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26
Treatment of Anal Carcinoma in the Elderly
Feasibility and Outcome of Radical Radiotherapy with or without
Concomitant Chemotherapy
Abdelkarim S. Allal M.D.1
Mirjana Obradovic M.D.2
France Laurencet M.D.1
Arnaud D. Roth M.D.3
Alexandra Spada M.D.3
Marc-Claude Marti M.D.3
John M. Kurtz M.D.1
1
Division of Radiation Oncology, University Hospital, Geneva, Switzerland.
2
Geneva Tumor Registry,2 Geneva, Switzerland.
3
Department of Surgery, University Hospital, Geneva, Switzerland.
BACKGROUND. For most cancers, information on treatment tolerance and results
for elderly patients is quite limited. This study was conducted to investigate the
feasibility and results of curative nonsurgical treatment of patients age 75 years or
older with anal carcinoma.
METHODS. From January 1976 through June 1996, invasive anal squamous cell
carcinoma was diagnosed in 58 patients age ⱖ75 years. Curative treatment was
administered to 47 patients (81%), of whom 42 received radiotherapy (RT), either
used alone (21) or associated with concomitant chemotherapy (CT). RT was administered in two sequences, the first in which a median dose of 39.6 gray (Gy) was
delivered with megavoltage photon beams, followed (after a median interval of 43
days) by a boost with either brachytherapy or external beam (median dose, 20 Gy).
CT started on Day 1 and generally consisted of 1 cycle of mitomycin C (MMC;
median dose, 9.5 mg/m2) and a 96-hour infusion of 5-fluorouracil (5-FU; median
dose, 600 mg/m2/day). The median follow-up for all patients was 48 months
(range, 5–163 months).
RESULTS. Of 40 patients (95%) who completed curative treatment, acute toxicity
resulted in shortening of the planned first irradiation sequence in 2 patients (1 in each
group) and an unplanned treatment break in 11 patients (4 in the RT group and 7 in
the RT-CT group). Grade 2 and 3 acute reactions (RTOG) were observed in 43% and
54% of patients, respectively. Among all Grade 3 reactions, 32% occurred in the RT
group and 68% in the RT-CT group. In patients receiving RT-CT, Grade 2–3 leukopenia
was observed in 25% of patients, Grade 2–3 fatigue was observed in 58% of patients,
and Grade 2 cardiac toxicity related to 5-FU occurred in 1 patient. At 5 years, the
overall survival was 54% (49% and 59% for the RT and RT-CT groups, respectively, P ⫽
0.28), and the actuarial local control rate was 78.5% (73% and 83% for the RT and
RT-CT groups, respectively, P ⫽ 0.36). Five patients presented with Grade 3– 4 late
complications, all of them in the RT-CT group.
CONCLUSIONS. The current series confirms the feasibility of sphincter-conserving
treatment for elderly patients who present with anal carcinoma. Rates of acute or
late complications appeared similar to those observed in younger patients, and the
oncologic results were at least as favorable as those commonly reported. Cancer
1999;85:26 –31. © 1999 American Cancer Society.
KEYWORDS: elderly patients, anal carcinoma, radiotherapy, chemotherapy,
sphincter conservation.
Address for reprints: Abdelkarim S. Allal, M.D.,
Hôpital Cantonal Universitaire de Genève, Division
de Radio-oncologie, 1211 Geneva 14, Switzerland.
Received February 25, 1998; revision received
May 14, 1998; accepted May 14, 1998.
© 1999 American Cancer Society
I
n Western countries, the rapid increase in the elderly population will
inevitably lead to a marked rise in the number of new cancer cases.1
Currently, nearly 60% of all cancers are diagnosed in patients age ⱖ65
years.2 Epidemiologic studies have demonstrated an increase in the
incidence of anal carcinoma in recent decades.3 Although this increase
may not be related solely to population aging, more than one-third of
Treatment of Elderly Patients with Anal Carcinoma/Allal et al.
patients presenting with anal carcinomas are age ⱖ70
years.4 Nonetheless, for elderly patients with anal carcinomas the feasibility of curative therapy and the outcomes of such treatments are poorly documented. To
our knowledge, no study of this uncommon disease in a
substantial series of geriatric patients has yet appeared
in the international literature. With these considerations
in mind, we retrospectively reviewed the types of treatment, treatment toxicities, and oncologic results in elderly patients presenting with anal carcinoma in Geneva, Switzerland.
MATERIALS AND METHODS
According to the Geneva Tumor Registry, between
January 1976 and June 1996 invasive anal squamous
cell carcinoma was diagnosed in 58 patients age ⱖ75
years. Six patients were treated palliatively because of
impaired general condition or metastatic disease, and
5 did not receive any oncologic treatment because of
metastatic disease (2), poor general condition (1), patient refusal (1), or an unknown reason (1). Curative
treatment was given to 47 patients, with radiotherapy
(RT; 23), radiotherapy and concomitant chemotherapy (RT-CT; 21), or surgery (3). The current analysis of
toxicity and oncologic results is limited to 42 patients
who underwent sphincter-conserving treatment. Excluded from this analysis were 11 patients who did not
receive curative therapy, 3 patients treated with radical surgery, and 2 patients treated with brachytherapy
alone. The characteristics of the 42 study patients are
displayed in Table 1.
Radiotherapy
Radiotherapy was delivered in a split course to 39
patients and in continous course to 1 patient, whereas
two patients received only the first sequence (see “Results”). External megavoltage beams (EBRT) were always used for the first sequence, whereas the second
consisted of a “boost” directed to areas of initial macroscopic disease, using interstitial brachytherapy for
27 patients and EBRT for 12 patients. Detailed treatment techniques have been reported previously.6 The
technical parameters of RT in the current study are
presented in Table 2. In the initial period, the first
sequence consisted of 30 Gy in 10 fractions (dose
specified at a median depth of 4 cm) delivered by a
direct perineal telecobalt field, complemented in all
but selected small tumors by 18 Gy through a posterior
presacral field (Papillon’s technique).7 In the mid1980s, the technique of EBRT was modified to treat
adequately the inguinal, external iliac, and hypogastric lymph nodes, using two large anteroposterior (AP/
PA) opposed pelvic fields with photons of 6 MV or
more. In addition, the total dose and dose per fraction
27
TABLE 1
Patient Characteristics
Characteristics
Median age, yrs (range)
Female/male
Tumor location
Canal ⫾ anorectal junction
Margin
Canal ⫹ margin
Tumor status
Primary
Recurrence postsurgery
Postexcisional biopsy
Histology
Keratinizing squamous
Basaloid and transitional
Undifferentiated
Clinical stage (UICC TNM5)
T2 (%)
T3
T4
N0
N1–3
RT
21 patients
RT-CT
21 patients
Total
42 patients
82 (75–90)
17/4
79 (75–87)
18/3
81 (75–90)
35/7
18
0
3
18
1
2
36
1
5
16
1
4
21
0
0
37
1
4
12
8
1
13
8
0
25
16
1
18 (86)
2
1
20
1 (5)
6 (28)
13
2
14
6 (29)
24
15
3
34
7
RT: radiotherapy; CT: chemotherapy; UICC: International Union Against Cancer.
were modified to avoid severe acute toxicities, typically delivering 40 Gy in 20 –22 fractions over 4 – 4.5
weeks. The boost type (EBRT or brachytherapy) was
chosen according to the extent of disease and the
patient’s general condition. Brachytherapy consisted
of a low dose rate interstitial iridium-192 implant performed 6 – 8 weeks after the end of EBRT; the dose was
calculated according to the rules of the “Paris system.”8 Patients who received an EBRT boost were
treated most commonly with photons of 6 MV or more
using various field arrangements.
Chemotherapy
Twenty-one patients (50%) received concomitant chemotherapy. This association was reserved initially for
advanced stages, but gradually was extended to include less advanced stages except patients with very
favorable tumors or in poor general condition. CT
usually started on Day 1 and consisted of one cycle of
MMC (median dose, 9.5 mg/m2) and a 96-hour continuous infusion of 5-fluorouracil (5-FU; median dose,
600 mg/m2/day). One patient received 5-FU alone.
During the boost treatment, five patients received a
second course of 5-FU (with MMC in three cases). The
doses of the different agents were adjusted according
to the age and general condition of each patient.
Statistical Evaluation
Actuarial local control rate, overall survival, and disease free survival rates were calculated by using the
28
CANCER January 1, 1999 / Volume 85 / Number 1
TABLE 2
Characteristics of Radiotherapy
Fields and doses (1st course)
AP/PA pelvic fields ⫹ other
Perineal ⫾ sacral fields
Boost technique (2nd course)
A) EBRT
Perineal field
AP/PA ⫾ lateral fields
Other techniques
B) Interstitial brachytherapy
Median dose–median dose rate
Median interval between courses
Median total treatment duration
RT
21 patients
RT-CT
21 patients
Total
42 patients
Median dose/
fraction/days
9⫹2
10
20 ⫹ 1
0
29 ⫹ 3
10
39.6 Gy/22/31
30 Gy/10/20
6
3
1
2
14
25 Gy–76 cGy/hr
37
73
6
1
3
2
13
20 Gy–75 cGy/hr
48
76
12
4
4
4
27
23 Gy–75 cGy/hr
43 days
75 days
20 Gy/10/12
RT: radiotherapy; CT: chemotherapy; EBRT: external beam RT; AP/PA: anteroposterior opposed fields; Gy: gray; cGy: centigray.
Kaplan–Meier method.9 Fisher’s exact test and the log
rank test were used to assess for significant differences
between simple proportions and survival curves.
RESULTS
Compliance and Toxicity
Because of acute toxicity, two patients refused to receive the brachytherapy boost (one in the RT group
and one in the RT-CT group). Moreover, the planned
first irradiation sequence was shortened in 2 patients
(1 in each group), and 11 required an unplanned treatment interruption (4 in the RT and 7 in the RT-CT
group), with a median split duration of 7 days (range,
2–34 days).
According to the Radiation Therapy Oncology
Group (RTOG) grading system,10 43% of patients presented with Grade 2 and 54% (53% in the RT group and
55% in the RT-CT group) with Grade 3 acute reactions.
Among all Grade 3 reactions, 32% occurred in the RT
group and 68% in the RT-CT group. Grade 3 reactions
concerned mostly pelvic/perineal skin (50%) and diarrhea (32%). Grade 3 skin reactions were observed in 19%
and 47% of the RT and RT-CT groups, respectively (P ⫽
0.08). In the RT-CT group, according to the World Health
Organization (WHO) grading system,11 Grade 2–3 leukopenia was observed in 25% of patients, Grade 2–3 fatigue
in 58%, and 1 Grade 2 cardiac toxicity related to 5-FU
was recorded. No Grade 4 acute toxicity or treatmentrelated death occurred in either group.
Thirty-five patients were evaluable for long term
complications (patients with available data), with 29 and
27 patients at risk at 2 and 3 years, respectively. Sixty-six
percent of late complications were RTOG Grade 1–2. All
Grade 3– 4 complications (5 patients) were observed in
female patients in the RT-CT group (Table 3). Grade 3
complications consisted of one severe anal stenosis and
one chronic diarrhea, both managed conservatively.
Grade 4 complications consisted of one case of anal
necrosis treated with abdominoperineal resection (APR)
and two cases of pelvic osteonecrosis and bone fracture
managed conservatively.
Clinical Outcome
At last follow-up, 13 patients were still alive and 1 was
lost to follow-up at 58 months without evidence of
disease. Of the patients who died, anal carcinoma was
considered the cause of death among 7, including
both patients who did not complete the planned treatment, and 3 patients died of a second malignancy. The
median follow-up for all patients was 48 months
(range, 5–163 months). The 5- and 8-year actuarial
overall survival rates were 54% and 36% (Fig. 1). No
significant difference was observed between the RT
and RT-CT groups (5-year survival, 49% vs. 59%, P ⫽
0.28). The 5-year disease free survival for all study
patients (Fig. 2) was 70% (65% and 74% for the RT and
RT-CT groups, respectively, P⫽ 0.42) and 74% for the
40 patients who completed the planned schedule.
During follow-up, 8 patients were documented to
have local (7) or locoregional (1) failures, and 3 had
distant metastases (Table 4). The 5-year actuarial local
control rate (Fig. 2) was 78.5% (73% and 83% for the
RT and RT-CT groups, respectively, P ⫽ 0.36). Salvage
surgery was attempted in 5 of 8 patients with locoregional failures (3 APR and 2 conservative surgery),
leading to definitive locoregional control in 3 patients.
DISCUSSION
In current oncologic practice, the management of elderly patients poses particular problems. Before arriv-
Treatment of Elderly Patients with Anal Carcinoma/Allal et al.
FIGURE 1. Actuarial overall survival for the 42 patients.
FIGURE 2.
29
Actuarial local control and disease free survival for the 42
patients.
ing at a decision, questions are frequently asked by the
patient, his family, and his physicians concerning
treatment tolerance, sequelae, and oncologic results.
However, because almost all prospective trials exclude
patients older than 75 years, reliable information on
tolerance and results of curative treatment for elderly
patients is often unavailable. Moreover, older patients
tend to be less regularly screened and subsequently
may more often present with advanced disease, and
they also tend to be treated inadequately or not at
all.12,13 These age-related variations may be related to
the patient’s real or perceived health status, the patient’s preferences, and his or her physician’s attitudes.14 In addition, discouraging findings regarding
the efficacy of treatment for elderly patients reported
for some malignancies15–17 might tend to encourage
less adequate management.
However, due particularly to progress in the management of comorbidities in elderly patients, curative
treatment has become more frequently used.18 Indeed, recent reports have stressed that advanced chronologic age is not sufficient justification for excluding
patients from optimal treatment with surgery, radiotherapy, or chemotherapy.19 –21 Moreover, age by itself
often does not represent a negative prognostic factor.22–24 In a study of 1619 patients from trials of the
European Organisation for the Research and Treatment of Cancer, Pignon at al.25 found no differences in
acute or late complications, nor in survival, among
different age groups of patients treated with pelvic
irradiation for various malignancies. Similar observations were reported regarding elderly patients treated
with radiotherapy for cervix carcinoma26 and for oropharyngeal cancers.21 However, to our knowledge, no
reports dealing exclusively with the treatment of anal
carcinomas in a geriatric population have previously
appeared in the literature.
The current study suggests that in Geneva elderly
patients with anal carcinoma do not appear to be less
adequately treated, as 47 of 58 (81%) of them underwent treatment given with curative intent. Moreover,
decisions to offer palliative treatment or to abstain
from specific oncologic therapy did not seem to be
primarily related to the age factor. The second finding
of this study was that a full course of curative radiotherapy, with or without concomitant chemotherapy,
was feasible for a significant proportion of those patients: 40 of 42 (95%). Radiotherapy technique and
dosage were quite similar to those usually employed at
our institution.27 However, for elderly patients, doses
of MMC and 5-FU were usually 20% lower than those
routinely given to younger patients.
Although retrospective assessment of toxicity is
problematic, some useful information could be drawn
from this study. As expected, acute toxicity was the
limiting factor, particularly in patients treated with
combined modalities, whereas more unplanned interruptions were required and the planned treatment gap
was longer than for patients treated with RT alone.
Moreover, whereas the proportion of patients presenting with Grade 3 acute toxicity was quite similar, the
number of Grade 3 complications was higher in the
RT-CT group. In particular, Grade 3 skin reactions
were more frequent in the RT-CT group (19% vs. 47%,
P ⫽ 0.08). Otherwise, systemic toxicity in the RT-CT
group was dominated by fatigue (Grade 2–3 in 58% of
patients), whereas hematologic toxicity (Grade 2–3
leukopenia in 25% of patients) and cardiac toxicity (in
1 patient) remained acceptable. The increase in acute
toxicities when chemotherapy is added to RT is well
documented in a prospective trial.28 Except for fatigue,
which seemed to be more marked in elderly subjects,
acute toxicities appeared to be similar to those reported in a prospective trial that included patients
younger than 76 years.29
30
CANCER January 1, 1999 / Volume 85 / Number 1
TABLE 3
Characteristics of Patients with Grade 3–4 Complications
Radiotherapy
Age TN
dose (EBRT ⴙ IB), Grade and type of
(yrs) stage Gy
complication
83
79
78
75
79
T2N0
T3N2
T3N0
T2N0
T3N1
39.6 ⫹ 24
39.6 ⫹ 24
43.6 ⫹ 20
39.6 ⫹ 25
39.6 ⫹ 24a
3: anal stenosis
3: diarrhea
4: anal necrosis
4: pubic osteonecrosis
4: femoral necks necrosis
Time to occurrence
(mos)
18
8
3
16
22
EBRT: external beam radiation therapy; IB: interstitial brachytherapy; Gy: gray.
a
EBRT boost.
Concerning late morbidities, Grade 3– 4 complications were observed only in the RT-CT group (Table 3).
However, the introduction of chemotherapy in Geneva coincided with the use of larger RT fields, and
patients treated with combined modalities tended to
have more advanced disease. As we have previously
reported, skeletal complications occur preferentially
in older women treated with combined modality therapy.30 Otherwise, the 14% rate of Grade 3– 4 late complications can be compared favorably with rates reported for younger patients.29
The most noteworthy finding was the 78.5%
5-year local control rate, which appeared to be at least
equivalent to that reported for younger patients.28,29
In our previous report, in which different factors influencing local control were analyzed, patients older
than 66 years were found to have a significantly higher
rate of local control than younger patients.27 This result should remove any doubt regarding the efficacy of
curative sphincter-conserving treatment in elderly patients with anal carcinoma. Similar conclusions were
reported by Valentini et al.31 from a study of a small
series of anorectal carcinomas in elderly patients.
Moreover, in the current series 5 of the 8 patients who
experienced failure after conservative treatment were
able to undergo salvage surgery, leading to definitive
locoregional control in 3 of them (Table 4). Despite the
advanced age of the patients, the actuarial overall
survival rate was 54% at 5 years, similar to that observed for younger patients.29 This rate tends to fall
rapidly after 5 years, essentially reflecting deaths due
to intercurrent diseases. Only 7 of the 28 deaths that
occurred among the 42 patients in this study (including the two patients who did not complete the
planned treatment) were caused by anal carcinoma.
In conclusion, the current series establishes the
feasibility of curative sphincter-conserving treatment
for elderly patients with anal carcinoma. Taking into
account the superiority of combined chemoradiotherapy in terms of local control,28,29 concomitant chemotherapy should be attempted whenever possible and
doses modulated according to the patient’s general
condition. Moreover, it may be appropriate to adapt
radiotherapy technique for elderly patients with early
stage disease, e.g., to irradiate only a small volume,
including the primary tumor area and the perirectal
lymph node drainage. A boost to the initial sites of
involvement could be undertaken after a dose of 36
gray (Gy); and for patients with good response to
initial chemoradiotherapy, the total dose could be limited to 55 Gy. For patients who tolerate chemotherapy,
two cycles should be administered if possible. Regarding patients for whom chemotherapy is considered
inappropriate, it should be borne in mind that a substantial proportion of patients can be cured with appropriately planned radiotherapy alone.
Acute toxicity represents the limiting factor of
such treatment. Indeed, although the objective grade
TABLE 4
Characteristics of Patients with Local/Locoregional Failure
TN stage
Radiotherapy dose
(EBRT ⴙ IB), Gy
Overall treatment
time (days)
Chemotherapy
(no. of cycles)
Site of recurrence
Time to
occurrence (mos)
T2N0
T3N0
T4N0
T2N2
T3N2
T2N0
T4N3
T2N0
24 ⫹ 25
28 ⫹ 30
50.4 ⫹ 20a
39.6 ⫹ 20a
39.6 ⫹ 24
30 ⫹ 30
39.6 ⫹ 19.8a
40b
68
52
77
102
81
143
105
30
No
No
No
No
Yes (1)
No
Yes (1)
Yes (1)
AC ⫹ inguinal & mesenteric nodes
AC
AC
AC
AC
AC
AC
AC
16
6
0
0
26
9
7
10
EBRT: external beam radiation therapy; IB: interstitial brachytherapy; AC: anal canal; Gy: gray.
a
EBRT boost.
b
The planned treatment was not completed.
Treatment of Elderly Patients with Anal Carcinoma/Allal et al.
of acute toxicities appeared to be similar to those
observed in younger patients, in our experience toxicity often seemed subjectively higher in elderly patients. Thus, in addition to the adequate management
of comorbidities, attention should be paid to nursing
care of the acute side effects and psychologic support,
to avoid treatment interruption and optimize patient
compliance. As stressed in our previous study of
chronic morbidity,30 limitation of treatment volumes
in conjunction with chemotherapy for elderly patients
may help decrease late complications, especially those
involving pelvic bones in women.
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