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Keywords:

  • endometrial carcinoma;
  • elderly;
  • radiation therapy;
  • outcome

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The current study was conducted to determine the influence of old age (age ≥ 70 years) on outcome in a group of patients with endometrial carcinoma who were treated with simple hysterectomy followed by adjuvant radiation therapy (RT).

METHODS

Between November 1987 and May 2000, 405 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB-II endometrial carcinoma were treated with postoperative RT. Intravaginal RT alone was given to 77% of patients (median dose, 21grays [Gy] given in 3 fractions). Additional postoperative external beam radiation therapy (EBRT) was given to 23% of patients (median dose, 45 Gy). Eighty-four patients were age ≥ 70 years and 321 patients were age < 70 years. The two groups were well balanced with regard to race, comprehensive surgical staging, aggressive histology, lymphovascular invasion, lower uterine segment involvement, cervical involvement, and the use of postoperative EBRT. Significantly more patients in the age ≥ 70 years group had other comorbidities such as obesity, diabetes mellitus, or hypertension (P = 0.02) and were found to have deep (> 50%) myometrial invasion (P = 0.008).

RESULTS

With a median follow-up time of 48 months, the 5-year locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) rates were 95%, 91%, and 90% respectively. On multivariate analysis, poor LRC was found to be correlated with age ≥ 70 years (P = 0.019) and lymphovascular invasion (P = 0.001). Poor DFS was found to be correlated with age ≥ 70 years (P = 0.03), lymphovascular invasion (P = 0.01), and aggressive histology (P = 0.001). Similarly, poor OS was found to correlate with age ≥ 70 years (P = 0.001), lymphovascular invasion (P = 0.01), aggressive histology (P = 0.01), and cervical involvement (P = 0.02). The same factors that were found to correlate with OS (age ≥ 70 years, lymphovascular involvement, aggressive histology, and cervical involvement) also appeared to correlate with disease-specific survival (P = 0.03, P = 0.008, P = 0.001, and P = 0.04, respectively). The 5-year actuarial rates of Radiation Therapy Oncology Group late complications that were ≥ Grade 3 (gastrointestinal tract, genitourinary tract, or vagina) were 3% in both groups.

CONCLUSIONS

Even when treated in a similar fashion, endometrial carcinoma patients age ≥ 70 years appear to fare worse than younger patients independent of other poor prognostic factors. The rate of complications from adjuvant RT, despite a higher rate of comorbidity in elderly patients, was found to be similar in both age groups. Endometrial carcinoma appears to be intrinsically more aggressive in older patients, thus mandating further improvement in their treatment strategies. Cancer 2003. © 2003 American Cancer Society.

The preponderance of data in the literature indicate that advanced age is a predictor of poor outcome in patients with endometrial carcinoma.1–4 Whether the poor outcome among elderly patients can be accounted for entirely by a more advanced stage at the time of diagnosis, histology, or treatment or whether endometrial carcinoma among the elderly is intrinsically more aggressive than in younger patients remains controversial.5, 6 In general, older patients with endometrial carcinoma tend to have deep myometrial invasion, poorly differentiated histology, or extrauterine spread.7, 8 However, the negative influence of advanced age on outcome still could be demonstrated in patients who underwent full surgical staging2 or those with well to moderately differentiated tumors.9

Perhaps the poor outcome in some of the reports in the literature could be attributed to the less aggressive adjuvant therapy (i.e., radiation therapy), offered to elderly patients.6 This is a valid argument, especially when dealing with elderly patients who are less likely than younger patients to receive recommended adjuvant therapy in general.10, 11 Therefore, to answer the question of whether advanced age is an intrinsically poor prognostic factor or whether it is because of less aggressive adjuvant therapy, it is important to compare the outcome according to age in a group of patients who all received adjuvant radiation therapy.

In the current climate of trying to omit adjuvant radiation therapy for all patients with early-stage endometrial carcinoma, it is important to first try to answer that question.12, 13 If older age is an intrinsically poor prognostic factor, then strategies regarding in whom therapy should be maximized rather than minimized should be the focus of our investigation in this group of patients. To further clarify the impact of age in patients with endometrial carcinoma, we present herein an analysis of the outcome of patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB-II endometrial carcinoma who all were treated, regardless of their age, with postoperative radiation therapy at a single institution.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The patient population was comprised of 405 patients with Stage IB-II endometrial carcinoma who were treated with postoperative radiation therapy at Memorial Sloan-Kettering Cancer Center (MSKCC) between November 1987 and May 2000. The patients ranged in age from 29–92 years with a mean age of 60 years and a median age of 62 years. There were 84 patients (21%) age ≥ 70 years and 321 patients (79%) age < 70 years. The race distribution was as follows: 88% of patients were white (358 patients), 6% of patients were African American (24 patients), 4% of patients were Hispanic (16 patients), and 1% of the patients were from other racial groups (7 patients). Comorbidity (defined as obesity, hypertension, or diabetes mellitus) was noted in 63% of patients (254 of 403 patients). Data regarding comorbidity was not known for 2 of the 405 patients.

All 405 patients underwent a simple hysterectomy. Total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed on 358 patients (88%) and laparoscopic-assisted vaginal hysterectomy and bilateral salpingo-oophorectomy was performed in 47 patients (12%). Pelvic washings were obtained in 84% of patients (n = 340), pelvic lymph node sampling in 27% of patients, and paraaortic lymph node sampling in 29% of patients. Comprehensive surgical staging, defined as pelvic washings and pelvic and paraaortic lymph node sampling, was performed in 56 patients (14%). The surgery was performed at MSKCC in 82% of patients (n = 332). On histologic examination there were 346 patients (85%) with FIGO Grade 1-2 endometrioid carcinoma and 59 patients (15%) who had aggressive histologies. Of the latter group, 29 patients (49%) had FIGO Grade 3 endometrioid carcinoma and 30 patients (51%) had papillary serous (PS) or clear cell (CC) histologies. FIGO Grade 3 and PC/CC were combined together because in a previous study we were unable to demonstrate a significant difference in outcome between the two groups.14 MSKCC pathologists reviewed all the pathologic materials at the time of diagnosis including those from patients who underwent their surgery at an outside institution. The depth of myometrial invasion was ≥ 50% in 65 patients (16%) and the cervix was involved in 51 patients (13%). Patients with clinical rather than occult cervical involvement were excluded from the current analysis because such patients generally were treated with preoperative radiation therapy or radical hysterectomy. The lower uterine segment was involved with tumor in 16% of the patients (n = 65). Lymphovascular invasion was identified in 17% of patients (n = 70), as shown in Table 1. The distribution according to FIGO staging, recognizing that the majority of patients had undergone incomplete surgical staging, was as follows: 298 patients had Stage IB disease (74%), 56 patients had Stage IC disease (14%), 22 patients had Stage IIA disease (5%), and 29 patients had Stage IIB disease (7%). Patients with Stages IA, Stage III, and Stage IV disease were excluded from the current analysis.

Table 1. Patient Characteristics
 No.%
  • G: grade; AH: aggressive histology; LVI: lymphovascular invasion; LUSI: lower uterine segment involvement; CI: cervical involvement; EBRT: external beam radiation.

  • a

    Comorbidity was evaluable in only 403 of 405 patients.

Age (yrs)  
 < 7032179%
 ≥ 708421%
Race  
 White35888%
 Other4712%
Invasion  
 < 50%34084%
 ≥ 50%6516%
Histology  
 G1–234685%
 AH5915%
LVI  
 Yes7017%
 No33583%
LUSI  
 Yes6516%
 No34084%
CI  
 Yes5113%
 No35487%
Comorbiditya  
 Yes25463%
 No14937%
EBRT  
 Yes9423%
 No31177%

All 405 patients in the current study received postoperative adjuvant radiation therapy at MSKCC. Any patients who underwent their surgery at MSKCC but received radiation therapy at an outside institution were excluded from the current analysis (n = 25). None of the patients had received prior pelvic radiation therapy. For patients who were considered to be at low risk for pelvic lymph node metastasis, high-dose rate intravaginal brachytherapy (IVRT) alone was given (77%; n = 311). The median total dose of IVRT was 21 grays (Gy) (range, 6–21 Gy) delivered in 3 fractions at 2-week intervals with the dose prescribed at a depth of 0.5 cm from the vaginal surface. Postoperative pelvic external beam radiation therapy (EBRT) was given to 94 patients (23%). The pelvic EBRT was combined with IVRT in 85 of 94 patients and was given alone in 9 of 94 patients. EBRT generally was given to those patients believed to be at high risk for pelvic lymph node metastasis. Of the 65 patients with ≥ 50% myometrial invasion, 48 (74%) received adjuvant EBRT. Similarly, 36 of the 51 patients with cervical involvement (71%) received EBRT. The median EBRT dose was 45 Gy (range, 36–50.4 Gy) given in 25 fractions followed by IVRT to a median dose of 15 Gy (range, 5–15 Gy) given in 3 fractions.

During the study time period (November 1987–May 2000), the “standard” radiation dose and schedule were defined as follows: for those patients treated with IVRT alone the total dose was 18–21 Gy in 3 fractions, and for those patients treated with EBRT the dose was 45 Gy in 25 fractions followed by IVRT to a total dose of 12–15 Gy in 3 fractions. Any variation, no matter how small, from the above-mentioned “standard” was considered noncompliance. Such strict definition of noncompliance was used as a surrogate for treatment tolerance or physician bias. A lower than standard dose of radiation therapy in an elderly patient who did not report any acute toxicity indicates that the treating physician lowered the dose solely based on the patient's age. Late complications of the gastrointestinal (GI) and genitourinary (GU) tracts as well as the vagina (mucosal membrane) were assessed in terms of Grade ≥ 3 Radiation Therapy Oncology Group (RTOG) late toxicity. Lower grades were not reported because they are very difficult to determine accurately from a retrospective study.

The median follow-up time, calculated from the date of surgery, was 48 months (range, 3–143 months). Associations between variables were tested using the chi-square test with the Yates correction for small sample size.15 Survival rates were calculated using the Kaplan–Meier product-limit method.16 Comparisons of survival curves were performed using the log-rank test.17 Independent prognostic factors were identified using the Cox stepwise regression analysis.18 For variables found to have independent prognostic value (P < 0.05) by multivariate analysis, relative risks (RR) with 95% confidence intervals (95% CI) were calculated.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

The group of patients who were age ≥ 70 years (n = 84) at the time of diagnosis and those age < 70 years (n = 321) were balanced with regard to race (white vs. other), histology (FIGO Grade 1 and Grade 2 vs. FIGO Grade 3 or PS/CC), the presence of lymphovascular invasion, lower uterine segment involvement, cervical involvement, and whether comprehensive surgical staging was performed. In the group of patients age ≥ 70 years, there were more patients who underwent their surgery at MSKCC (89% vs. 80%; P = 0.07) and more patients who received postoperative EBRT (31% vs. 21%; P = 0.08) compared with patients in the group age < 70 years, but the difference did not reach statistical significance. However, the two groups differed significantly in two aspects (Table 2. There were significantly more patients with ≥ 50% invasion and with comorbidity in the group of patients age ≥ 70 years compared with the group of patients age < 70 years (29% vs.13% [P = 0.008] and 74% vs. 60% [P = 0.02], respectively).

Table 2. Distribution of Variables According to Age
 ≥ 70 yrs (n = 84)< 70 yrs (n = 321)P value
  • AH: aggressive histology; LVI; Lymphovascular vasion; LUSI: lower uterine segment involvement; CI: cervical involvement; CSS: comprehensive surgical staging; EBRT: external beam radiation.

  • a

    Comorbidity was evaluable in only 403 of 405 patients.

Comorbiditya   
 Yes61 (74%)193 (60%)0.02
 No21 (26%)128 (40%) 
Race   
 White74 (88%)284 (86%)0.9
 Other10 (12%) 37 (14%) 
Invasion   
 < 50%60 (71%)280 (87%)0.008
 ≥ 50%24 (29%) 41 (13%) 
AH   
 Yes17 (20%) 42 (13%)0.1
 No67 (80%)279 (87%) 
LVI   
 Yes18 (21%) 52 (16%)0.3
 No66 (79%)269 (84%) 
LUSI   
 Yes16 (19%) 49 (15%)0.5
 No68 (81%)272 (85%) 
CI   
 Yes10 (12%) 41 (13%)0.9
 No74 (88%)280 (87%) 
CSS   
 Yes 8 (10%) 48 (15%)0.2
 No76 (90%)273 (85%) 
EBRT   
 Yes26 (31%) 68 (21%)0.08
 No58 (69%)253 (79%) 

Patterns of Recurrence

Out of 405 patients, 26 (6%) developed a disease recurrence. There were 10 of 84 disease recurrences (12%) in the group of patients age ≥ 70 years compared with 16 of 320 disease recurrences (5%) in the group of patients age < 70 years (P = 0.03). Sites of recurrence included the vagina/pelvis in 15 of 405 patients (4%), the paraaortic lymph nodes in 10 patients (3%), and distant recurrences in 22 patients (5%). In 15 of the 26 patients who developed a disease recurrence, there was more than 1 site of recurrence. There were 3 of 405 isolated vaginal recurrences (1%) and 1 recurrence in the pelvic and paraaortic lymph nodes. The most common site of distant recurrence was the lung (12 of 22 patients) followed by intraabdominal dissemination (6 of 22 patients) and supraclavicular/axillary lymph nodes (3 of 22 patients). In the 6 patients with intraabdominal disease, 4 were age ≥ 70 years and 2 were age < 70 years (P = 0.02). Thirty-nine of 405 patients died (10%), with 20 of them dying because of disease progression.

Locoregional Control

The 5-year vaginal/pelvic control rate for the entire group was 95% (95% CI, 93–98%). In patients age ≥ 70 years, the 5-year vaginal/pelvic control rate was 89% (95% CI, 80–98%) compared with 97% (95% CI, 95–99%) for those patients age < 70 years (P = 0.02), as shown in Figure 1. For patients with lymphovascular invasion, the 5-year control rate was 85% (95% CI, 76–95%) compared with 97% (95% CI, 96–100%) for those without lymphovascular invasion (P = 0.001). The presence of aggressive histology was found to be marginally significant (P = 0.058). The depth of myometrial invasion, lower uterine segment involvement, and cervical involvement did not appear to significantly influence locoregional control, as shown in Table 3. On multivariate analysis, only age ≥ 70 years (RR: 3 and 95% CI, 1–10; P = 0.019) and the presence of lymphovascular invasion (RR: 5 and 95% CI, 2–14; P = 0.001) retained their significance as predictors of poor locoregional control.

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Figure 1. Loco regional control (LRC) and patient age. P = 0.02.

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Table 3. Vaginal/Pelvic Control Rate (Univariate Analysis)
 5-year95% CIP value
  1. 95% CI: 95% confidence interval; AH: aggressive histology; LVI: Lymphovascular invasion; LUSI: lower uterine segment involvement; CI: cervical involvement.

Age (yrs)   
 < 7097%95–990.02
 ≥ 7089%80–98 
Myometrial invasion   
 < 50%95%93–980.3
 ≥ 50%93%86–100 
AH   
 Yes92%86–1000.058
 No96%94–99 
LVI   
 Yes85%76–950.001
 No97%96–100 
LUSI   
 Yes96%91–1000.9
 No95%93–98 
CI   
 Yes95%89–1000.7
 No95%93–98 

The influence of the type of radiation therapy used on locoregional control was evaluated. The 5-year rate was 96% (95% CI, 93–98%) for those patients treated with IVRT alone compared with 95% (95% CI, 90–100%) for those patients treated with additional EBRT (P = 0.3). Even when the analysis was limited to patients with deep invasion or cervical involvement (n = 101), the 5-year locoregional control rate was 93% (95% CI, 79–100%) for those treated with IVRT alone compared with 95% (95% CI, 90–100%) for those who received EBRT (P = 0.6). In the subset of patients who were age ≥ 70 years, the 5-year locoregional control rate was 88% (95% CI, 77–100%) for those treated with IVRT alone compared with 90% (95% CI, 77–100%) for those treated with EBRT (P = 0.5).

Disease-Free Survival

The 5-year disease-free survival (DFS) rate was 91% (95% CI, 8995%). In patients age ≥ 70 years, the 5-year DFS rate was 82% (95% CI, 72–94%) compared with 93% (95% CI, 90–97%) for those patients age < 70 years (P = 0.03) as shown in Figure 2. For patients with lymphovascular invasion, the 5-year DFS rate was 81% (95% CI, 71–92%) compared with 94% (95% CI, 91–97%) for those without lymphovascular invasion (P = 0.001). The 5-year DFS rate was 94% (95% CI, 91–97%) for patients with FIGO Grade 1 and 2 versus 76% (95% CI, 63–90%) for those with aggressive histology (P = 0.001). Cervical involvement also was found to be a significant predictor of poor DFS (P = 0.048). The depth of myometrial invasion and lower uterine segment involvement did not appear to significantly influence DFS, as shown in Table 4. On multivariate analysis, age ≥ 70 years (RR: 2 and 95% CI, 1–13; P = 0.03), the presence of lymphovascular invasion (RR: 3 and 95% CI, 2–4; P = 0.01), and aggressive histology (RR: 3 and 95% CI, 1–8; P = 0.001) retained their significance as predictors of poor DFS.

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Figure 2. Disease-free survival (DFS) and patient age. P = 0.03.

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Table 4. Disease-Free Survival Rate (Univariate Analysis)
 5-year95% CIP value
  1. 95% CI: 95% confidence interval; AH: aggressive histology; LVI: lymphovascular invasion; LUSI: lower uterine segment involvement; CI: cervical involvement.

Age (yrs)   
 <7093%90–970.03
 ≥7082%72–94 
Myometrial invasion   
 <50%92%89–960.1
 ≥50%86%75–97 
AH   
 Yes76%63–900.001
 No94%91–97 
LVI   
 Yes81%71–920.001
 No94%91–97 
LUSI   
 Yes86%76–960.07
 No92%90–96 
CI   
 Yes83%69–980.048
 No92%90–96 

In the group of patients age ≥ 70 years, there was a significantly higher rate of deep invasion and numerically more patients (albeit not significant) with aggressive histology. Therefore, the influence of age on DFS was evaluated in the subset of patients without deep invasion or aggressive histology (i.e., those with Stage IB, Grade 1 and 2 endometrioid carcinoma [n = 259]). The 5-year DFS in those patients age < 70 years in this subset was 96% (95% CI, 93–99%) compared with 88% (95% CI, 75–100%) for those patients age ≥ 70 years (P = 0.059).

Survival

The 5-year overall survival (OS) rate was 90% (95% CI, 86–94%). In patients age ≥ 70 years, the 5-year OS rate was 80% (95% CI, 69–92%) compared with 92% (95% CI, 89–96%) for those patients age < 70 years (P = 0.006) as shown in Figure 3. For patients with lymphovascular invasion, the 5-year OS rate was 74% (95% CI, 62–87%) compared with 93% (95% CI, 90–97%) for those without lymphovascular invasion (P = 0.001). The 5-year OS rate was 92% (95% CI, 89–96%) for patients with FIGO Grade 1 and 2 versus 75% (95% CI, 62–89%) for those with aggressive histology (P = 0.001). Cervical involvement was also was found to be a significant predictor of poor OS, with an OS rate of 80% (95% CI, 68–93%) reported for those patients with cervical involvement compared with 91% (95% CI, 88–95%) for those without cervical involvement (P = 0.004). Patients with ≥ 50% myometrial invasion (P = 0.02) and those with lower uterine segment involvement (P = 0.02) also were found to have a worse OS, as shown in Table 5. On multivariate analysis, age ≥ 70 years (RR: 4 and 95% CI, 2–7; P = 0.001), the presence of lymphovascular invasion (RR: 3 and 95% CI, 1–5; P = 0.01), aggressive histology (RR: 2 and 95% CI, 1–5; P = 0.01), and cervical involvement (RR: 3 and 95% CI, 1–5; P =0.02) retained their significance as predictors of poor OS.

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Figure 3. Overall survival (OS) and patient age. P = 0.006.

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Table 5. Overall Survival Rate (Univariate Analysis)
 5-year95% CIP value
  1. 95% CI: 95% confidence interval; AH: aggressive histology; LVI: Lymphovascular invasion; LUSI: lower uterine segment involvement; CI: cervical involvement.

Age (yrs)   
 <7092%89–960.006
 ≥7080%69–92 
Myometrial invasion   
 <50%91%88–950.02
 ≥50%82%71–94 
AH   
 Yes75%62–890.001
 No92%89–96 
LVI   
 Yes74%62–870.001
 No93%90–97 
LUSI   
 Yes82%71–930.02
 No91%88–95 
CI   
 Yes80%68–930.004
 No91%88–95 

Because advanced age correlates with poor overall survival in general, the influence of age on disease-specific survival (DSS) was assessed instead. The overall 5-year DSS rate was 94% (95% CI, 91–97%). The 5-year DSS for patients age ≥ 70 years was 89% (95% CI, 81–98%) compared with 95% (95% CI, 92–98%) for those age < 70 years (P = 0.02), as shown in Figure 4. On multivariate analysis, the same factors that correlated with poor OS also were found to correlate with poor DSS (age ≥ 70 years [RR: 3 and 95% CI, 1–9; P = 0.03], the presence of lymphovascular invasion [RR: 4 and 95% CI, 1–9; P = 0.008], aggressive histology [RR: 4 and 95% CI, 2–11; P = 0.001], and cervical involvement [RR: 3 and 95% CI, 1–8; P = 0.04]).

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Figure 4. Disease-specific survival (DSS) and patient age. P = 0.02.

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Compliance and Complications

Compliance with radiation therapy was assessed in terms of who received their treatment according to the general guidelines in the Department of Radiation Oncology at MSKCC during the study time period. When IVRT was given alone, the typical dose was 18–21 Gy given at 6–7 Gy per fraction. Such treatment was given to 300 of 311 patients (96%) treated with IVRT alone in the current study. The remaining 11 patients received their IVRT as follows: in 5 patients the dose per fraction was reduced from 6–7 Gy to 5 Gy to decrease the dose to the vaginal surface, 3 patients withdrew from treatment on their own even though they did not report any toxicity, in 2 patients the dose of 1 of the 3 fractions was reduced to < 7 Gy based on physician preference, and in 1 patient the dose of the first of 3 fractions was decreased from 7 to 5 Gy because of delayed vaginal healing after surgery. The guidelines also stated that when postoperative EBRT was given, the typical dose of 45 Gy in 25 fractions followed by IVRT to a total dose of 12–15 Gy at 4–5 Gy per fraction be delivered. This combination was given to 80% of the patients in the current study (75 of 94 patients). The remaining 19 patients were treated as follows: 9 received EBRT alone (6 because of physician or patient preference and 3 because of acute toxicity during EBRT), in 7 patients the dose of EBRT was not 45 Gy (6 cases were because of physician preference and 1 case was the result of stroke), and in 3 patients the dose of 1 of the 3 fractions was different from the other 2 fractions (2 were physician preference and in 1 case the dose of the last fraction was increased from 4 Gy to 5 Gy because of time delays from a previous fraction). Thus, the overall rate of treatment deviation in the current study was 7% (30 of 405 patients 11 of whom were treated with IVRT alone and 19 of whom were treated with EBRT plus IVRT). Of these 30 patients, 10 were age ≥ 70 years and 20 were age < 70 years (P = 0.12). If the reason for the deviation was acute toxicity only, the corresponding rates were 1% (1 of 84 patients) versus 1% (4 of 321 patients), respectively (P = 0.6). If the deviation was for reasons other than acute toxicity, the corresponding rates were 11% (9 of 84 patients) versus 5% (16 of 321 patients), respectively (P = 0.09). The influence of deviation in dose on vaginal/pelvic control also was evaluated. The recurrence rate was 7% (2 of 30 patients) for those patients with a deviation compared with 3% (13 of 375 patients) for those patients without a deviation (P = 0.6).

Of the 405 patients, 9 (2%) developed late complications of the vagina, GI tract, or GU tract that were ≥ Grade 3. None of the nine patients had any deviation in their radiation therapy (five treated with IVRT alone and four treated with EBRT plus IVRT). The 5-year actuarial rate of ≥ Grade 3 complications for the whole group was 3% (95% CI, 1–4%). In the patients age ≥ 70 years, the 5-year actuarial rate was 3% (95% CI, 0–7%) compared with 3% (95% CI, 1–5%) in the patients age < 70 years (P = 0.7). The influence of comorbidity on overall complications was evaluated. The 5-year actuarial rate was 3% (95% CI, 0–5%) in those patients with or those without comorbidity (P = 0.7). The impact of the type of radiation therapy used was found to be of borderline significance. The 5-year rate was 3% (95% CI, 0–4%) in those patients treated with IVRT alone compared with 5% (95% CI, 0–9%) in those patients treated with EBRT plus IVRT (P = 0.056). The overall 5-year rates of GI, GU, and vaginal complications were 2% (95% CI, 0–3%), 1% (95% CI, 0–2%), and 1% (95% CI, 0–1%), respectively. The influence of age on each of these complications is shown in Table 6.

Table 6. The 5-Year Late Complications Rate (Grade ≥ 3) According to age
ComplicationAge ≥ 70 yrsAge < 70 yrsP value
  1. GI: gastrointestinal; 95% CI: 95% confidence interval; GU: genitourinary.

GI2% (95% CI, 0–4)2% (95% CI, 0–3)0.9
GU2% (95% CI, 0–5)1% (95% CI, 0–2)0.12
Vaginal0%1% (95% CI, 0–2)0.4

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

According to published cancer statistics for 2003,19 the estimated number of newly diagnosed cases of endometrial carcinoma in the U.S. is expected to be 40,100. The overall prognosis for the majority of patients with endometrial carcinoma is very good. According to the FIGO 2001 report,20 the 5-year survival rate for 6260 patients with endometrial carcinoma (Stage I–IV disease) who were treated between 1993–1995 was 76.5%. However, despite this, the number of patients who die from this disease remains significant with an estimated expected number of deaths in 2003 of 6800. Furthermore, the mortality rate from this disease is on the rise. The difference in the 5-year relative survival rates between 1974–1976 and 1992–1997 according to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program was statistically significant (88% vs. 84%; P < 0.05), in favor of the earlier time period.19

Therefore, there are considerable efforts being made in an attempt to identify certain prognostic factors that could predict poor outcome even in patients with early-stage disease. One such factor has been patient age. In the prospective randomized trial of Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) for Stage I disease, Creutzberg et al.21 reported that a patient age ≥ 60 years was an independent predictor of death from endometrial carcinoma (hazard ratio of 3.1 and 95% CI, 1.2–8; P = 0.02). The data in the literature also suggest that there is incremental increase in the risk of dying from endometrial carcinoma with increasing age. In a review of 819 patients with Stage I-II endometrial carcinoma from the Gynecologic Oncology Group database, Zaino et al. demonstrated that the RR increased from 1 for patients who were age ≤ 45 years (reference) at the time of diagnosis to 2 for patients age 55 years, 3.4 for patients age 65 years, and to 4.7 for patients age ≥ 75 years.2

In the current study, patient age ≥ 70 years was found to be an independent predictor of poor local-regional control (RR: 3 and 95% CI, 1–10; P = 0.019), DFS (RR: 2 and 95% CI, 1–13; P = 0.03), and OS (RR: 4 and 95% CI, 2–7; P = 0.001). The negative impact of advanced age remained manifest even after using DSS rather than OS as an endpoint (RR: 3 and 95% CI, 1-9; P = 0.03). An attempt was made to reduce any potential bias between the patients age ≥ 70 years and those age < 70 years. The two groups were balanced with regard to race, extent of surgery, histology, lymphovascular invasion, lower uterine segment involvement, and cervical involvement. In the group of patients age ≥ 70 years, more patients had their surgery performed at MSKCC and more patients received EBRT, but the differences did not reach statistical significance (P = 0.07 and P = 0.08 respectively). Patients age ≥ 70 years were more likely to have deep invasion (P = 0.008) but the depth of invasion was not found to be an independent predictor of outcome in the current series. Thus the imbalance according to the depth of invasion cannot account for the difference in outcome according to age.

The frequent association between older age in endometrial carcinoma patients on the one hand and, conversely, deep myometrial invasion and aggressive histologies always raises the possibility that the poor outcome in older patients is entirely the result of such an association. In the current study, patient age ≥ 70 years was found to be a predictor of poor locoregional control, DFS, OS, and DSS independent of other poor prognostic factors. Even after excluding patients with aggressive histologies or deep myometrial invasion, the 5-year DFS rate still was inferior in those patients who were age ≥ 70 years compared with their younger counterparts (88% vs. 96%; P = 0.059). The data from the literature, in general, support this finding. In the PORTEC randomized trial, which was limited to patients with Stage IB, Grade 2and 3 disease and those with Stage IC, Grade 1 and 2 disease, older age was found to be an independent predictor of poor outcome.21 Older age also was found to be an independent predictor of poor survival in patients with Stage I disease, including those with PS and CC histologies (HR: 4.62 and 95% CI, 2.59–8.23) according to the 2001 FIGO report.20 Furthermore, Abeler et al.22 reported on 181 patients with CC endometrial carcinoma and found older age to be a significant predictor of poor DFS on multivariate analysis (P = 0.03). Stewart et al. reported on 119 patients with high-risk features (i.e., deep myometrial invasion or aggressive histologies) who were treated with whole abdominal radiation therapy.23 Older age was found to be a significant predictor of poor DFS on multivariate analysis (P = 0.004). Therefore, it is reasonable to conclude from the current study as well as others that the influence of advanced age is independent of other poor prognostic factors such as deep myometrial invasion or aggressive histologies.

The impact of the type of radiation therapy used on vaginal/pelvic control was evaluated in the current study. The results showed no difference in the control rate between patients treated with IVRT alone and those treated with EBRT plus IVRT for the whole group and for the subset of patients age ≥ 70 years (P = 0.5). In addition, because EBRT was given to more patients with deep myometrial invasion or cervical involvement, the impact of the type of radiation therapy used was evaluated in this group of patients but there was still no significant difference detected (P = 0.6).

With regard to radiation toxicity, it sometimes is assumed that elderly patients in general tolerate treatment poorly, but the available data in the literature do not support that view. Pignon et al. reviewed nine trials of the European Organization for Research and Treatment of Cancer to investigate whether a threshold age exists beyond which pelvic radiation therapy generates more toxicity. There were 1619 patients who were divided into 6 age categories beginning with age ≤ 50 years up to age ≥ 70 years. The RR of severe late toxicity (Grade > 2) was reported to range from 1 for those patients age < 50 years to 1.55 to those patients age ≥70 years (P = 0.32).24 More specifically, in patients treated with adjuvant pelvic radiation therapy in the PORTEC trial,25 the 5-year rate of late complications was not significantly higher in patients age > 70 years compared with younger patients (P = 0.68).

In the current series, patient age ≥ 70 years was not found to be associated with a higher rate of Grade ≥ 3 late toxicity of the vagina, GI tract, or GU tract (overall 3% in both age groups; P = 0.7). Compliance with what is considered the “standard” radiation therapy also was found to be similar in both groups (P = 0.12). More important, the rate of deviation because of acute toxicity was the same (1% in both groups; P = 0.6). The rate of vaginal/pelvic recurrence was 7% in patients with deviation from the “standard” radiation dose compared with 3% for patients without such a deviation (P = 0.6). Although the difference was not statistically significant, it is important to encourage not only older patients but at times the treating physician to try to complete the prescribed treatment to obtain the highest rate of control, realizing that radiation toxicity does not correlate with age.

Why older patients with early-stage endometrial carcinoma tend to fare worse independent of other factors is not clear. Nevertheless, clinical efforts should be directed toward maximizing the therapeutic ratio in those patients. The notion of limited life expectancy should not hinder that effort because survival to the age of 80 years and beyond has been reported to have increased in many developed countries.26 The remaining life expectancy of a white female age 75 years is estimated to be 11.7 years.27 Recent data have suggested that laparoscopic staging in elderly patients with gynecologic malignancies appears to be well tolerated.28 Perhaps the use of laparoscopy as a staging tool to better direct subsequent therapies instead of laparotomy might be useful in this group of patients. Whether pelvic EBRT is superior to IVRT in elderly patients with early-stage endometrial carcinoma could not be determined accurately from this retrospective study because EBRT generally was given to those patients with deep invasion or those with cervical involvement. The toxicity data regarding pelvic Intensity Modulated Radiation Therapy (IMRT) are promising.29 It would be interesting to evaluate such treatment techniques in elderly patients with endometrial carcinoma to determine whether IMRT could reduce the toxicity of conventional pelvic radiation therapy even further. The data from the literature indicate that elderly women with gynecologic malignancies tolerate chemotherapy rather well.30 Because of the relatively high rate of disease recurrence in elderly patients with endometrial carcinoma, such patients should be encouraged to participate in clinical trials attempting to assess the benefit of adjuvant chemotherapy in patients with high-risk endometrial carcinoma. Such encouragement is important because elderly patients in general have been shown to be underrepresented in cancer clinical trials.31

Some of the limitations of the current study relate to its retrospective nature with all its inherent biases. We attempted to reduce such biases by comparing the two groups of patients according to known clinical/pathologic prognostic factors as well as surgical/radiation therapy factors. The cutoff age of 70 years is arbitrary, but it has been used extensively in the medical literature in general when comparing elderly patients with younger ones. Full surgical staging was not used routinely in the current study. However, the rate was not significantly different between the two groups. It could be argued that a comparison of patients who were treated with surgery alone with those patients who received postoperative radiation therapy would have been useful. However, such a comparison would be difficult to perform because all patients with Stage IB-II endometrial carcinoma are offered adjuvant radiation therapy at MSKCC. Furthermore, the purpose of the current study was to determine the influence of old age on outcome in a group of patients who were treated with adjuvant radiation therapy.

Even when treated in a similar fashion, patients with endometrial carcinoma who are age ≥ 70 years appear to fare worse than younger patients, independent of other poor prognostic factors. The rate of complications from adjuvant radiation therapy, despite a higher rate of comorbidity in elderly patients, was found to be similar in both age groups. Endometrial carcinoma appears to be intrinsically more aggressive in older patients, thus mandating further improvement in their treatment strategies.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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