cancer chemotherapy near the end of life: the time

Tumori, 93: 417-422, 2007
CANCER CHEMOTHERAPY NEAR THE END OF LIFE:
THE TIME HAS COME TO SET GUIDELINES FOR ITS APPROPRIATE USE
Andrea Angelo Martoni1, Stephan Tanneberger2, and Vita Mutri1
1
Medical Oncology Unit, S. Orsola-Malpighi Hospital, Bologna; 2Fondazione ANT Italia, Bologna, Italy
Aims and background: This study retrospectively analyzes the use
of chemotherapy in patients who died of advanced cancer either
after having been in care at the Medical Oncology Unit (MOU) of
the University Hospital of Bologna, Italy, or after having been assisted in their terminal disease phase by the Bologna Oncological Hospice at Home (OHH) of the Associazione Nazionale Tumori (ANT) Italia Foundation. In the latter group, the prescription
and delivery of chemotherapy had been performed by doctors of
medical oncology departments other than the MOU.
Results: Between January 2003 and September 2005, 793
deaths of patients were recorded (MOU: 312; OHH: 481). At
least one cycle of chemotherapy had been received by 445 patients (56.1%). The most common cancer types were lung can-
cer (26.7%), colorectal cancer (14.8%), and breast cancer
(11.2%). At the time of the last chemotherapy (l-CT), the median age of the patients was 68 years (range, 22-98 years) and
the median KPS was 70 (range, 40-100). The median interval
between l-CT and death was 71 days (range, 1-1913 days). One
hundred and one patients (22.7%) had received their l-CT in
the last 30 days of their life, 86% of them having intermediately
chemosensitive (71%) or chemoresistant (14%) tumors. The
l-CT in the last month of life was first line in 56% of cases and
consisted of costly new-generation drugs in 36.6% of cases.
Conclusions: The study suggests the urgent need to lay down
guidelines for the appropriate use of chemotherapy in advanced cancer patients with a short life expectancy.
Key words: end of life, palliative chemotherapy, terminal patient.
Introduction
Although many observers believe that cancer
chemotherapy is overused at the end of life, there are no
publications specifically dedicated to this topic in Europe. This is in contrast to the United States, where clear
trends in the aggressiveness of cancer care near the end
of life have been reported1,2. The conclusions of the US
reports stress that it is questionable whether such care
has positive effects on survival or quality of life.
Undoubtedly, the problem deserves greater attention
from oncologists. Overtreatment at the end of life is
mainly an ethical problem in palliative care and one of
the great sources of patient anxiety. Moreover, overuse
of drugs and spiraling health-care costs are a well-known
challenge to public health systems. However, performing
a delicate balancing act between cure and palliation often
becomes an ethical dilemma since the prediction of an
individual patient’s life expectancy is accurate in only
about 30-40% of cases3,4 and clinicians consistently overestimate survival5. Discontinuing anticancer treatment
therefore requires much skill on the part of the doctor.
Furthermore, mass-media-educated patients and their
families increasingly contribute to putting pressure on
the medical oncologist “to take action”.
By means of the present study we have tried to find
an answer to the following questions concerning the use
of cancer chemotherapy at the end of life:
1. Is the situation in a European area different from that
in the United States and is it influenced by the skepticism expressed in some American papers?
2. What is the clinical status of the patients receiving
such chemotherapy?
3. Is there a difference between patients with
chemotherapy-sensitive and chemoresistant tumors?
4. What types of drugs are used?
The study analyzes the use of chemotherapy (CT)
and the interval between the last CT course and death in
patients who died of advanced cancer and who had been
treated at a university hospital medical oncology unit or
had been assisted in their terminal disease phase by a
non-profit home-care program in the area of Bologna,
northern Italy, after having received chemotherapy from
medical oncologists in other hospitals of the Emilia-Romagna region.
Materials and methods
Patients
This is a retrospective study carried out on cancer patients followed by the Medical Oncology Unit of S. Orsola-Malpighi Hospital in Bologna (MOU) or by the Oncological Hospice at Home (OHH) of the Associazione
Nazionale Tumori (ANT) Italia Foundation in the
Bologna area, who died between January 2003 and September 2005. The OHH is a non-profit-making organization that provides home assistance to patients with very
advanced cancer who are generally no longer suited to
receive cytotoxic chemotherapy6. The OHH patients had
previously been followed up by a hospital department
and had received some form of CT. In the present analy-
Correspondence to: Andrea Angelo Martoni, Medical Oncology Unit, S. Orsola-Malpighi Hospital, Via Albertoni 15, 40138 Bologna, Italy.
Tel +39-051-6362206; fax +39-051-6362207; e-mail martoni@aosp.bo.it
Received October 16, 2006; accepted February 23, 2007.
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AA MARTONI, S TANNEBERGER, V MUTRI
sis, patients assisted by MOU and subsequently by OHH
were assigned to the MOU series. Consequently, the patients of the OHH group received cytotoxic chemotherapy treatment at a hospital department other than the
MOU in the Bologna province or other areas of EmiliaRomagna. The analysis was carried out using MOU and
OHH files, searching for patients who died in the period
studied. Data concerning sex, age and type of primary tumor were collected from these patients’ case histories.
Definition of last chemotherapy
Patients who had begun at least one CT regimen for advanced disease at any time during their lifetime were selected from the general group of deceased patients. Last
chemotherapy (l-CT) was defined as the last administration of anticancer drugs. The type of cytotoxic agents, the
number of the cycle and of the treatment line, the interval
in days between the date of last administration and the
date of death, age and KPS at the time of l-CT were collected from the patient’s case history and analyzed. The
following classification was adopted in order to analyze
the results according to tumor chemosensitivity: highly
sensitive tumors (breast, ovary, testis, lymphoma and
leukemia), intermediately sensitive tumors (lung, colorectum, head and neck, esophagus, uterus, unknown primary,
bladder, peritoneum) and low chemosensitive/chemoresistant tumors (kidney, pancreas, melanoma, soft tissue
sarcomas, liver, CNS, stomach, prostate, thyroid). The cytotoxic agents were classified into 2 groups: 1) old-generation drugs and 2) new-generation drugs. The cost for the
hospital of each single anticancer agent was calculated on
a month-long treatment basis.
Data analysis
The data were collected in an Excel Windows-Office
XP (Microsoft) spreadsheet, by means of which they
were subsequently processed.
years but was higher in OHH patients than in MOU patients (77 vs 66 years). In the vast majority of patients
(94.2%) the cause of death was cancer, with no differences between the 2 series; in 5 patients (0.7%) death
was related to the toxicity of the treatments received.
Patients who had received CT
Four hundred and forty-five of the 793 deceased patients (56.1%) had received at least 1 cycle of chemotherapy for advanced cancer: 157 of these belonged to the
OHH series (35.3%) and 288 to the MOU series (64.7%).
The characteristics of the patients who had received CT
and the description of the l-CT are reported in Table 2.
This analysis refers to the total number of patients treated
without differentiating between the 2 series, as there were
no substantial differences, with the exception of the median age of the patients, which continued to be higher in
the OHH than in the MOU series (71 vs 66 years). The
interval between l-CT and death was 71 days (range,
1-1913 days). A shorter interval was reported for patients
with lung and pleura tumors than for patients with colorectal, breast and other tumors (46 days vs 75, 80 and 78
days, respectively). In 79.1% of patients l-CT was delivered over the last 6 months. Information on KPS at the
time of l-CT was available only for the MOU series: the
median KPS was 70 (range, 40-100). The most common
primary tumors were lung and pleural cancer, colorectal
cancer and breast cancer, while other primary tumors accounted for 47.3%. The tumor distribution according to
chemosensitivity was as follows: high 19.8%, intermediate 58.0%, and low 22.2%. The majority of the patients
belonging to the third group had been treated in their last
6 months of life. L-CT consisted of conventional drugs in
57.1% of cases, while 35.8% has been treated with newgeneration drugs. In about 50% of the patients, l-CT was
first-line CT and in 46.5% of cases it was at the fourth or
subsequent cycle.
Chemotherapy in the last month of life
Results
A total of 793 deceased patients were identified in the
time period considered: 312 in the MOU database and
481 in the OHH database. Their general characteristics
are reported in Table 1. The median age at death was 73
Table 3 shows the main characteristics of 101 patients, corresponding to 22.7% of patients who had received CT and to 12.7% of all considered patients, who
had received CT in their last 30 days of life. They included 72.3% men and 69.3% patients aged ≥65 years.
Table 1 - General characteristics of deceased patients
General characteristics
Patients screened
Median age (range)
Men/women
Causes of death
Cancer
Toxicity
Other causes
Unknown
Patients who had received palliative CT
OHH
MOU
Total
481
77 (33-103)
259 (54%) / 222 (46%)
312
66 (22-89)
184 (59%) / 128 (41%)
793
73 (22-103)
443 (56%) / 350 (44%)
461 (95.8%)
2 (0.4%)
18 (3.9%)
–
157 (32.4%)
286 (91.7 %)
3 (1%)
9 (3.1%)
14 (4.9%)
288 (92.3%)
747 (94.2%)
5 (0.7%)
27 (3.6%)
14 (1.9%)
445 (56.1%)
OHH, Oncological Hospice at Home; MOU, Medical Oncology Unit, University Hospital, Bologna; CT, chemotherapy.
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GUIDELINES FOR CANCER CHEMOTHERAPY NEAR THE END OF LIFE
Table 2 - Patient and CT characteristics according to interval between last CT and death
Pts who had received CT
No. (%)
Pts with last CT
in last 180 days before death
No. (%)
Pts with last CT
>180 days before death
No. (%)
Patients who had received palliative CT
445 (100)
352 (79.1)
93 (20.9)
Sex
Men
Women
264 (59.3)
181 (40.7)
216 (81.8)
136 (75.1)
48 (18.2)
45 (24.9)
Age
Median (range)
<65 years
≥65 years
68 (22-98)
176 (39.6)
269 (60.4)
67 (22-98)
150 (85.2)
202 (75.1)
71 (37-87)
26 (14.8)
67 (24.9)
KPS
Median (range)
70-100
<70
Data not available*
70
249
39
157
(40-100)
(56.0)
(8.7)
(35.3)
70
205
27
120
(40-100)
(82.3)
(69.2)
(76.4)
70
44
12
37
(40-100)
(17.7)
(30.8)
(23.6)
Primary tumor
Colorectal
Lung and pleura
Breast
Others
66
119
50
210
(14.8)
(26.7)
(11.2)
(47.3)
53
102
39
158
(80.3)
(85.7)
(78.0)
(75.3)
13
17
11
52
(19.7)
(14.3)
(22.0)
(24.7)
CT sensitivity**
High
Intermediate
Low
88 (19.8)
258 (58.0)
99 (22.2)
66 (75.0)
206 (79.8)
80 (80.8)
22 (25.0)
52 (20.2)
19 (19.2)
Cytotoxic drugs
Old drugs
New drugs
Data not available
254 (57.1)
160 (35.9)
31 (7.0)
196 (77.2)
133 (83.1)
23 (74.2)
58 (22.8)
27 (16.9)
8 (25.8)
Lines of CT
1
2-3
>3
Data not available
222
168
45
10
(49.9)
(37.8)
(10.1)
(2.2)
176
133
37
6
(79.3)
(79.2)
(82.2)
(60.0)
46
35
8
4
(20.7)
(20.8)
(17.8)
(40.0)
Number of cycles
1
2-3
>3
Data not available
79
154
207
5
(17.8)
(34.6)
(46.5)
(1.1)
62
131
156
3
(78.5)
(85.1)
(75.4)
(60.0)
17
23
51
2
(21.5)
(14.9)
(24.6)
(40.0)
*KPS at the time of the last CT not available in patients of OHH; **highly sensitive tumors: breast, ovary, testis, lymphoma and leukemia; intermediately sensitive tumors: lung and pleura, colorectal, head and neck, esophagus, uterus, unknown primary, bladder, peritoneum; low sensitive tumors: kidney,
pancreas, melanoma, soft tissue sarcoma, liver, CNS, stomach, prostate, thyroid.
KPS, Karnofsky performance status; CT, chemotherapy; OHH, Oncological Hospice at Home.
KPS was not available in 30.7% of the cases and was
70-100 in 60.4% and <70 in 8.9%. Lung and pleural
cancer accounted for 40.6% of this group of patients,
colorectal cancer for 16.8% and breast cancer for 4%.
The majority (71.2%) of patients had intermediately
chemosensitive tumors, while patients with highly
chemosensitive and poorly chemosensitive tumors
were 14.9% and 13.9%, respectively. The l-CT was
first line in more than half of these patients (56.4%)
and it was at the first cycle in 25.7%, at the second or
third cycle in 39.6%, and at the fourth or subsequent
cycle in 34.7% of cases. The l-CT was the first cycle of
first-line treatment in 15 (15%) patients: they had lung
cancer (7), colorectal cancer (3) and other tumors (5); 4
of these patients had chemoresistant tumors. Table 4
describes the type of cytotoxic drugs included in the
last CT. It was represented by old-generation-drug-
based regimens in 55.5% of cases and new-generationdrug-based regimens in 36.6% of patients. The most
common drug in the new-drug-containing regimens
was gemcitabine (19.8%). The mean monthly cost of
old-generation and new-generation drugs was € 70.38
(range, € 3.70 to € 215.60) and € 954.92 (range, €
725.67 to € 1289.90), respectively.
Discussion
In the majority of patients with advanced cancer the
aim of anticancer drug treatment is palliation, which
comprises improvement in quality of life and sometimes
overall survival. The use of palliative chemotherapy in
advanced cancer patients has progressively grown over
the last few decades and it also involves increasing numbers of patients with a short life expectancy. The market
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AA MARTONI, S TANNEBERGER, V MUTRI
Table 3 - Analysis of last CT in the last month of life
No.
(%)
101
(100)
73
28
(72.3)
(27.7)
Age
Median (range)
<65 years
≥65 years
69
31
70
(22-84)
(30.7)
(69.3)
KPS
Median (range)
70-100
<70
Data not available*
70
61
9
31
(40-100)
(60.4)
(8.9)
(30.7)
Primary tumor
Lung and pleura
Colorectal
Breast
Others
41
17
4
39
(40.6)
(16.8)
(4)
(38.6)
CT sensitivity**
High
Intermediate
Low
15
72
14
(14.9)
(71.2)
(13.9)
Line of CT
1st
2nd-3rd
>3rd
Data not available
57
34
9
1
(56.4)
(33.7)
(8.9)
(1.0)
Number of cycles
1
2-3
>3
26
40
35
(25.7)
(39.6)
(34.7)
Patients with last CT in the last 30 days of life
Sex
Men
Women
*KPS at the time of the last CT not available in patients of OHH; **definition is reported in the section Materials and methods.
KPS, Karnofsky performance status; CT, chemotherapy; OHH, Oncological Hospice at Home.
Table 4 - Cytotoxic drugs included in the last CT in the last
month of life
Total number of patients
Cytotoxic drugs
Old-generation drugs*
New-generation drugs
Gemcitabine
Oxaliplatin
Capecitabine
Taxanes
Oral vinorelbine
Irinotecan
CT+monoclonal antibody
Data not available
No.
(%)
101
(100)
56
37
20
5
5
3
2
1
1
8
(55.5)
(36.6)
(19.8)
(5)
(5)
(3)
(2)
(0.9)
(0.9)
(7.9)
*Antimetabolites (methotrexate, fluoropyrimidines, cytosine arabinoside,
thiopurines, hydroxyurea); alkylating agents (melphalan); dialkyltriazenes (dacarbazine); anthracyclines (doxorubicin, epirubicin, daunomycin); bleomycin; mitomycin C; vinca alkaloids (vinblastine, vincristine); podophyllotoxin derivatives (VP-16); platinum analogs (cisplatin, carboplatin); mitoxantrone.
CT, chemotherapy.
availability of a greater number of anticancer drugs as
well as better supportive care has contributed to this
phenomenon. In addition, the increased use of CT in patients with advanced disease and with a poor life ex-
pectancy has been supported by large clinical trials carried out in the palliative care setting which have demonstrated limited advantages of some cytotoxic agents
compared with the best supportive therapy, with statistical power but with dubious clinical significance7,8.
As mentioned in the Introduction, many observers
believe that cancer chemotherapy is now overused at
the end of life, but up until now this issue has raised little interest in clinical research in Europe, with the exception of a few reports published as abstracts9,10. By
contrast, the subject has been much analyzed and discussed in the USA by Emanuel and coworkers11. These
authors studied chemotherapy use in cancer patients
who died in 1996, aged at least 66 years at death, in the
six 30-day periods preceding death at the inpatients’,
the outpatients’, or carrier Medicare files in Massachusetts and California. Their study showed that 26% to
33% of patients had received CT in the last 6 months of
life and that 9% had received it in the last month of life,
with no differences in the prevalence of use between
people with cancer responsive to CT and cancer unresponsive to CT.
Our study illustrates the situation in Bologna, capital
of the Emilia-Romagna region in northern Italy, as an
example of what typically occurs in a European area. It
shows that 56.1% of deceased patients had received at
least one CT cycle for advanced disease; this amounts
to 44.4% if one considers the last 6 months of life. The
percentage was lower in the OHH series than in the
MOU series (32.4% vs 92.3%). As the percentage of
OHH patients who had received CT for advanced disease is similar to that reported in the American study, it
is likely that the OHH sample was representative of the
complex and varied case mix of advanced cancer patients destined to die because of the disease, also including patients with very advanced disease at diagnosis and/or severe deterioration in their clinical status
and/or very old age who had been excluded from cytotoxic CT. On the other hand, patients belonging to the
hospital series represent a population selected specifically to receive anticancer therapy.
As the study aimed to outline the use of CT especially in the last phase of the disease, we focused on those
patients who received l-CT in the last month of their
lives. They represented 22.7% of those who had received CT and 12.7% of the whole series of deceased
patients. The latter percentage is similar to that observed by Emanuel and colleagues11. Although there are
many differences between the 2 studies in terms of data
selection and collection, the nearly overlapping fraction
of cancer patients who received CT at the end of life
might express a common and generalized phenomenon.
As in the US study, the use of CT in the last month of
life in our study did not appear to be influenced by the
tumor’s chemosensitivity: most of the patients had tumors with intermediate or low chemosensitivity. In addition, our study indicates that in more than half of the
patients, the l-CT in the last month of life was first line.
The same observation was reported in an another Italian
GUIDELINES FOR CANCER CHEMOTHERAPY NEAR THE END OF LIFE
study performed in the area of Venice and published only in abstract form, in which 54% of 164 cancer patients
treated with CT in the last month of life had not previously received CT for advanced disease10.
These findings raise questions as to a) the motivations that are at the basis of the decision to start CT in
very advanced cancer patients; b) the aims of this CT
and the patient selection criteria; and c) the doctor’s
skill in formulating accurate prognostic judgments.
One of the main reasons for deciding to start CT for
very advanced disease is the patient’s request. A recent
systematic review of the literature regarding patient
preferences for CT near the end of life shows that the
patient’s perspective is different from that of a person in
good health. Patients are willing to undergo treatments
that have minor benefits with major toxicity. However,
at the same time, the patient’s request does not stem
from realistic and truthful information on the different
treatment options and the likelihood of successful treatments or adverse effects12. On the other hand, the reasons for prescribing CT in patients with poorly responsive or even resistant tumors were clearly not based on
scientific evidence. Many factors concerning the information/communication process may underlie the physician’s behavior: the physician may not be able to inform; the physician does not provide information so as
to avoid emotional distress; the physician chooses not
to be fully honest in an attempt to preserve hope; the
physician does not inform the patient because the patient is unable to accept what the physician is saying13.
Increasing the physician’s awareness as well as providing correct and complete information suited to the
patient’s cultural, psychological and social level and activating earlier a palliative care program at home or at a
hospice institution is the path to be followed in order to
lessen and even abolish this improper use of CT.
In our study, more than 50% of patients who had received CT in the last month of life were at their first
line of treatment and 15% even at the first cycle of firstline treatment. As the majority of these patients suffered
from intermediately or poorly chemosensitive tumors, it
seems clear that also the clinical evaluation criteria at
the basis of the decision to prescribe CT are brought into question. Indeed, the palliative effect of CT may be a
reasonable objective in such patients even if it can only
be achieved in a minority. In these patients, the likelihood of a predominantly negative effect on their quality
of life is higher than that of obtaining an improvement.
From this study it emerges that, prior to prescribing CT,
particular attention should be paid to patients aged over
65 with non-optimal KPS. However, other factors omitted from the present analysis, such as disease extent,
presence of comorbidities, and functional status should
be included in the decision whether or not to prescribe
CT for palliative purposes. Our study shows that older
patients with advanced lung cancer to whom CT, most
421
commonly in the form of gemcitabine, is prescribed are
the ones with a higher likelihood of being close to death
and of having little chance of attaining a palliative effect from the treatment. These observations have recently rekindled the debate on the alternative uses of palliative CT or supportive care in advanced cancer patients
approaching the last phases of their lives14,15.
An important matter concerns the physician’s skill
in making an accurate prognosis and informing the patient and his/her relatives of it in the most appropriate
manner. The scientific literature on the doctor’s skill in
making prognoses near the end of life has been systematically reviewed by Glare et al.5 They found that
although clinician predictions were correlated with actual survival, they tended to overestimate survival. In a
previous study carried out at the ANT OHH, long-term
clinical experience showed it was possible to improve
the accuracy of a clinical estimation of life expectancy; however, many difficulties also arose for physicians who were well trained in end-of-life care, with
accurate predictions being made most often for breast
and gastrointestinal cancer and least often for urogenital and lung cancer3. A recent meta-analysis on the impact of prognostic factors in advanced cancer confirmed a level A evidence-based correlation for clinical
survival prediction, albeit with a series of limitations
that clinicians ought to be aware of, while recommendations on the use of other prognostic factors such as
performance status, symptoms associated with cancer
anorexia-cachexia syndrome, dyspnea, delirium, and
some biological factors (leukocytosis, lymphocytopenia and C-reactive protein) only reached level B16. The
observations from our study, along with data from the
literature, call for prospective studies on accurate
prognostication models that incorporate clinical survival predictions.
In conclusion, this study underlines the need to lay
down guidelines for the decision-making process of
prescribing, continuing and stopping CT in cancer patients near the end of life. Among the main factors to be
considered, such as the expected sensitivity to the treatment, the adverse effects, and the impact on quality of
life (which not only implies physical suffering but also
psychological distress and unrealistic hopes), skill in
accurately estimating the patient’s prognosis and in
communicating with patients and their families plays a
key role in defining the appropriateness of CT near the
end of life. Inappropriate use of CT in the palliative
care setting may have important negative consequences
both for patients and the health-care system. The main
consequence for the patients is the risk of being administered a useless, toxic and potentially life-threatening
treatment, actually resulting in a substantial worsening
of the quality of life. The major consequences for the
health-care system are the risk of wasting resources that
might be efficiently allocated elsewhere.
422
AA MARTONI, S TANNEBERGER, V MUTRI
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