or participant’s guardian.
Treatment techniques differed according to tumor exten-
sion and individual feasibility. Sixteen patients received
intra-arterial (i.a.) chemotherapy through an angiocath-
eter, 13 of which with additional chemofiltration. Nineteen
patients received i.a. chemotherapy through an implanted
intra-arterial port catheter, 9 of which with additional che-
mofiltration. 5 patients received a sequence of therapies with
altering techniques of angiocatheter and implanted port cath-
eter, 4 of which with additional chemofiltration. Fifty seven
patients received isolated thoracic perfusion in addition to
the port- or angiocatheter technique. The total number of
i.a. chemotherapy procedures was 500, out of which 126
were angiocatheter techniques, 214 were administered via
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263Journal of Cancer Research and Clinical Oncology (2019) 145:261–268
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port catheters and 160 had additional isolated thoracic perfu-
sion. Median number of treatment cycles per patient was 4.5.
Two patients received irradiation after i.a. chemotherapy.
The patients were divided into subgroups according to prior
treatment and staging. Patients without any pretreatment
and patients with prior radiotherapy or radiochemotherapy
were separated. Further partition was dependent on staging.
Staging groups included I–III, IVA, and IVB/C. A detailed
patient description is shown in Table1.
The median age was 59years (range 35–84), and there
were more male (n = 67) than female (n = 58) patients;
however, the median age was similar. The largest subgroup
was advanced stage HNC IVA with 59 patients (17 with
prior radiotherapy, 42 without any prior therapy). Stages
I–III were merged into one subgroup with 16 patients (4
with prior radiotherapy, 12 without any prior therapy).
Stages IVB and IVC were merged into one subgroup with
22 patients (14 with prior radiotherapy and 8 without any
prior therapy). The median observation time was 39months
(minimum 10months).
Short‑term intra‑arterial infusion techniques
Several techniques for short-term intra-arterial drug delivery
were developed. They all allow for the direct infusion of
chemotherapeutic drugs into the tumor-supplying artery and
all are combinable with drug filtration, which in most cases
is applied. A major criterion of short-term intra-arterial infu-
sion is the infusion time of 5–12min.
Intra-arterial port system (i.a. port) forshort-term infusion
A JetPort-Allround catheter (PfM, Cologne, FRG) is
implanted into the common carotid artery, which allows for
repeated infusions without further surgery. Drugs can eas-
ily be infused intra-arterially through the port. The infusion
time is 5–12min. Drug filtration can be conducted at the
same time in the subclavian vein with a Sheldon catheter.
Short-term intra-arterial infusion throughanangiocatheter
For arterial infusion through an angiocatheter, the catheter
is inserted into the femoral artery in the groin under local
anesthesia, and its tip is directed into the common carotid
artery under X-ray monitoring. For drug filtration, a double
channel central venous access is used (Sheldon catheter).
Short-term intra-arterial (i.a.) infusion viatheport catheter
orangiocatheter combined withisolated thoracic perfusion
(ITP)
In addition to an i.a. port infusion or angiocatheter infusion
of chemotherapeutics (as described in 1. and 2.), an isolated
thoracic perfusion (ITP) can be applied to further increase
drug concentrations at the tumor area without increasing
the dosage. Drug infusion is administered through the angi-
ocatheter inserted via the femoral artery and ITP is con-
ducted with a stopflow balloon catheter (Dispomedica, Ham-
burg, FRG) that stops the blood flow with balloons in the
aorta and vena cava. Blood flow is stopped contemporarily
with infusion time and is continued several minutes after
the infusion ends. The total time of ITP is 15min (Fig.1).
For drug filtration, the perfusion channels of the stopflow
balloon catheters were used.
Technique selection anddrug regimen
Patients without or only minor pretreatment and up to WHO
stage IVB received i.a. chemotherapy via angiocatheters
or implanted port catheters according to the individual
Table 1 Head and neck cancer
patient distribution according
to their staging and if prior
irradiation was applied
Patients without prior irradiation did not receive any other treatment prior to intra-arterial short-term infu-
sion chemotherapy
Stage all I II III IVA IVB I VC
Total 97 2 9 5 59 5 17
Prior radiotherapy 35 1 1 2 17 3 11
No radiotherapy 62 1 8 3 42 2 6
Fig. 1 Scheme of isolated thoracic perfusion combined with intra-
arterial short-term infusion via a jetport allround catheter. Due to the
reduced circulating blood volume, tumors are exposed to higher con-
centrations of cytotoxics
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264 Journal of Cancer Research and Clinical Oncology (2019) 145:261–268
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feasibility. Heavily pretreated patients and patients with
distant metastases were submitted to additional ITP.
Drug combinations for short-term i.a. chemotherapy
with chemofiltration were cisplatin (40–50mg), adriamy-
cin (15–30mg) and mitomycin C (10–15 mg) per treatment
cycle (5 to 12min infusion time, treatment cycles in three
weeks intervals). If i.a. chemotherapy is applied without
chemofiltration, lower dosages of cytotoxics are used. If
additional ITP is applied, drug combinations were cisplatin
(70–100mg), adriamycin (30–50mg) and mitomycin C
(15–20mg) per treatment cycle (5 to 12min infusion time,
treatment cycles in 3weeks intervals). The specified dosages
are total dosages.
Criteria forresponses andadverse events
Tumor responses were assessed in accordance with Response
Evaluation Criteria in Solid Tumors (RECIST version 1.1) at
2–8weeks after every second treatment cycle. CT, Magnetic
Resonance Imaging (MRI), and Positron Emission Tomog-
raphy (PET) evaluated responses.
Pain controlled by < 50% analgesic administration
20days after treatment was considered objective pain relief.
Adverse events were assessed according to the common ter-
minology criteria for adverse events of the national cancer
institute.
Statistical analysis
Statistics have been calculated with 95% confidence lim-
its. Survival times were estimated using the Kaplan–Meier
product limit estimator and follow-up for surviving patients
was minimum 10months, median follow-up was 39months.
Survival times were stratified according to clinical varia-
bles that may affect survival and logrank-tests were used
to verify significance. Statistical analyses were performed
using MediasStat software, version 28.5.14.
Results
Blood distribution inthetumor region ofhead
andneck cancer patients
The intra-arterial catheter was used for tissue staining by
injecting indigocarmine blue. Regions with good blood sup-
ply showed distinct staining while regions with decreased
blood supply showed little or no staining (Fig.2a). Natu-
rally, HNC exhibited high infiltrations of blood vessels, and
therefore, are accessible for staining as well as chemotherapy
(Fig.2b).
Six–eightmonths after irradiation, connective tissue
fibrosis affects the local blood supply, and the preirradiated
area does not stain.
Survival rates ofHNC patients receiving short‑term
intra‑arterial infusion chemotherapy are dependent
onprior irradiation
Overall survival times have been estimated using the
Kaplan–Meier products and staging groups have been clus-
tered for reaching reasonable patient numbers. One-year
survival was 59%, 82%, and 93%, respectively, for staging
groups IV B/C, IVA and I–III. Two-year survival rates were
22%, 53% and 86% for the same staging groups. Three-year
survival was 17%, 42%, and 65% for staging groups IV B/C,
IVA and I–III (Fig.3).
The observed survival of HNC patients after intra-arterial
infusion chemotherapy is strongly dependent on prior irra-
diation, and therefore, needs to be considered separately.
After a median observation time of 39 months, 3 out of 35
Fig. 2 a, b Preirradiated areas
do not stain after intra-arterial
injection of blue dye, while non-
irradiated and well-vascularized
areas stain blue
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265Journal of Cancer Research and Clinical Oncology (2019) 145:261–268
1 3
patients with prior irradiation were still alive (since 11, 24,
and 74months), and 29 out of 62 patients without any pre-
treatment were still alive (median 39 months, range 10–221
months). The median survival for stage I–III patients with-
out irradiation was not reached. After 44.5 months, 75% of
the patients were still alive. The median survival of stages
I–III and IVA was decreased for patients with prior irra-
diation. Survival times of stage I–III and stage IVA HNC
groups, treated with short-term i.a. chemotherapy differed
significantly if prior irradiation had been administered or
not (p value < 0.01 and p value < 0.005).The median sur-
vival for stages IVB/C was slightly lower for patients with
prior irradiation than for patients without pretreatment (9.5
vs 11months) (Fig.4a). Survival times showed a slightly
positive effect for non-pretreated patients but without sig-
nificance (p value < 0.6).
Importantly, if advanced cases with very large tumor
masses of the primary tumor are considered, a divergence
in the survival rates of patients with or without pretreatment
can be detected. In patients who received prior radiation or
no pretreatment, a tumor diameter of more than 4cm (T3/
T4) yields a median survival of 9 or 22.5months, respec-
tively (Fig.4b).
Fig. 3 Survival times for head
and neck cancer patients after
short-term intra-arterial chemo-
therapy. Patients were clustered
into staging groups and survival
times were estimated with the
Kaplan–Meier product limit
estimator
Fig. 4 a and b: Median and overall survival rates for HNC patients with and without prior irradiation
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266 Journal of Cancer Research and Clinical Oncology (2019) 145:261–268
1 3
Response rates ofHNC patients receiving short‑term
intra‑arterial infusion chemotherapy
Response rates for HNC patients vary significantly with
regard to prior radiation therapy. The response was evaluated
in comparison to the results of the CT scan. The subgroup
without any prior therapy (n = 62) responded better to short-
term intra-arterial chemotherapy than the subgroup with
prior radio- or radiochemotherapy (n = 35) in all stages. For
the patients without pretreatment, 25%, 14%, and 0% cases
of complete response were reached for stages I–III, IVA, and
IVBC, respectively. In addition, 42%, 38%, and 68% of par-
tial response were reached for the same staging groups. For
the patients with prior radio- or radiochemotherapy, com-
plete response was only reached for 6% of the stage IVA
group and none of the other staging groups. Partial response
was reached for 25%, 24%, and 29% for staging groups I–III,
IVA, and IVBC, respectively (pretreated patients). A clinical
picture of response is shown in the supplement figure.
Adverse effects andquality oflife
No cases of dysphagia, xerostomia, or neurological dam-
age in terms of functional speech loss or ototoxicity were
noted with the given drug combinations, dosages, and infu-
sion times. No patient required a tracheostomy or tube feed-
ing. The bone marrow depression was within the accept-
able range of grade 2 for patients without pretreatment.
The patients who had undergone prior chemoradiation with
extensive doses of systemic chemotherapy exhibited WHO
grade 3–4 bone marrow depression after intra-arterial expo-
sure at moderate doses. Complete reductions in pain were
yielded in 25% of stage IVB/C patients without pretreatment,
and in 14% of stage IVB/C patients with prior irradiation.
Discussion
Standard therapy of HNC consists of a combination of radi-
otherapy with high-dose intravenous chemotherapy but,
despite good tumor control rates and long survival rates,
outcomes remain unsatisfactory due to the severe side effects
and poor quality of life. Three-year overall survival with
standard therapy range between 25% and 75% depending
on tumor size, extension, free surgical margins or relapse.
With intensity-modulated radiotherapy (IMRT), proton
therapy and immune checkpoint inhibition, new treatment
options have been established, especially in tumors that posi-
tively test for human papilloma virus. So far, no definitive
data are available and the standard treatment with radiother-
apy and high-dose chemotherapy is still used in most cases.
In specialized centers, however, short-term intra-arterial
chemotherapy provided interesting results in phase II and
III studies. Short-term intra-arterial infusion chemotherapy
with chemofiltration has been shown to reach high cyto-
static concentrations at the tumor site while maintaining
low concentrations in the unaffected areas of the rest of the
body. Adverse effects have shown to be correspondingly
low. Good response rates can be reached even for very large
tumor masses and in advanced staged patients. Intra-arterial
infusion for HNC treatment has also been performed with
different infusion times, drug dosages and combinations but
never with additional isolated thoracic perfusion. This tech-
nique increases the local exposure to drugs (Ye etal. 2016;
Suzuki etal. 2016).
Independent of genetic, molecular and virus infection
data, short-term intra-arterial infusion chemotherapy is a
noteworthy option for HNC patients. A good blood supply
in the tumor is crucial for the response; if it is present, even
very large tumor masses show a prompt response. Since
blood supply is mostly reduced in preirradiated tumors, at
approximately 6–8months postirradiation, especially in
tumors > 4cm (T3/T4), a reduced response behavior even
to i.a. chemotherapy is observed.
Limitations of this study are the missing data on human
papillomavirus (HPV) status and the lack of homogeneity
according to patient groups and treatment modalities. Preir-
radiation has been shown to affect the treatment response
but radiation dosages are divergent. Detailed response rates
according to treatment technique cannot be provided due to
inhomogeneous patient characteristics and too small patient
cohorts.
However, since these techniques outperform others and
show high drug concentration rates at the tumor site while
maintaining low drug concentrations in the healthy parts of
the body, high response rates and low adverse effects, the
techniques are worth considering not only for HPV-negative
patients but also for other patients with head and neck can-
cer. A rearrangement of the possible treatment options for
different patient groups should be made in terms of changing
the sequence of treatments with priority given to the treat-
ment that does not block possible further treatments and has
a good chance of response.
Special attention should be given to the different kinds
of intra-arterial application pathways. Infusion times of
5–12min have empirically been shown to yield the highest
tumor tissue concentrations, optimal drug exposure and best
response rates (Aigner etal. 1988).
Drug exposure can be increased by means of intra-arterial
infusion of slightly higher dosages with simultaneous che-
mofiltration of the venous return from the tumor site (Aigner
etal. 1983, 2016). Maximally increased drug exposure is
achieved when the intra-arterial infusion is combined with
isolated perfusion techniques (Aigner etal. 2018; Guadagni
etal. 2004, 2007).
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267Journal of Cancer Research and Clinical Oncology (2019) 145:261–268
1 3
The drug dosages for intra-arterial application in general
can be lower than those required for intravenous application;
nevertheless, i.a. application yields higher drug concentra-
tions during the first pass through the tumor site. The intra-
arterial bolus infusion with “systemic” dosages, however,
by itself may generate toxic systemic drug levels. As shown
in the Netherlands Cancer Institute’s randomized study of
systemic versus chemoradiation for HNC, no study arm has a
significant advantage with respect to survival. Even though it
causes fewer side effects in the subject, intra-arterial angio-
graphic chemotherapy requires much more effort than sim-
ple intravenous injection (Rasch etal. 2010).
Prior chemoradiotherapy has a negative influence on
response to intra-arterial chemotherapy because of impaired
blood supply due to connective tissue fibrosis. With regard
to the good survival rates and consistent quality of life with
nearly no toxicity, short-term intra-arterial chemotherapy
for HNC could be considered as a first option in a treatment
protocol, and if initial treatment fails, patients undergo irra-
diation (Aigner etal. 2018).
Conclusions
Short-term intra-arterial infusion chemotherapy applied with
an implanted port system or an angiocatheter and optionally
combined with isolated thoracic perfusion seems to be an
effective treatment option for HNC patients, even with very
large tumor masses. This method results in good response
rates while keeping adverse events low.
Acknowledgements The authors wish to acknowledge Rita Schlaf for
her help and assistance with the statistics used in this report.
Funding Not applicable.
Compliance with ethical standards
Conflict of interest Karl Reinhard Aigner declares that he has no con-
flict of interest. Emir Selak declares that he has no conflict of interest.
Kornelia Aigner declares that she has no conflict of interest.
Ethical approval All procedures performed in studies involving human
participants were in accordance with the ethical standards of the insti-
tutional and/or national research committee and with the 1964 Helsinki
declaration and its later amendments or comparable ethical standards.
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://creat iveco
mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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