Chemotherapy for metastatic colon cancer: No effect on survival when the dose is reduced due to side effects

Abstract

Background:
5-Fluorouracil (5FU), Folinic acid (FA), and Oxaliplatin (FOLFOX) or 5FU, FA, and Irinotecan (FOLFIRI) are standard regimens for palliative chemotherapy of metastatic colon cancer. Since data showing the influence of dose reduction in palliative treatment are rare, the objective of this single center, retrospective study was to further characterize the influence of dose reduction on efficacy of these therapeutic regimens.

Methods:
One hundred nine patients, diagnosed with stage IV colon cancer between 2004 and 2012 and receiving palliative first-line chemotherapy with either FOLFOX or FOLFIRI regimens in our outpatient clinic were analyzed for treatment efficacy. Patients who received dose reductions due to side effects usually received doses of 80% or lower of per protocol dose. Survival data were obtained from the Regensburg Tumor Registry. Survival analysis was performed using Kaplan-Meier statistical analysis and multivariable analysis.

Results:
A dose reduction due to side effects was necessary in 46 (42%) patients. Dose reduction was independent of age. Major reasons for dose reduction were neutropenia (30%) followed by polyneuropathy (16%) and diarrhea (14%). Dosage was more often reduced in patients receiving FOLFOX based therapy. Comparison of patients with dose reduction versus patients with full dosage showed no significant difference on overall survival (p = 0.430). Subgroup analysis revealed dose reduction in patients with N2 stage disease was associated with improved survival. Patients who underwent dose reduction received more cycles of chemotherapy (13.7 vs. 10.8 cycles) and cumulative dosage was similar in both groups.

Conclusion:
Contrary to our expectations, the need to reduce chemotherapy dosage due to side effects does not indicate a worse prognosis in our retrospective analysis. We believe this can in part be explained by better adaption to interindividual pharmacokinetics and longer time of treatment.

Full text

R E S E A R C H A R T I C L E Open Access
Chemotherapy for metastatic colon cancer:
No effect on survival when the dose is
reduced due to side effects
Stefan Munker
1*
, Michael Gerken
2
, Petra Fest
3
, Claudia Ott
1
, Elisabeth Schnoy
1
, Stefan Fichtner-Feigl
4
,
Philipp Wiggermann
5
, Martin Vogelhuber
6
, Wolfgang Herr
6
, Christian Stroszczynski
5
, Hans Jürgen Schlitt
4
,
Matthias Evert
7
, Michael Reng
8
, Monika Klinkhammer-Schalke
2
and Andreas Teufel
1*
Abstract
Background: 5-Fluorouracil (5FU), Folinic acid (FA), and Oxaliplatin (FOLFOX) or 5FU, FA, and Irinotecan (FOLFIRI)
are standard regimens for palliative chemotherapy of metastatic colon cancer. Since data showing the influence of
dose reduction in palliative treatment are rare, the objective of this single center, retrospective study was to further
characterize the influence of dose reduction on efficacy of these therapeutic regimens.
Methods: One hundred nine patients, diagnosed with stage IV colon cancer between 2004 and 2012 and receiving
palliative first-line chemotherapy with either FOLFOX or FOLFIRI regimens in our outpatient clinic were analyzed for
treatment efficacy. Patients who received dose reductions due to side effects usually received doses of 80% or
lower of per protocol dose. Survival data were obtained from the Regensburg Tumor Registry. Survival analysis was
performed using Kaplan-Meier statistical analysis and multivariable analysis.
Results: A dose reduction due to side effects was necessary in 46 (42%) patients. Dose reduction was independent
of age. Major reasons for dose reduction were neutropenia (30%) followed by polyneuropathy (16%) and diarrhea
(14%). Dosage was more often reduced in patients receiving FOLFOX based therapy. Comparison of patients with
dose reduction versus patients with full dosage showed no significant difference on overall survival (p= 0.430).
Subgroup analysis revealed dose reduction in patients with N2 stage disease was associated with improved survival.
Patients who underwent dose reduction received more cycles of chemotherapy (13.7 vs. 10.8 cycles) and
cumulative dosage was similar in both groups.
Conclusion: Contrary to our expectations, the need to reduce chemotherapy dosage due to side effects does not
indicate a worse prognosis in our retrospective analysis. We believe this can in part be explained by better adaption
to interindividual pharmacokinetics and longer time of treatment.
Keywords: Dose reduction, Cancer, Colorectal cancer, Chemotherapy
Background
Colon cancer is the third most common cancer and a
major cause of morbidity and mortality worldwide [1].
During the last few decades, improvement in therapeutic
regimens for advanced colorectal cancer led to a dra-
matic increase in efficacy, reduction of mortality rates,
and improved survival. Upon diagnosis, 20% of newly
diagnosed colorectal cancer patients present with
metastatic disease with no curative treatment options
currently available. Among the chemotherapy regimens
considered effective in palliative treatment, Irinotecan or
Oxaliplatin in combination with 5-Fluorouracil regi-
mens are standard back bones of current systemic
treatment [2,3].
These chemotherapy regimens were initially tested for
efficacy in well-defined study populations not necessarily
reflecting average (multimorbid older) patients in real
* Correspondence: stefan.munker@klinik.uni-regensburg.de;
andreas.teufel@klinik.uni-regensburg.de
1
Department of Internal Medicine I, University Hospital Regensburg,
Franz-Josef-Strauss Allee 11, 95053 Regensburg, Germany
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, 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. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Munker et al. BMC Cancer (2018) 18:455
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life settings [4,5]. Clinicians increasingly realize the
shortcoming of the initial studies [6] since these mostly
included younger patients better able to cope with
adverse side effects or toxicities [7]. But especially in
elderly and comorbid patients, side effects, organ
toxicities and therefore potentially limited survival need
to be considered [8]. In clinical practice, these effects are
prevented or mitigated by a dose reduction of chemo-
therapy with the suspected consequence of worse tumor
related survival [9]. We therefore believe that there is a
need to further investigate the impact of dose reduction
of the currently used therapeutic “standard”regimens on
survival and side effects in different subgroups. Hence,
we performed a retrospective analysis of our patient
cohort with advanced stage colorectal cancer patients to
assess outcome of reduced chemotherapy dosage.
Methods
Study design
A retrospective analysis was performed based on clinical
data obtained from the population-based clinical cancer
registry at the Regensburg Tumor Center in Eastern
Bavaria, Germany. Epidemiological data and survival
were investigated in a cohort of colon cancer diagnosed
between 2004 and 2012 receiving chemotherapy in the
outpatient clinic of the University Medical Center
Regensburg. Patients with stage IV colorectal cancer
undergoing palliative combination chemotherapy were
divided into dose reduction (≤80%) and full dosage
(100%) groups. We intend to analyze survival time by
Kaplan Meier method and to estimate 2- and 3-year sur-
vival rates and mean and median survival time. Data col-
lection and retrospective analysis of patient information
were anonymized in accordance with the Declaration of
Helsinki, and in line with the Bavarian Law of Cancer
Registration.
Background and data collection
The baseline cohort of the present study consisted of pa-
tients with the ICD-10-GM (http://www.dimdi.de/static/
de/klassi/icd-10-gm/index.htm) diagnosis C18, i.e. a ma-
lignant neoplasm of colon. 109 patients with advanced
stage colon carcinoma (UICC Stage IV) with histologi-
cally confirmed adenocarcinoma of the colon between
2002 and 2012 receiving palliative chemotherapy in our
University Medical Center were included in the study.
Neuroendocrine tumors were excluded. 3 Patients re-
ceiving only 5FU based chemotherapy regimens without
Irinotecan or Oxaliplatin were excluded. Prior to pallia-
tive chemotherapy, 72 patients received palliative or
oncological tumor resection. In this subgroup, the
diagnosis of metastasized colon cancer was made during
surgery or in follow up examinations. Patients were rou-
tinely assessed prior to chemotherapy by a physician
trained in oncology. Efficacy evaluation was performed
by CT scans in 3-month intervals. Patients who died of
cancer unrelated causes and patients with death within
one month after start of palliative chemotherapy were
censored.
Baseline characteristics are shown in Table 1. For
assessing comorbidities a scoring according to the
Charlson Score comorbidities index [10] was performed
Additional file 1: Table S1. Patients receiving either
FOLFOX, FOLFIRI or sequentially both chemotherapy
regimens were included in this study. Mode of adminis-
tration was exclusively i.v.. Chemotherapy dosing values
were calculated and registered with a chemotherapy
planning software (OnkoDAT®) [11]. A patient was con-
sidered receiving reduced dosage of chemotherapy if he
received ≥3 cycles of less than 80% of 5FU, Oxaliplatin,
or Irinotecan. Survival information were obtained from
the Regensburg Tumor Center founded in 1991. The
Cancer registry includes epidemiological and clinical
data from all consenting patients with malignancies
diagnosed and treated in Eastern Bavaria (2.1 million
population). All data were extracted, recorded, and fed
into a central database by trained personnel. The pa-
tients’life status and disease recurrence were ascertained
from clinical reports, death certificates issued by the
local public health departments, and the registration
offices of the respective residential districts. Data were
processed and secured according to the Bavarian Law of
Cancer Registration.
Statistical analysis
Continuous data were described as means, median,
minimum, maximum values and standard deviation,
and categorical data were expressed as absolute
frequencies and relative percentages. Patient charac-
teristics were compared with t-tests for normally
distributed continuous data, otherwise by means of
non-parametric Mann-Whitney-U- and Chi-square
tests for categorical variables. Tumor-specific survival
rates (OS) were analyzed from the start of palliative
chemotherapy until the event of death or last patient
contact. Survival rates of patients with and without
dose reduction were described by Kaplan-Meier analysis.
Survival differences were tested for statistical significance
by the two-sided Log Rank in Kaplan-Meier analyses; the
level of significance was set to 0.05. The follow-up period
and survival times were right censored using December
31, 2012 as cut-off date. To determine the influence of
further co-variables on overall survival, we performed
univariable and multivariable regression analysis using
Cox proportional hazard models. In multivariable analysis,
the hazard ratio (HR) was adjusted for the co-variables
age, sex, TNM status, grading, lymph vessel invasion, vein
invasion, Charlson score for comorbidities, surgery and
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Table 1 Patient characteristics according to dosage reduction and in total
Dosage reduction
Yes (<=80% dosage) No (=100% dosage) Total T-test Chi
2
N(%) N(%) N(%) pvalue
Age Mean/Median 56.5 59.0 58.4 58.0 57.6 59.0 .440
< 65 32 69.6% 42 66.7% 74 67.9% .749
> = 65 14 30.4% 21 33.3% 35 32.1%
Sex Male 29 63.0% 46 73.0% 75 68.8% .267
Female 17 37.0% 17 27.0% 34 31.2%
T stage T3 17 37.0% 23 36.5% 40 36.7%
T4 22 47.8% 22 34.9% 44 40.4% .205
Tx 7 15.2% 18 28.6% 25 22.9%
N stage N0 4 8.7% 5 7.9% 9 8.3%
N1 14 30.4% 16 25.4% 30 27.5% .796
N2 18 39.1% 23 36.5% 41 37.6%
Nx 10 21.7% 19 30.2% 29 26.6%
Grading G2 27 58.7% 40 63.5% 67 61.5%
G3 18 39.1% 19 30.2% 37 33.9% .419
Gx 1 2.2% 4 6.3% 5 4.6%
L stage L0 6 13.0% 7 11.1% 13 11.9%
L1 23 50.0% 15 23.8% 38 34.9% .010
Lx 17 37.0% 41 65.1% 58 53.2%
V stage V0 13 28.3% 11 17.5% 24 22.0%
V1 14 30.4% 10 15.9% 24 22.0% .030
Vx 19 41.3% 42 66.7% 61 56.0%
Charlson Comorbidity Score 6 32 69.6% 44 69.8% 76 69.7%
7 7 15.2% 13 20.6% 20 18.3%
8 6 13.0% 4 6.3% 10 9.2% .336
9 0 0.0% 2 3.2% 2 1.8%
10 1 2.2% 0 0.0% 1 0.9%
Oncological resection/Surgery Yes 35 76.1% 37 58.7% 72 66.1% .059
No 11 23.9% 26 41.3% 37 33.9%
No. of CTX lines 1 11 23.9% 17 27.0% 28 25.7%
2 23 50.0% 34 54.0% 57 52.3%
3 11 23.9% 11 17.5% 22 20.2% .587
4 0 0.0% 1 1.6% 1 0.9%
5 1 2.2% 0 0.0% 1 0.9%
Biological Yes 21 45.7% 26 41.3% 47 43.1% .648
No 25 54.3% 37 58.7% 62 56.9%
CTX regimen sequence FOLFOX- > FOLFIRI 30 65.2% 27 42.9% 57 52.3%
FOLFIRI- > FOLFOX 3 6.5% 13 20.6% 16 14.7% .044
FOLFOX 10 21.7% 13 20.6% 23 21.1%
FOLFIRI 3 6.5% 10 15.9% 13 11.9%
Total 46 100.0% 63 100.0% 109 100.0%
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further chemotherapy, i.e. number of lines and regimens.
Again, a two-sided p-value of 0.05 was considered to indi-
cate statistical significance. Hazard ratios and correspond-
ing 95% confidence intervals (CI) were calculated and
considered statistically significant when the CI excluded 1.
0. All analyses were performed using IBM SPSS Statistics,
version 23.0.
Results
Reduction of chemotherapy dosage
Among 109 patients 67% (73/109) of the patients
received both (FOLFOX and FOLFIRI) regimens sequen-
tially. The majority 78% (57/73) began with FOLFOX
and changed during the course of disease to FOLFIRI,
21% (23/109) of the patients received exclusively FOL-
FOX, whereas FOLFIRI chemotherapy regimens were
used exclusively in 12% (13/109) of patients. 43% (47/109)
received additional treatment with a biological agent.
Upon discretion of the treating physician, in most
cases dosage was reduced to 80% of the protocol dosage.
We therefore used reduction to 80% of protocol dosage
as a cut off to investigate the clinical effectiveness of
standard chemotherapy in patients receiving reduced
dosage.
In 42% (46/110) of our patients a dose reduction to
80% or less was performed during the course of chemo-
therapy. Those 46 patients who received a dose reduc-
tion, received in average 14 chemotherapy cycles in our
clinic (Mean: 13.7 cycles; + −12.3 cycles). Patients
continuing on protocol chemotherapy doses, received
10.5 cycles (stdv 10.8, p= 0.149). In more detail, the
majority of chemo cycles (72%, median: 81%; stdv: 27%)
in these patients were applied with reduced dosage.
Average cumulative dosage and dose intensities for 5-
Flourouracil, Irinotecan and Oxaliplatin were calculated
for full dosage and dose reduction subgroups (Table 2).
As expected, relative dose intensities were significantly
different. Even though a trend to a higher cumulative
dosage can be observed, t-test revealed no significant
differences for cumulative dosages.
Dose reduction in subgroups –analysis of distribution
In preparation to compare survival rates, we compared
the distribution of the co-variables age, sex, TNM status,
grading, lymph vessel invasion, vein invasion, Charlson
score for comorbidities, surgery and further chemother-
apy, i.e. number of lines and regimens in the dose reduc-
tion and full dosage group.
No significant difference was seen except for lymph
vessel and vein invasion, CTX regimen and adverse side
effects, when Chi-square test for independence was per-
formed. As expected, subgroups of patients suffering
from severe symptoms/side effects related to chemother-
apy such as diarrhea (p< 0.001), PNP (p< 0.001), or
neutropenia (p= 0.02) received dose reduction almost
exclusively. Detailed summary of the distribution of dose
reductions in different subgroups is given in Table 1.
Reasons for dose reduction
The most common reason for dose reduction of chemo-
therapy was neutropenia (30%). Other common side
effects leading to dose reduction were polyneuropathy
(16%) and diarrhea (14%). Polyneuropathy was generally
due to treatment with Oxaliplatin (10 patients, 14%).
Diarrhea was observed at similar rates in both Oxalipla-
tin (6/48 patients, 13%) and Irinotecan treated patients
(4/30 patients, 13%). Less common reasons for dose
reduction included mostly symptom-related causes,
hyperemesis, worsening of general condition, hand foot
syndrome and mucositis. A complete overview of the
reasons for dose reduction of chemotherapy is shown in
Table 3.
Table 2 Dose intensity and cumulative dosage for the dose-reduction and full dosage subgroups
Substance Dose group Mean in mg standard deviation p-value
Cumulative Dosage 5-Fluorouracil 100% 54,934 55,617 0.42
< 80% 64,321 61,824
Oxaliplatin 100% 1046 852 0.34
< 80% 1245 976
Irinotecan 100% 2861 3295 0.77
< 80% 3099 3296
Dose intensity 5-Fluorouracil 100% 5383 1450 0.002
< 80% 4547 1178
Oxaliplatin 100% 173 31 0.03
< 80% 156 35
Irinotecan 100% 311 74 0.04
< 80% 274 65
P-values were calculated with t-test
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Survival in dose reduced versus full dose 5-FU based
regimens
In terms of tumor-specific survival, we did not observe
any differences between patients receiving full dose and
reduced dose chemotherapy (Log Rank, p=0.430)(Fig. 1).
Median survival for patients receiving full dosage was 13.
0 months (Mean 19.1), for patients with dosage reduction
14.9 months (Mean 21.2). Two-year survival was 19.5%
(full dosage) vs 35.8% (reduced dosage). Three-year
survival rate of patients with full dose and reduced dose
chemotherapeutic treatment was 19.5% and 9.1%. A uni-
variable Cox regression rendered a hazard ratio of 0.841
(95% CI 0.547–1.294; p=0.431) for the dose reduction
group versus full reduction. After adjustment for age, sex,
TNM status, grading, lymph vessel invasion, vein invasion,
Charlson score for comorbidities, surgery and further
chemotherapy, i.e. number of lines and regimens in a mul-
tivariable Cox regression analysis the hazard ratio for pa-
tients with dose reduction was 0.861 (95% CI 0.492–1.506;
p=0.600)Table4.
Efficacy –subgroup analysis
We performed a subgroup analysis to identify potential
subgroups in which reduction of chemotherapy might be
beneficial or harmful. Table 5summarizes survival in
several subgroups with respect to dose reduction. In
most subgroups, no significant differences in survival
were observed. Unexpectedly, in the stage N2 lymph
node subgroup with 41 patients dose reduction was
associated with improved survival (Log Rank p= 0.024).
Discussion
Over the past decades a considerable progress has been
made in the management of colorectal cancer by med-
ical oncologists. The studies leading to these advances
were predominantly performed on young and healthy
populations; hence the common practice of dose reduc-
tion in elderly or frail patients was not a primary issue.
Thus, these studies were mainly performed on a sub-
group not suffering from relevant co-morbidities and
being in good performance status.
In recent years, the need to investigate real life popula-
tions and the common practice of dose reduction has
been recognized by the scientific community. However,
(retrospective) studies investigating the effects of dose
reduction in a palliative setting have been published but
are still sparse. In 2001, a retrospective analysis of
Fig. 1 Kaplan Meier analysis of survival in patients with reduced and full dosage of standard chemotherapy back bone (FOLFIRI, FOLFOX). Survival
analysis showed no difference in survival (p= 0.430, Log Rank)
Table 3 Reasons for dose reduction
Distribution of adverse effects N%
Leukopenia 20 30%
Polyneuropathy 11 16%
Diarrhea 10 14%
Worsening of general condition 6 9%
Hand-foot-syndrome 5 7%
Thrombocytopenia 5 7%
Hyperemesis 3 4%
Elevated bilirubin 2 3%
Deterioration of kidney function 1 1%
Mucositis 1 1%
Not specified 5 7%
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patients with Stage II-III colon cancer demonstrated
that in an adjuvant setting 5-FU based chemotherapy
may be safely administered in the elderly, but this
study did not elaborate the dose reduction needed
[12]. In 2011 Langley et al. published the Focus II
study, a first randomized controlled trial including
only the frail and old patients with colorectal cancer.
This study incorporated primary dose reduction as
the standard treatment for all treatment arms. How-
ever, it was not designed to investigate whether dose
Table 4 Results of univariable and multivariable Cox-regression for survival according to dosage reduction
95% CI for HR
pvalue Hazard ratio Lower Upper
Univariable Cox-regression
Dosage reduction No 1.000
Yes .431 .841 .547 1.294
Multivariable Cox-regression
Dosage reduction No 1.000
Yes .600 .861 .492 1.506
Age continuous .118 .981 .958 1.005
Sex Male 1.000
Female .446 1.264 .692 2.310
T stage T3 1.000
T4 .229 1.541 .761 3.117
TX .890 .916 .265 3.170
N stage N0 1.000
N1 .981 .988 .345 2.824
N2 .713 1.225 .415 3.615
NX .927 .922 .161 5.266
Grading G2 1.000
G3 .302 1.354 .761 2.407
GX .458 .576 .134 2.474
L stage L0 1.000
L1 .726 1.215 .408 3.620
LX .289 .469 .116 1.901
V stage V0 1.000
V1 .872 .920 .334 2.531
VX .164 2.620 .675 10.165
Charlson Score 6 1.000
7 .750 .892 .443 1.797
8 .909 .954 .426 2.138
9 .609 1.605 .262 9.822
Oncological resection/Surgery No 1.000
Yes .227 .483 .149 1.570
No of CTX lines continuous .797 1.053 .712 1.556
Biological CTX No 1.000
Yes .178 .663 .364 1.207
CTX regimen FOLFOX- > FOLFIRI 1.000
FOLFIRI- > FOLFOX .691 1.177 .527 2.627
FOLFOX .001 3.601 1.656 7.827
FOLFIRI .921 .945 .309 2.892
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reduction itself could be performed if required with-
out affecting PFS or OS [13].
In order to evaluate whether dose reduction has an
effect on survival in patients with advanced colorectal
cancer and suffering from side effects under standard
treatment dose, we performed this retrospective ana-
lysis of such patients in our outpatient clinic. In our
current study, we chose a cutoff for dose reduction of
80% since in our experience a dose reduction to 80%
is a commonly performed reduction in case of
adverse reactions. Since only very few patients re-
ceived further dose reduction (n= 4), we chose not to
include these patients as a separate group with dose
reduction of ≤50% but rather included these patients
in the group of patients with reduction of chemother-
apy dosage. Thus, the overall average dose reduction
in this patient group was even more than 20%. In
thesepatients,adosereductionwasappliedtothe
Table 5 Subgroup analysis. Comparison of the survival after dose reduction versus full dosage in different subgroups analyzed by
Kaplan-Meier procedure and Log-Rank test (Chemotherapy (CTX))
Dosage reduction Log-rank
Yes (≤80%) No (100%)
Mean (Median) survival in months p-value
Age < 65 22.0 (14.6) 17.1 (12.0) .170
≥65 18.8 (14.9) 21.2 (15.8) .764
Sex Male 23.5 (16.0) 18.6 (14.9) .339
Female 17.2 (13.1) 17.4 (12.7) .170
T stage T3 27.8 (26.4) 25.8 (14.9) .525
T4 15.6 (13.8) 14.1 (12.7) .960
Tx 24.3 (10.4) 14.1 (7.7) .273
N stage N0 25.9 (23.6) 30.5 (14.9) .851
N1 20.7 (13.9) 24.1 (12.3) .669
N2 21.3 (26.4) 13.3 (16.7) .024
Nx 20.4 (16.0) 13.2 (7.7) .294
Grading G2 24.1 (17.8) 22.0 (16.1) .570
G3 17.5 (14.5) 10.6 (10.4) .062
Gx 26.8 (26.8) 25.5 (3.0) .808
L stage L0 19.7 (17.8) 30.7 (21.0) .541
L1 23.3 (13.9) 16.9 (17.5) .485
Lx 18.1 (14.8) 16.3 (12.0) .561
V stage V0 28.8 (23.6) 26.9 (21.0) .828
V1 20.3 (13.9) 15.7 (16.7) .311
Vx 16.9 (14.5) 15.9 (11.8) .671
Charlson Score for Comorbidities 6 20.6 (14.8) 19.6 (12.0) .424
7–10 23.3 (15.0) 19.6 (16.1) .632
Oncological resection/Surgery Yes 22.1 (14.9) 23.8 (17.5) .997
No 19.6 (12.9) 12.9 (7.6) .301
No. of CTX lines 1 10.1 (10.4) 8.4 (3.0) .565
2 23.1 (17.9) 23.5 (15.8) .896
3 24.7 (23.6) 16.6 (12.3) .238
Biological CTX Yes 29.4 (26.8) 23.5 (11.8) .371
No 13.2 (13.1) 14.6 (14.9) .823
CTX regimen sequence FOLFOX- > FOLFIRI 22.0 (20.2) 26.5 (17.5) .425
FOLFIRI- > FOLFOX 12.3 (12.3) 16.4 (14.9) .631
FOLFOX 9.7 (12.9) 7.7 (3.6) .829
FOLFIRI 62.3 (90.7) 13.0 (3.9) .300
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majority of cycles (72%), emphasizing that this group
predominantly received a reduced chemotherapy
dosage throughout the course of therapy.
In daily clinical routine, clinicians are more likely to
reduce the dose of elderly patients. Therefore, one might
assume that in the elderly (> 65 years) in our collective
dose reduction would be more common. However, dose
reduction was evenly distributed among younger and
elderly patients and thus independent of age. Also,
additional subgroup analysis (T-stage, N-stage, M-stage,
gender, and chemotherapy regimen) showed an even
distribution of dose reduction.
Since clinical trials showed the effectiveness of per
protocol chemotherapy, in theory a reduced dosage of
chemotherapy would be expected to affect survival,
which has also been confirmed by several publications
for other entities [9]. It is therefore common belief, that
dose reduction should be avoided. Additionally, clini-
cians choose a dose reduction often due to symptom-
related causes or deterioration of laboratory findings.
Many of these reasons (recurring neutropenia, deterior-
ation of general condition) are associated with a poor
clinical outcome. Therefore, one might assume, that
dose reduction is more common in patients with clinical
features suggesting a poor prognosis. Interestingly,
statistical analysis of our data showed that a moderate
dose reduction does not affect survival significantly.
In a recently published manuscript, the influence of
the relative dose intensity (RDI, of adjuvant 5FU and
Oxaliplatin combination treatment in veterans with
Stage III colon cancer had been further investigated.
Aspinalli et al. showed that a major reduction of RDI
(< 70%) to be associated with worse overall survival in
this patient group [14]. In addition to the bias of the
patient group which consisted mainly of male veterans,
there was a bias towards dose reduction in the frail and
elderly. In comparison with our study also the magnitude
of dose reduction was more pronounced.
When Oxaliplatin was introduced to the treatment of
CRC, a retrospective analysis of three phase II studies of
pretreated colorectal cancer showed that higher dose
intensity leads to improved survival [15]. In contrast to
our study, these study populations had been pretreated
and in two out of the three studies patients’inclusion
age was limited to younger patients. In another more
recent study, Nakayama et al. showed that a dose reduc-
tion in metastasized CRC led to poorer survival of the
respective (Irinotecan) patient group. A comparison with
our study population is difficult, since per protocol
Irinotecan dosage in Japan is already 12% lower than in
the western countries and further dose reduction adds
up to even more pronounced dose reductions. For the
patient group receiving Oxaliplatin only PFS was signifi-
cantly associated to RDI [16].
Nevertheless, in clinical practice, patients often experi-
ence side effects and need dose reduction. For these
patients, our data in treatment-naive patients suffering
from stage IV colorectal cancer, suggest that a moderate
dose reduction does not necessarily result in less effi-
cacy. Until now, only limited data were reported on this
issue, which we believe to be of high clinical relevance.
Thus, we suggest further randomized studies potentially
leading to more personalized treatment strategies
depending on tolerance of treatment and co-morbidities
and a more side effect oriented approach on chemo-
therapy dosing.
Conclusion
In our group of patients with colorectal cancer
treated in a palliative setting, the need for a moderate
reduction of chemotherapy due to side effects has no
measurable effect on survival. This may be in part
due to better adaption to interindividual pharmaco-
kinetics and to a longer treatment of patients with
reduced chemotherapy dosage if side effects cause
dose reduction.
Additional file
Additional file 1: Table S1. Summary of comorbidities. (DOCX 13 kb)
Acknowledgements
We greatly appreciate all the authors for their endeavor.
Availability of data and materials
The datasets used and/or analysed during the current study are available
from the corresponding author on reasonable request.
Comment
Part of this study was presented at the ASCO GI Meeting 2017 San Francisco.
Permission was obtained for final publication [17].
Authors’contributions
SM, MG, AT carried out the primary data analysis. SM, AT, SFF, CS, HJS, CO,
ES, PW, MV, WH, ME, MR, PF, MKS were responsible for the treatment of
patients with CRC at the Regensburg University Medical Center. SM, AT, MG,
PW and HJS helped to draft the manuscript. All authors read and approved
the final manuscript.
Ethics approval and consent to participate
Due to the analysis of data from a clinical cancer registry, no ethics approval
was necessary. This was confirmed by the Ethics Committee at the
Regensburg University, Regensburg, Germany.
Competing interests
The authors declare that they have no competing interest.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Munker et al. BMC Cancer (2018) 18:455 Page 8 of 9
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Author details
1
Department of Internal Medicine I, University Hospital Regensburg,
Franz-Josef-Strauss Allee 11, 95053 Regensburg, Germany.
2
Cancer Center,
Institute for quality assurance and health services research, University of
Regensburg, Regensburg, Germany.
3
Medical Informatics Unit, University
Hospital Regensburg, Regensburg, Germany.
4
Department of Surgery,
University Hospital Regensburg, Regensburg, Germany.
5
Department of
Radiology, University Hospital Regensburg, Regensburg, Germany.
6
Department of Internal Medicine III, University Hospital Regensburg,
Regensburg, Germany.
7
Department of Pathology, University Hospital
Regensburg, Regensburg, Germany.
8
MedicDAT GmbH, Regensburg,
Germany.
Received: 23 May 2016 Accepted: 16 April 2018
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