Chemoradiation for invasive cervical cancer in elderly patients: outcomes and morbidity

Authors

  • M. GOODHEART,

    Corresponding author
    1. Departments of *Obstetrics and Gynecology and †Radiation Oncology, University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center; and ‡Department of Biostatistics, University of Iowa College of Public Health, Iowa City, Iowa
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  • G. JACOBSON,

    1. Departments of *Obstetrics and Gynecology and †Radiation Oncology, University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center; and ‡Department of Biostatistics, University of Iowa College of Public Health, Iowa City, Iowa
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  • B.J. SMITH,

    1. Departments of *Obstetrics and Gynecology and †Radiation Oncology, University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center; and ‡Department of Biostatistics, University of Iowa College of Public Health, Iowa City, Iowa
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  • L. ZHOU

    1. Departments of *Obstetrics and Gynecology and †Radiation Oncology, University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center; and ‡Department of Biostatistics, University of Iowa College of Public Health, Iowa City, Iowa
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Michael Goodheart, MD, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 4630 JCP, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52240, USA. Email: michael-goodheart@uiowa.edu

Abstract

Age may impact survival and treatment in cervical cancer patients. We sought to determine if treatment and survival were different in elderly patients and whether chemoradiation increased morbidity. We performed a retrospective chart review to identify patients treated with definitive radiation therapy at the University of Iowa Hospitals and Clinics between 1997 and 2001. Three hundred sixty-four patients had a new diagnosis of invasive cervical cancer, of which 150 patients were treated with radiation. We excluded patients treated postoperatively or with palliative intent, leaving 96 patients treated with definitive radiation therapy. Patients were divided into two age categories: elderly (≥65) and nonelderly (<65). We compared these groups with respect to treatment received, morbidity, and survival. Sixty-nine (72%) women were less than 65 years old, and 27 (28%) women were greater than or equal to 65 years old. Chemoradiation was associated with decreased mortality (P < 0.01). The decrease in mortality did not differ between the two age cohorts (all causes: P = 0.66; cancer specific: P = 0.65), nor was there a difference in the complication rate due to chemoradiation (P = 0.70). Although elderly patients were more likely to be diagnosed with nonsquamous histologies (P < 0.01), their odds of receiving chemoradiation were 0.35 (95% CI: 0.13–0.90) times the odds for nonelderly. Elderly cervical cancer patients more often have nonsquamous histology and are likely to receive only radiation therapy compared to younger patients. Treatment with chemoradiation was associated with similar survival increases in both age cohorts. Complication rates between the two were similar. Chemoradiation should be considered in elderly patients with invasive cervical cancer.

The primary treatment for advanced cervical cancer has been definitive radiation therapy. Even with appropriate doses, pelvic and systemic failures can be significant. Based on improved results in other treatment sites, cooperative groups have investigated the question of whether combined chemotherapy and radiation could improve survival and decrease failures in patients with advanced disease. Between 1999 and 2002, six randomized trials were published investigating combined treatment modalities, of which five showed improved progression-free survival and overall survival in patients treated with concurrent cisplatin-based chemotherapy and radiation therapy compared to radiation therapy alone(1–6). The National Cancer Institute (NCI) mailed a clinical announcement on February 1999 suggesting that strong consideration should be given to the addition of chemotherapy to radiation therapy in the treatment of invasive cervical cancer(7).

Our institution adopted a policy of chemoradiation in the late 1990s. A significant proportion of our patients with invasive cervical cancer are elderly as defined as age 65 or greater. We performed a retrospective analysis of elderly and nonelderly patients diagnosed with cervical carcinoma treated during this period. Our aims were to determine if treatment outcomes were different in elderly versus nonelderly patients, what proportion of our patients were treated with combined chemoradiation versus radiation alone, and whether chemoradiation substantially increased treatment morbidity in elderly patients.

Materials and methods

We performed a retrospective chart review to identify patients treated with definitive radiation therapy at the University of Iowa Hospitals and Clinics between 1997 and 2001. The University of Iowa Hospitals and Clinics Institutional Review Board approved this study. During the study period, 364 patients had a new diagnosis of invasive cervical cancer. Of these, 150 patients were treated with radiation. We excluded patients treated postoperatively or with a palliative intent. A total of 96 patients were treated with definitive radiation therapy and were included in the analysis. Patients were divided into two age categories: elderly (age >65) and nonelderly (age <65). We compared these patient groups with respect to type of treatment received, morbidity, and survival.

Treatment

All patients received pelvic radiation. External radiation therapy was delivered to the pelvis with 10 or 18 MV photons utilizing computed tomography–based treatment planning. Treatment fields extended from the L4–L5 interspace to the bottom of the obturator foramina or 3 cm below the lowest level of disease. Lateral fields encompassed the sacrum, pelvic lymph nodes, and cervical tumor. Para-aortic radiation was administered for pathologically proven disease or image positive para-aortic lymph nodes. When para-aortic treatment was indicated, the pelvic and para-aortic areas were treated with a contiguous field with the superior border of treatment starting at the L1–L2 interspace or above the highest level of known para-aortic disease. Custom shielding was utilized on all fields. External radiation treatment to the volumes described above consisted of 45–50.4 Gy delivered at 1.8 Gy per fraction for 25–28 fractions. The dose was prescribed to the 100% isodose line with respect to the isocenter. This isodose line encompassed the cervix, uterus, tumor, presacral, and pelvic lymph nodes, as well as the upper vagina.

External beam radiation was followed by intracavitary brachytherapy or an alternative form of boost. The majority of patients had low-dose rate after loading cesium applications. A total of 35–40 Gy was prescribed to point A to be delivered in one or two insertions. Point A was defined as 2 cm above the external os, as marked by the tandem flange, and 2 cm lateral to the tandem. The ICRU (International Commission on Radiation Units and Measurements) bladder and rectal points were identified, and the prescription limited by the bladder dose total (external and internal radiation) to below 85 Gy and the rectal dose total to below 75 Gy(8). The exceptions are described as follows. Four elderly and one nonelderly patient had brachytherapy delivered by interstitial implants (27–40 Gy) because of tumor geometry precluding tandem and ovoid placement. Two patients, one elderly and one nonelderly, had both intracavitary and interstitial implants (52 and 40 Gy). Two elderly and eight nonelderly patients did not receive brachytherapy, either because of refusal or because of complicating medical conditions that precluded placement. One of these patients had an IMRT (intensity modulated radiation therapy) boost of 10.8 Gy.

Chemotherapy administration was considered when performance status and laboratory values were acceptable. The final decision to deliver chemotherapy was made by the treating physician. Laboratory values included absolute neutrophil count greater than or equal to 1500 per cubic millimeter, platelet count greater than or equal to 100,000 per cubic millimeter, SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) values not greater than 1.5 times above normal values, and Gynecologic Oncology Group (GOG) performance status of at least two. All chemotherapies were administered intravenously with pre- and posthydration given when appropriate, and pre- and postchemotherapy antiemetics prescribed at the discretion of the treating physician. The chemotherapies administered included 52 patients treated with a platinum-based agent alone. There were 9 patients who received weekly cisplatin at 50 mg/m2 (number of cycles ranging 2–4), 42 patients who received weekly cisplatin at 40 mg/m2 (number of cycles ranging 2–6), and 1 patient who received two weekly cycles of carboplatin at an AUC (area under the curve) = 2. Included in this count are two patients treated on GOG 165 arm I who received weekly cisplatin at 40 mg/m2 for five and six cycles. There were two patients treated on GOG 165 arm III who received weekly 5-fluorouracil at 225 mg/m2 for five and six cycles, and one patient treated on an institutional-sponsored protocol involving weekly topotecan at 2.5 mg/m2 for five cycles. The sixth patient who received treatment on protocol listed in Table 1 under the “Protocol” section was treated by Radiation Therapy Oncology Group 90-01 and was randomized to the radiation-only arm.

Table 1.  Demographic comparisons between elderly and nonelderly patients (N = 96)
FactorNumber of patients (%)P value
Elderly (n = 27)Nonelderly (n = 69)
  • a

    Other histologies include small cell, clear cell, papillary serous, adenoid cystic, and poorly differentiated.

  • b

    DVT: nine patients, PE: two patients, and DVT with PE: two patients.

  • c

    Brachytherapy consists of intracavitary radiation, interstitial radiation, or both.

  • d

    When administered, chemotherapy was given in addition to radiation, as 100% of patients received some form of radiotherapy.

  • e

    A platinum-based agent was used 96% of the time.

Age (years)
 Median7647 
 Range65–8931–63 
Stage
 I5 (18)11 (16)0.59
 II10 (37)29 (42) 
 III11 (41)21 (30) 
 IV1 (4)8 (12) 
Histology
 Squamous14 (52)59 (85)<0.01
 Adenocarcinoma6 (22)4 (6) 
 Adenosquamous4 (15)2 (3) 
 Othera3 (11)4 (6) 
Residual disease
 No disease18 (67)42 (61)0.60
 Disease9 (33)27 (39) 
Complications
 Yes6 (22)20 (29)0.61
 No21 (78)49 (71) 
Thromboembolic diseaseb
 Yes2 (7)11 (16)0.60
 No25 (93)58 (84) 
Protocol
 Yes0 (0)6 (9)0.19
 No27 (100)63 (91) 
Radiation treatment
 Radiation alone2 (7)8 (12)0.55
 Radiation with brachytherapyc25 (93)61 (88) 
Chemotherapy treatmentd
 No chemotherapy12 (44)15 (22)0.03
 Chemotherapye15 (56)54 (78) 

There were 14 patients treated with combination chemotherapy consisting of 7 patients treated with cisplatin and 5-fluorouracil combinations (number of cycles ranging 1–3), 3 patients treated with cisplatin and taxane combinations, either paclitaxel or docetaxel (number of cycles ranging 1–3), 3 patients treated with platinum and etoposide combinations (number of cycles ranging 1–3), and 1 patient treated with a combination of cisplatin and topotecan for three cycles. The majority of the chemotherapy-treated patients (57%) received between four and five cycles of platinum-based therapy.

Toxicity analysis

Treatment-related complications were defined as complications that were felt to be the direct result of the patients’ treatment for cervical carcinoma. The complications requiring hospitalization or surgery caused a severe impairment in the functional ability of the patient, were felt to be life threatening, or met criteria to be included as a grade 3 or 4 toxicity as per the Common Terminology Criteria for Adverse Events(9). It was difficult to decipher which of the different treatment modalities administered were directly responsible for each of the treatment toxicities listed and to what percentage each treatment contributed to each toxicity. This was especially true for the patients treated with combination therapy. There were 27 patients treated with radiation therapy only, and those who experienced major toxicities are reported in the results section. There were no patients treated with chemotherapy alone and therefore no toxicities were directly attributable to chemotherapy only. Of note, for the patients treated with combined chemoradiation, we encountered no grade 3 or 4 toxicities due to neutropenia, thrombocytopenia, nausea, vomiting, or any other classic chemotherapy-associated toxicity. We also reviewed the incidence of thromboembolic events (TE) in our patient cohort. Although TE did not meet the above-stated definition of a complication, we included this in our evaluation as a separate analysis to follow up on previously reported data from our institution(10).

Statistical methods

Statistical analysis focused on comparisons between age cohorts of elderly (≥65) and nonelderly (<65) patients. Effects of other treatment-related factors, such as histologic subtypes (squamous, adenosquamous, or other) and cancer stages (I, II, III, or IV), were also considered. The Kruskal–Wallis test was used to compare the distributions of cancer stages between age cohorts. Fisher exact test was used to compare age cohorts with respect to other treatment-related categorical factors. Odds ratios (ORs) comparing elderly to nonelderly patients were estimated and compared across levels of treatment-related factors with logistic regression. Subsequent survival analysis of overall and cancer-specific survivals was performed. Survival was defined as the time from cancer diagnosis to the event of interest (all-causes mortality and cancer-specific mortality). Subjects for whom the event of interest was not observed were treated as censored observations in the analysis. Survival curves were estimated with the methods of Kaplan–Meier. Univariate and multivariate Cox proportional hazards regression models were used to assess the effects on survival of age and other treatment-related covariates. All statistical tests were two sided and carried out at the 5% level of significance.

Results

During the time period from January 1997 to December 2001, there were 96 patients who met entry criteria. Age ranges for the entire cohort were 31–89 years with a mean of 55 years and a median of 52 years. The study cohort was divided into two groups, which consisted of 69 (72%) women who were less than 65 years old and comprised the nonelderly group and 27 (28%) women who were 65 years old or older and comprised the elderly group. Table 1 provides demographic comparisons of the two groups. For the nonelderly cohort, ages ranged from 31 to 63 with a median of 47 years, and for the elderly cohort, ages ranged from 65 to 89 with a median of 76 years. Follow-up for the two groups was similar and ranged from 1 to 95 months with a mean of 48 months for the elderly group and 40 months for the nonelderly group. Follow-up for the surviving patients ranged from 33 to 95 months with a mean of 66 months. Clinical stage of disease was divided as follows between elderly and nonelderly, respectively: stage I (5/11), stage II (10/29), stage III (11/21), and stage IV (1/8), with no stage differences identified between the age groups (P = 0.59). Likewise, histologic subtypes were divided as follows: squamous carcinoma (14/59), adenocarcinoma (6/4), adenosquamous (4/2), and other (3/4), which included adenoid cystic (1 elderly), clear cell (1 elderly), papillary serous (1 nonelderly), poorly differentiated (1 elderly), and small cell (3 nonelderly). As noted in Table 1, it was more common for the nonelderly patients to be diagnosed with squamous carcinomas. Overall, 59 (85%) nonelderly patients were diagnosed with squamous carcinomas as opposed to 14 (52%) elderly patients, while it was more common for elderly patients to be diagnosed with nonsquamous histologies such as adenocarcinoma, adenosquamous, small cell, clear cell, papillary serous, adenoid cystic, and poorly differentiated carcinomas (P < 0.01).

Among the elderly and nonelderly patient cohorts, we found no differences between the two groups with respect to the presence or absence of residual disease after treatment (P = 0.60), nor was there a difference noted in the complication rate between the two groups (P = 0.61). As a follow-up to our previous paper, we reviewed the incidence of TE in this patient cohort. A total of 13 patients of the 96 included in this study (13.5%) experienced TE. Two patients were in the elderly group and the remaining 11 were in the nonelderly group. Of the two elderly patients with TE disease, one patient had a pulmonary embolism (PE) and one patient had both a deep venous thrombosis (DVT) and a PE. Both of these patients are alive and well without evidence of disease. Of the 11 nonelderly patients with TE disease, 9 patients had DVT, 1 patient had a PE, and 1 patient was diagnosed with both a DVT and a PE. Of the 11 nonelderly patients, 8 have died and the remaining 3 are alive without evidence of disease. Although there was no association between TE and age (P = 0.60), survival or chemotherapy administration (data not shown), we did find a 13.5% incidence of TE in this patient population, which is consistent with our findings of a 16.7% incidence in our previously studied patient population with cervical carcinoma(10).

Although there was no statistical difference between elderly and nonelderly patients being treated on a protocol (P = 0.19), possibly due to the overall small number of patients in this subanalysis, it is interesting to note that no elderly patients were treated on protocol and only six (9%) of the nonelderly were treated on protocol. The majority of patients (>90%) in both treatment groups were treated off protocol.

The two patient cohorts were compared with respect to treatment modality. Treatment modalities included radiation alone, with or without brachytherapy, or in combination with chemotherapy. All patients received some form of radiotherapy. As shown in Table 1, independent of patients receiving chemotherapy, the most commonly administered radiation treatment regimen to both groups was external beam radiotherapy with brachytherapy administered to 25 (93%) patients in the elderly group and 61 (88%) patients in the nonelderly group, as opposed to external beam radiotherapy alone (P = 0.55). Most nonelderly patients (n = 54, 78%) were treated with chemotherapy, in addition to radiotherapy, when compared to elderly patients (n = 15, 56%) (P = 0.03). Administered types of chemotherapy varied but primarily consisted of platinum-based agents. Of the entire 96 patient cohort, 27 (28%) patients, both elderly and nonelderly, did not receive chemotherapy. When chemotherapy was administered, a platinum-based agent, either alone or in combination, was used 96% of the time, with cisplatin at 40–50 mg/m2 being the most common regimen in 51 (74%) cases.

We were interested in whether the elderly or nonelderly patient populations were more likely to receive chemotherapy in addition to radiation therapy and if this additional treatment had any influence on the complication rate or survival between the two groups. Table 2 provides the estimated odds of receiving chemotherapy in addition to radiation therapy in the elderly versus nonelderly patient cohorts. Overall, the odds of chemotherapy administration among elderly patients were 0.35 (95% CI: 0.13–0.90) times the odds among nonelderly. The ORs were further stratified by histology and stage of disease and were compared across strata with logistic regression techniques. As indicated in the table, there is no significant difference between the ORs among patients with squamous histology and those with other histologies (P = 0.18), nor is there a trend in the ORs across the disease stages (P = 0.48). Our data demonstrate that elderly patients are significantly less likely to receive chemotherapy (P = 0.03). The differential treatment with chemotherapy was not observed to change with advancing stage nor did it differ across histologic subtypes. The estimated complication and mortality relative risks associated with the addition of chemotherapy to radiation therapy are given in Table 3 for elderly and nonelderly patients, separately. In statistical comparisons, no significant differences between the two age groups were observed for the relative risks of complications (P = 0.70), all-causes mortality (P = 0.66), or cancer-specific mortality (P = 0.65).

Table 2.  OR of receiving chemotherapy in elderly versus nonelderly patients stratified by histology and stage
FactorOR95% CIP value
  • a

    Comparison of OR across factor levels.

  • b

    Other histologies include adenocarcinoma, adenosquamous, small cell, clear cell, papillary serous, adenoid cystic, and poorly differentiated.

All patients0.35(0.13, 0.90)0.03
Histology
 Squamous0.34(0.10, 1.13)0.18a
 Otherb0.07(0.01, 1.53) 
Stage
 I0.20(0.03, 1.23)0.48a
 II0.31(0.11, 0.87) 
 III0.48(0.13, 1.75) 
 IV0.73(0.08, 7.14) 
Table 3.  Estimated relative risks (RR) of complications, all-cause mortality, and cancer-specific mortality associated with chemotherapy administration in elderly and nonelderly patients with cervical carcinoma
OutcomeElderly (n = 27)Nonelderly (n = 69)P value
RR95% CIRR95% CI
  • a

    Includes thromboembolic disease, fistula formation, cystitis/proctitis, pelvic necrosis, ureteral obstruction, and bowel obstruction.

Complicationsa0.85(0.33, 2.19)1.12(0.41, 3.11)0.70
All-cause mortality0.63(0.18, 1.55)0.48(0.21, 1.07)0.66
Cancer-specific mortality0.87(0.22, 3.47)0.45(0.20, 1.02)0.65

Treatment-related morbidities are summarized as follows. There were 13 patients (13.5%) who developed TE, 2 in the elderly group and 11 in the nonelderly group. In the elderly group, one patient developed both a DVT and a PE who was treated with radiotherapy alone and one patient developed a PE who was treated with combination therapy. Of the 11 nonelderly patients who developed TE, 1 patient was treated with radiation alone and developed a DVT. Of the patients treated with combination therapy, one patient developed both a DVT and a PE, one developed a PE, and eight developed a DVT. Of the seven patients (7.3%) who developed fistulas, all were between the ages of 35 and 53 and were therefore counted in the nonelderly group. One patient developed both a rectovaginal and a vesicovaginal fistula, two patients developed rectovaginal fistulas, and four patients developed vesicovaginal fistulas. All patients received combination chemoradiation except the two patients with rectovaginal fistulas who received radiation therapy only. There were five patients (5.2%) who developed cystitis, proctitis, or colitis. Two patients were in the elderly group, one who developed cystitis received radiotherapy alone and the other developed proctitis and received combination therapy. Of the remaining three patients in the nonelderly group, one who developed colitis received radiotherapy alone and the other two patients developed proctitis, with one receiving radiotherapy only and the other receiving combination therapy. There were two patients (2.1%) who had severe radiation necrosis. Both patients were diagnosed with stage IIIB disease and underwent radiation therapy only and developed grade 4 radiation necrosis. The 40-year-old patient required uterine artery embolization to control vaginal hemorrhage, and the 72-year-old patient required hyperbaric oxygen treatments in addition to blood transfusions to control chronic vaginal bleeding. Two patients (2.1%) developed bowel obstructions. Both patients were diagnosed with stage IIIB disease and were treated with combination therapy. The 52-year-old patient underwent loop colostomy and is alive and well. The 74-year-old patient was managed conservatively with bowel rest and central venous nutrition. She ultimately decided to enter into hospice care and died 4 months after her diagnosis. There was one patient who developed a ureteral stricture posttreatment. This 27-year-old patient with stage IIA disease underwent combination therapy and 7 months after completing therapy developed a distal left ureteral stricture with left flank pain and irritative voiding symptoms. She underwent successful left-to-right transureteroureterostomy and is currently alive and well.

Table 4 lists the factors important in cancer-specific survival that were identified in Cox regression analysis. As noted, advanced stage (univariate: P = 0.02; multivariate: P = 0.04) and treatment with brachytherapy in addition to external beam radiotherapy (univariate: P < 0.01; multivariate: P < 0.01) were significant factors in both univariate and multivariate analysis, while multivariate analysis showed a significant decreased risk for squamous histology relative to adenocarcinoma (P < 0.01) and a survival advantage for the administration of chemotherapy in addition to radiation therapy (P = 0.03). Factors identified by univariate and multivariate analysis to be significant in overall survival are listed in Table 5. All factors examined by univariate analysis were noted to be significant in predicting overall survival and included age (P = 0.02), advanced stage (P = 0.04), squamous histology (P = 0.01), the presence of residual disease (P < 0.01), brachytherapy given in addition to external beam radiotherapy (P < 0.01), and the administration of chemotherapy (P = 0.01). Factors important in multivariate analysis include the presence of residual disease (P < 0.01), brachytherapy given in addition to external beam radiotherapy (P = 0.04), and the administration of chemotherapy (P = 0.02).

Table 4.  Cox univariate and multivariate analysis of factors important in cancer-specific survival for patients with cervical carcinoma
FactorUnivariate analysisMultivariate analysis
RR95% CIP valueRR95% CIP value
  • RR, relative risk of cancer-specific death.

  • a

    Referent category.

  • b

    Other histologies include small cell, clear cell, papillary serous, adenoid cystic, and poorly differentiated.

  • c

    Brachytherapy consists of intracavitary radiation, interstitial radiation, or both.

  • d

    When administered, chemotherapy was given in addition to radiation, as 100% of patients received some form of radiotherapy.

  • e

    A platinum-based agent was used 96% of the time.

Age
 <65a11
 ≥651.40(0.66, 2.99)0.380.95(0.40, 2.26)0.91
Stage
 Ia11
 II0.82(0.25, 2.68)0.740.98(0.28, 3.44)0.98
 III2.77(0.92, 8.35)0.073.39(1.06, 10.82)0.04
 IV4.43(1.28,1 5.34)0.024.18(0.83, 21.10)0.08
Histology
 Adenocarcinomaa11
 Squamous0.43(0.16, 1.14)0.090.21(0.07, 0.63)<0.01
 Otherb0.71(0.17, 2.98)0.630.46(0.10, 1.98)0.29
 Adenosquamous1.84(0.49, 6.91)0.370.25(0.05, 1.20)0.08
Radiation treatment
 Radiation alonea11
 Radiation with brachytherapyc0.21(0.09, 0.49)<0.010.20(0.07, 0.60)<0.01
Chemotherapy treatmentd
 No chemotherapya11
 Chemotherapye0.52(0.26, 1.06)0.070.38(0.17, 0.89)0.03
Table 5.  Cox univariate and multivariate analysis of factors important in overall survival for patients with cervical carcinoma
FactorUnivariate analysisMultivariate analysis
RR95% CIP valueRR95% CIP value
  • RR, relative risk of all-cause mortality.

  • a

    Referent category.

  • b

    Other histologies include small cell, clear cell, papillary serous, adenoid cystic, and poorly differentiated.

  • c

    Brachytherapy consists of intracavitary radiation, interstitial radiation, or both.

  • d

    When administered, chemotherapy was given in addition to radiation, as 100% of patients received some form of radiotherapy.

  • e

    A platinum-based agent was used 96% of the time.

Age
 <65a11
 ≥651.98(1.10, 3.57)0.021.66(0.85, 3.25)0.13
Stage
 Ia11
 II0.67(0.26, 1.71)0.410.88(0.32, 2.47)0.81
 III2.23(0.94, 5.30)0.061.89(0.73, 4.93)0.19
 IV2.96(1.02, 8.55)0.042.05(0.44, 9.63)0.36
Histology
 Adenocarcinomaa11
 Squamous0.356(0.16, 0.79)0.010.51(0.21, 1.31)0.16
 Otherb0.541(0.16, 1.81)0.320.83(0.22, 3.09)0.78
 Adenosquamous1.543(0.50, 4.77)0.450.78(0.19, 3.22)0.73
Residual disease
 No diseasea11
 Disease12.66(6.26, 25.53)<0.0110.06(4.68, 21.63)<0.01
Radiation treatment
 Radiation alonea11
 Radiation with brachytherapyc0.20(0.09, 0.42)<0.010.34(0.12, 0.98)0.04
Chemotherapy treatmentd
 No chemotherapya11
 Chemotherapye0.47(0.26, 0.85)0.010.41(0.19, 0.87)0.02

Overall and cancer-specific survival curves are provided in Figure 1 to compare treatment modality and age cohorts. In panel A1, the overall 5-year survival for patients treated with combination therapy was 64.8% compared to 33.3% for the radiotherapy-only group (P = 0.01). In panel A2, the overall 5-year survival for the less than 65-year-old group was 60.1%, whereas in the elderly cohort it was 44.4% (P = 0.02). Panels B1 and B2 show the curves for cancer-specific survival stratified by treatment modality and age at diagnosis, respectively. In panel B1, the cancer-specific survival was 68.5% for the combination therapy group and 49.7% for the radiotherapy-only group (P = 0.07). In panel B2, the cancer-specific survival was 61.6% for the less than 65-year-old group and 70.8% for the elderly group (P = 0.38).

Figure 1.

Kaplan–Meier survival curves for A) overall survival and B) cancer-specific survival stratified by (1) treatment received and (2) age.

Discussion

Invasive carcinoma of the cervix is decreasing in incidence in the United States and developed countries where screening programs are well established. Worldwide, it is the second most common invasive malignancy in females(11). The disease has a bimodal distribution, with peaks in the 30–39 and 60–69 age groups(12). Public policy and screening programs primarily focus on younger patients, which results in many elderly patients not receiving the proper screening and care they need. The American Cancer Society recommends that the upper age limit of screening should be 70 years old(13). The US Preventative Services Task Force suggests that screening can stop at age 65(14), yet in a data analysis from the Surveillance, Epidemiology and End Results program, the incidence of cervical carcinoma is higher in the patient population above 65 compared to those below 65 years of age(15). According to this same study, survival in this elderly population is also decreased when compared to their younger counterparts. In those patients 65 years and older, the 5-year relative survival rate is 50% compared to 62% for those less than 65 years old(15). Based on data from the NCI, 25% of new cervical cancer cases and 41% of deaths from cervical cancer in the United States occur in the 13% of the population that is 65 years of age or older(16). This age group is predicted to include 20% of the population by the year 2030. Women in this age group are less likely to be screened for cervical carcinoma than their younger counterparts(17), and as a result, the incidence of cervical carcinoma in the elderly patient population may continue to increase.

Our study dates were purposely placed surrounding the NCI clinical announcement on the addition of cisplatin-based chemotherapy to standard radiotherapy for advanced-stage cervical carcinoma. This clinical alert was based on five major randomized studies published from 1999 to 2000 that showed a significant improvement in survival with the addition of cisplatin-based chemotherapy to radiation as compared to radiation therapy alone for locoregionally advanced cervical cancer. The publication of these studies and a clinical alert by the National Institutes of Health led to a change in the standard of care for the treatment of this entity. These studies were open to women of all ages who met the study criteria, including an adequate performance status. Elderly women were not excluded from these studies, but they represented fewer than 10% of the patients enrolled. As a result of this change in clinical practice and a lack of reports specifically comparing different treatment modalities in elderly patients, we were interested in determining whether there was a difference in treatment modalities employed based on age and if the overall outcomes were different with respect to survival and complications between elderly and nonelderly patients.

We noted, as have others(18,19), that elderly patients were more often diagnosed with nonsquamous histologies. In our study, the elderly were not more likely to be diagnosed at a more advanced stage than younger patients, which agrees with another published report(19). We found it noteworthy that the elderly cohort had no increased complications when compared to the nonelderly cohort, although elderly patients were less likely to receive chemotherapy. It appears that neither stage nor histology was a factor when determining whether to administer chemotherapy to the different cohorts as shown in Table 2. It also appears that the administration of chemotherapy alone did not increase the risks of complications, all-cause mortality, or cancer-specific mortality in the elderly compared to the nonelderly (Table 3). Although more nonelderly patients received chemotherapy, the administration did not appear to be based on histology or stage. If the complication rates are no different, consideration should be given to treating these patient populations in a similar manner.

We found patients who received combination therapy and were less than 65 years old survived longer, although there was no difference in cancer-specific survival. The literature is replete with multiple articles both in support of these data(15,18,20) and others refuting our results(19,21–23). Comparison with our study is difficult because treatment in most of these articles is limited to radiation therapy only. Our study supports the data from the NCI clinical announcement demonstrating an increased survival for patients treated with combination therapy. Our data show that younger patients with cervical carcinoma survived longer despite demographic similarities to the older patients. This may be partially explained by the expected actuarial decrease in survival with increasing age in the general population. In our cohort, there was no difference in cancer-specific survival between the two groups based on age at diagnosis. We were encouraged by the data demonstrating no stage or histology bias in the decision to administer chemotherapy to elderly or nonelderly patients (Table 2) and that the impact of chemotherapy did not cause an increase in the complication rate among elderly patients as compared to younger patients. Our data support the administration of chemoradiation to elderly patients with cervical carcinoma who have an adequate performance status. In our study, chemoradiation was associated with improved survival in elderly patients with no excess treatment-related morbidity when compared to younger patients.

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