Definitive chemoradiotherapy for advanced cervical cancer: should it be different in the elderly?

European Journal of Obstetrics & Gynecology and Reproductive Biology 192 (2015) 86–89

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Definitive chemoradiotherapy for advanced cervical cancer: should it be different in the elderly? Inacelli Queiroz de Souza Caires *, Karla Teixeira Souza 1, Marcelo Vailati Negra˜o 1, Julia Andrade de Oliveira 1, Romualdo Barroso-Sousa 1, Rafael Caires Alvino de Lima 1, Paulo Marcelo Gehm Hoff 1, Maria del Pilar Estevez Diz 1 Department of Clinical Oncology, Instituto do Caˆncer do Estado de Sa˜o Paulo – ICESP/Faculdade de Medicina do Estado de Sa˜o Paulo – HC/FMUSP, Av. Dr. Arnaldo, 251, Cerqueira Ce´sar, Sa˜o Paulo, CEP: 01246-000, Brazil

A R T I C L E I N F O

A B S T R A C T

Article history: Received 30 October 2014 Received in revised form 16 April 2015 Accepted 19 May 2015

Background: Cervical cancer (CC) is the second most common cancer in Brazilian women, and approximately 10% of cases occur in elderly patients (pts). In this age group, disease is usually diagnosed in more advanced stages and oncological therapies are usually less intensive, due to comorbidities and impaired performance status. Methods: Retrospective analysis of pts 65 years old with CC admitted at a Brazilian University Cancer Center from August 2008 to February 2012. We performed a descriptive analysis of baseline performance status (PS), disease stage (FIGO), histology, body mass index (BMI), treatment received and overall survival, using the Kaplan–Meier method. Results: 900 medical records were analyzed and 75 pts (8%) fulfilled the inclusion criteria. Median age was 73.4 years old (5.5 years). Squamous cell carcinoma (SCC) was the most common histology (71 pts, 94.7%). 67 (89.3%) had PS 0 or 1 and 52 pts (69.3%) were eutrophic (BMI 18.5–25 kg/m2). At presentation, disease staging consisted of 18 pts (24%) stage I, 35 pts (46.7%) stage II, 8 pts (10.7%) stage III, 12 pts (16%) stage IVa and 2 pts (2.7%) stage IVb. 24 pts (32%) underwent surgery (hysterectomy, adnexectomy, pelvic and paraaortic lymphadenectomy). Adjuvant treatment with radiotherapy (RT) was performed in 13 pts (total dose of external RT in pelvis ranged from 39.6 to 45 Gy, parametrial boost ranged from 14 to 20 Gy and 4 inserts from 7 to 7.5 Gy of brachytherapy); 8 of them received concomitant platinum-based chemotherapy (CT). 30 pts underwent definitive CRT, 17 definitive RT, 1 palliative CT and 3 best supportive care. In the CRT group, 18 pts received cisplatin (CDDP 40 mg/m2/w/6w) and 12 carboplatin (AUC 2/w/6w). During definitive CRT, treatment was discontinued in 39% of pts who received CDDP and 25% of pts who received carboplatin, all due to treatment toxicities. CDDP was associated with more nefrotoxicity (5 pts, 28%) than carboplatin (1 pt, 8.3%). The CDDP group also presented more radiodermatitis and stroke. However, myelosuppression and diarrhea were similar in both groups. After a 26.1-month follow-up, median OS was not reached. Conclusions: Despite advanced age, more than 60% of pts underwent complete CRT treatment. Thus, age should not be the only factor to guide therapeutic decisions in CC. Carboplatin was better tolerated than CDDP in CRT group, but prospective trials are necessary to evaluate the best treatment option in this population. ß 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Elderly Cervical cancer Surgery Radiotherapy Chemoradiotherapy

Background Cervical cancer (CC) is the second and third most common women’s malignancy in Brazil and in the world respectively. It is also the fourth leading cause of cancer deaths in women in this

* Corresponding author. Tel.: +55 11 36862686. E-mail address: [email protected] (I.Q.d.S. Caires). 1 Tel.: +55 11 36862686. http://dx.doi.org/10.1016/j.ejogrb.2015.05.007 0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.

country [1,2]. The age distribution of new cases of CC is bimodal, with peaks at 30–39 years and 60–69 years [3]. Currently, 10–20% of patients with CC are diagnosed at age 65 years. However, due to aging of the general population, the trend is that more elderly patients will be diagnosed with the disease [4]. Age remains a controversial independent prognostic factor. Previous analyzes demonstrated that young women with CC not only have a more aggressive disease than older women, but also a higher mortality rate [5]. In other studies, advanced age seems to be associated with increased cancer-specific mortality [6,7].

I.Q.S. Caires et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 192 (2015) 86–89

Meanwhile, Spanos et al. and Gao et al. detected no differences between these groups [8,9]. Thus, the role of age as a prognostic factor in CC remains unanswered. Elderly women with CC receive different treatment when compared to younger women. Generally, these patients undergo less invasive procedures, such as minor surgery in early stage disease, and modifications of standard treatment in locally advanced disease. A significant proportion of elderly women with CC receive only palliative care and the reason for this is not well established. Impaired performance status (PS), advanced stage disease and association of multiple comorbidities may all be contributing factors [10]. This study aims to evaluate treatment and survival of patients diagnosed with CC at age 65 or older in a Brazilian Cancer Center. We analyzed the tolerance and the toxicity of platinum-based chemoradiotherapy (CRT) and, finally, the differences of treatment with cisplatin (CDDP) and carboplatin in this age group. Patients and methods We conducted a retrospective analysis of the medical records of patients age 65 or older with histologically confirmed CC that were treated at Instituto do Caˆncer do Estado de Sa˜o Paulo (ICESP)/ Hospital das Clı´nicas da Faculdade de Medicina da Universidade de Sa˜o Paulo (HC-FMUSP) from August 2008 to February 2012. This study was approved by the local Ethics Committee. A descriptive analysis was performed regarding histology, disease stage, performance status (PS), body mass index (BMI), anemia, renal function, comorbidities and treatment received. Tumor histology was separated into squamous cell carcinoma (SCC), adenocarcinoma and others. Disease was classified according to the International Federation of Gynecology and Obstetrics (FIGO) stages I–IV. PS was measured using the Eastern Cooperative Oncology Group (ECOG) scale. BMI was used to assess the nutritional status of patients as follows: underweight (<18.5 kg/m2), eutrophic (18.5–24.9 kg/m2) and overweight (25 kg/m2). Anemia was classified as hemoglobin (Hb) levels 10 mg/dL and renal function was estimated by creatinine clearance (CrCl) using the Cockcroft-Gault formula. Renal failure was defined as the presence of CrCl <60 mL/min. The comorbidities assessed included cardiovascular and pulmonary diseases and dementia. Treatment included surgery, exclusive radiotherapy (RT), primary CRT, palliative chemotherapy (CT) and best supportive care (BSC). The surgery performed was hysterectomy with adnexectomy and pelvic and paraaortic lymphadenectomy. Patients submitted to conization and/or trachelectomy were excluded from the study. RT included external beam irradiation of the entire pelvis and brachytherapy. Total dose delivered ranged from 39.6 to 45 Gy in the pelvis and a parametrial boost of 14– 20 Gy divided among six weeks of treatment. Intracavitary high dose brachytherapy consisted of 4 insertions of 7–7.5 Gy. CRT was performed with CDDP 40 mg/m2 or carboplatin AUC 2 given as a weekly dose during all six weeks of external beam RT. Tolerance was estimated based on the number of patients who finished the planned treatment and toxicities were graded using the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE) V4.0. CT consisted of a platinum agent in association with a taxane and all patients received BSC. Statistical analysis Frequency distributions between categorical variables were compared using chi-square tests and the Fisher exact test. Overall survival (OS) was estimated by the Kaplan–Meier method and was defined as time to death from any cause or, for living patients, the last

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date of medical consultation. Statistical analyses were performed with SPSS software version 21.0 (IBM, Armonk, NY, USA). Results We identified 900 pts with CC treated with RT and CT from August 2008 to February 2012. Medical records were analyzed and 75 pts (8%) fulfilled the inclusion criteria. Patient characteristics are described in Table 1. Median age was 73.4 years (5.5 years). SCC was the most common histology (71 pts, 94.7%). Most patients (67, 89.3%) had good PS (0 or 1) and were eutrophic (52, 69.3%). At initial presentation, 18 pts (24%) were stage I (IA1 5, IA2 3, IB1 6, IB2 4), 35 (46.7%) stage II (IIA 9, IIB 26), 8 (10.7%) stage III (IIIA 5, IIIB 3), 12 (16%) stage IVA and 2 (2.7%) stage IVB. Most patients (62, 82.7%) had Hb 10 mg/dL at baseline and had persistent anemia after treatment (51.6%). Most of the group had normal serum creatinine before (56 pts, 74.6%) and after treatment (49 pts, 65.3%). Cardiovascular comorbidities were frequently observed in the study population (47 pts, 57.3%), and hypertension was the most common. Dementia and pulmonary diseases were present in 5 (6.6%) and 4 (5.3%) pts respectively. A total of 24 individuals (32%) underwent surgery. Of the 13 pts with indications for adjuvant treatment, 5 performed RT and 8 CRT. The drug of choice was CDDP for 4 pts and carboplatin for the other 4. No adverse events were observed in the RT group. Patients treated with CDDP presented a good tolerance to CRT, with 100% of Table 1 Patient characteristics. Total (n = 75) Median age (years) ECOG performance-status score – no. (%) 0–1 2 BMI (kg/m2) – no. (%) <18.5 18.5–24.99 >25 Histology – no. (%) Squamous cell carcinoma Adenocarcinoma Others Stage I IA1 IA2 IB1 IB2 II IIA IIB III IIIA IIIB IV IVA IVB

73.4  5.5 67 (89.3%) 8 (10.7%) 6 (8.0%) 52 (69.3%) 17 (22.7%) 71 (94.7%) 3 (4.0%) 1 (1.3%) 18 5 3 6 4 35 9 26 8 3 5 14 12 2

Total (n = 75)

(46.7%)

(10.7%)

(18.6%)

P

Pre-treatment Hemoglobin (mg/dL) – no. (%) 10 62 (82.7%) >10 13 (17.3%) CrCl (mL/min) – no. (%) >60 56 (77.8%) 60 16 (22.2%) Comorbidities Cardiovascular Pulmonary Dementia

(24%)

Post-treatment 51 (72.8%) 19 (27.2%)

0.1668

49 (68%) 23 (32%)

0.2604

47 (57.6%) 5 (6.6%) 4 (5.3%)

BMI, body mass index; ClCr, creatinine clearance.

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88 Table 2 Performed treatment.

Number of patients Surgery Adjuvant treatment Adjuvant radiotherapy Adjuvant chemoradiotherapy Cisplatin Carboplatin Radiotherapy alone Chemoradiotherapy alone Cisplatin Carboplatin Chemotherapy alone Best supportive care Total

24 13 5 8 4 4 17 30 18 12 1 3 75

Completed treatment regimen

(32%) 5 7 4 3 14 19 11 8

(22.7%) (40%)

(1.3%) (4%) (100%)

patients being able to complete the treatment schedule, and only one patient treated with carboplatin failed to complete the treatment regimen due to actinic cystitis, diarrhea and other external causes. Of the 47 pts with locally advanced CC, 17 (36.2%) underwent RT, 11 due to physician choice and 6 due to PS impairment or associated comorbidities. A total of 14 pts in this group completed the treatment regimen. The remaining patients with locally advanced disease (30 pts, 63.8%) received CRT, of which 18 received CDDP and 12 carboplatin (Table 2). The use of carboplatin was due to renal failure in all 12 cases. Before treatment, 14 pts (82.3%) in the RT group and 27 pts (90%) in the CRT group presented anemia. After treatment, most patients persisted with anemia (14 (87.5%) in the RT group and 19 (63.3%) in the CRT group) and there was no statistically significant difference before and after treatment in both groups (P = 0.65 and P = 0.16, respectively). Most patients in the RT group did not present renal failure in the moment of CC diagnosis (15 pts, 88.2%) and treatment did not lead to a statistically significant worsening of renal function (11 pts, 64.7%) (P = 0.16). In the CRT group, the results were similar with 19 (65.5%; 29 pts with available data) and 18 (64.2%; 28 pts with available data) patients presenting normal kidney function before and after treatment respectively (P = 1.0). During primary CRT, treatment was discontinued in 11 pts (36.7%), 7 in the CDDP group and 4 in the carboplatin group, all due to treatment related toxicities (Table 3). Five patients (27.8%) in the CDDP group developed renal failure during treatment, with a median decrease of 23% from baseline creatinine clearance (P = 0.0584), while only 1 patient (8.3%) in the carboplatin group presented nephrotoxicity (P = 1.00). Also, CDDP was associated with a greater incidence of radiodermatitis and stroke. Opposite to these findings, myelosuppression and diarrhea were similar in both groups (Table 4). Table 3 Platinum-based chemoradiotherapy.

Total Completed treatmenta

Cisplatin

Carboplatin

Total

P

18 (60%) 11 (61.12%)

12 (40%) 8 (66.67%)

30 (100%) 19

1.0000

a

Patients that received at least 200 mg/m2 of cisplatin or 5 weekly cycles of carboplatin AUC 2. Table 4 Post-treatment toxicities. Toxicities (G3)

Cisplatin

Carboplatin

P

Renal Anemia Gastrointestinal Cardiovascular Cutaneous

5 1 1 1 1

1 1 1 0 0

0.0584

Fig. 1. Overall survival curve.

Only 1 patient performed palliative CT with carboplatin and paclitaxel and 3 pts received best supportive care only. The median follow up period was 26.1 months and median OS was not reached by the end of the study period (Fig. 1). Discussion Due to aging of the general population, there has been increasing interest in cancer treatment among the elderly. Currently, these patients tend to receive less aggressive treatment as observed in breast, lung, cervical and ovarian cancer studies [10–13]. A similar tendency has been observed in the treatment of myeloproliferative disorders [14]. In our study, we examined the CC prevalence in older women at a Cancer Center in Brazil and made a descriptive analysis of the treatment in this group. The prevalence of CC was 8%, with a median age of 73.4 years at diagnosis, which is equivalent to other analysis (8.8–12.5%), even though it represents the second most common female cancer in Brazil [7,10]. In the elderly population, CC was diagnosed at a more advanced stage (IIB–IV), as was demonstrated in other series [9,15,16]. This provides evidence that this population usually receives a later diagnosis of the disease [9,15,16]. Despite this fact, most patients still had a good PS and an adequate nutritional status at diagnosis, which would enable more intensive oncological treatment, such as CRT. The most common histological type identified was SCC. This was expected since a large cohort study confirmed SCC to be the most common histology in the elderly population [7]. However, a large number of poorly differentiated neoplasms, adenocarcinomas and non-epithelial malignancies were diagnosed in this age group as well [7,10]. Anemia is frequently described as a complication of cancer and of cancer treatment. Moreover, studies show that anemia may even be associated with increased mortality in these patients [17,18]. Despite the large proportion of patients presenting with anemia at the time of diagnosis, this did not impact treatment decisions in the study population. Also, our study did not demonstrate an increased mortality as a consequence of this complication in the elderly population. The study population included a total of 75 pts, all within an advanced age group. Despite advanced age, only 3 pts received BSC alone and 72 pts received some type of cancer treatment, either curative or palliative. Surgical treatment was performed in approximately one third of patients and 54.1% of them were

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submitted to adjuvant treatment. Most patients with locally advanced disease underwent CRT and approximately 66% of them completed the treatment regimen. After a median follow-up of 26.1 months, median OS was not reached, probably as a consequence of good disease control. Other studies addressed the impact of RT in elderly patients with cervical neoplasms. Sakurai et al. had previously examined the use of RT in the elderly dividing the patients into 3 groups: <70, 70–79 and 80 years. In this study, the 5-year overall survival rate was lower in the older group when compared to the younger groups (58%, 50% and 33%, respectively). However, the 5-year cancer specific survival was similar among groups (70%, 68% and 65%) [19]. More importantly, this study demonstrated that comorbidities were more frequently associated to treatment complications than age itself [19]. Mitchell et al. assessed women with locally advanced CC treated with RT and found that 5-year recurrence and mortality rates were higher among elderly patients. However, when patients who did not receive brachytherapy and who had a treatment pause greater than 3 days were excluded from the analyses, there were no significant differences between age groups [20]. Another study by Gao et al. separated patients with CC into 2 age groups, <65 and 65 years, and evaluated survival after CRT. After a median followup of 36.5 months, there was no significant difference in survival rates between the different age groups (73.1% and 72.9% respectively (P > 0.05)) [9]. Similar studies found that low accrual and undertreatment are frequent among older age groups. The GOG Trial that validated platinum-based CRT as standard treatment for locally advanced CC included 94 pts (17.8%) older than 60 years and only 17 older than 70 years [21]. Also, elderly women with CC were less likely to receive CRT when compared to young women with equivalent disease stage despite them having similar toxicity rates. More importantly, both groups had similar survival rates when treatment with CRT was performed [22]. These data suggest that undertreatment of elderly patients seems to be a more important prognostic factor than age alone. Therefore, if the patient is in good clinical condition, there is no reason to deprive them of standard treatment. These studies provide some evidence that elderly patients are able to tolerate radiotherapy, with or without chemotherapy, and should be submitted to this form of treatment when indicated not only for symptom control, but also for reduction in cancer related deaths. Our data demonstrated that the use of CDDP during CRT was associated with greater renal toxicity and, consequently, with more treatment discontinuations when compared to carboplatin. Currently, most of the data directly comparing carboplatin and CDDP as radiosensitizers are originated from small, non randomized or uncontrolled trials. Despite these limitations, one study compared both CRT regimens and demonstrated that carboplatin appears to be equally effective and less toxic than cisplatin [23]. Therefore, carboplatin may be an alternative when treating patients with multiple comorbidities or kidney dysfunction. However, until further trials address this issue, CRT with CDDP remains the standard of care for patients with CC. The limitations of our study are those inherent to any retrospective study. Also, the presence of a younger control group would allow us to compare outcomes between different age groups and add further information to CC treatment. Lastly, the small sample size was a consequence of a single institution study and limits generalization of our findings to different populations. Despite these limitations, our study is one of the few addressing outcomes and treatment tolerance in elderly patients with cervical cancer. It also demonstrates the importance of administering proper cancer treatment to these patients based on their

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performance status and comorbidities and not limiting treatment options based on advanced age alone. In so doing, these patients may achieve equivalent oncological outcomes when compared to younger age groups. Conclusions Elderly patients should receive standard cancer treatment for cervical cancer in the same manner as occurs with younger patients. Treatment decisions should be based on performance status and comorbidities since elderly patients present similar clinical outcomes and treatment tolerance when compared to younger patients. References [1] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v1.2, Cancer incidence and mortality worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010, Available from: http://globocan.iarc.fr [accessed May 2011]. [2] http://www2.inca.gov.br/wps/wcm/connect/tiposdecancer/site/home/ colo_utero. [3] Hacker NF. Uterine cervix. In: Berek JS, Hacker NF, editors. Practical gynecologic oncology. Philadelphia: Lippincott Williams and Wilkins; 2000. p. 407–56. [4] Seamon LG, Tarrant RL, Fleming ST, et al. Cervical cancer survival for patients referred to a tertiary care center in Kentucky. Gynecol Oncol 2011;123:565–70. [5] Lybeert MLM, Meerwaldt JH, van Putten WLJ, et al. Age as a prognostic factor in carcinoma of the cervix. Radiother Oncol 1987;9(2):147–51. [6] Huang HJ, Chang TC, Hong JH, et al. Prognostic value of age and histologic type in neoadjuvant chemotherapy plus radical surgery for bulky (>/=4 cm) stage IB and IIA cervical carcinoma. Int J Gynecol Cancer 2003;13(2):204–11. [7] Wright JD, Gibb RK, Geevarghese S, et al. Cervical carcinoma in the elderly. An analysis of patterns of care and outcome. Cancer 2005;103(1):85–91. [8] Spanos Jr WJ, King A, Keeney E, Wagner R, Slater JM. Age as a prognostic factor in carcinoma of the cervix. Gynecol Oncol 1989;35(1):66–8. [9] Gao Y, Ma J-L, Gao F, Song L-p. The evaluation of older patients with cervical cancer. Clin Interv Aging 2013;8:783–8. [10] Sharma C, Deutsch I, Horowitz DP, et al. Patterns of care and treatment outcomes for elderly women with cervical cancer. Cancer 2012;118:3618–26. [11] Bouchardy C, Rapiti E, Fioretta G, et al. Undertreatment strongly decreases prognosis of breast cancer in elderly women. J Clin Oncol 2003;21:3580–7. [12] Sundararajan V, Hershman D, Grann VR, Jacobson JS, Neugut AI. Variations in the use of chemotherapy for elderly patients with advanced ovarian cancer: a population-based study. J Clin Oncol 2002;20(1):173–8. [13] Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol 2007;25:5570–7. [14] Menzin J, Lang K, Earle CC, et al. The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med 2002;162:1597– 603. [15] Coker AL, Du XL, Fang S, Eggleston KS. Socioeconomic status and cervical cancer survival among older women: findings from the SEER-Medicare linked data cohorts. Gynecol Oncol 2006;102(2):278–84. [16] Rijke JM, van der Putten HWHM, Lutgens LCHW, et al. Age-specific differences in treatment and survival of patients with cervical cancer in the southeast of The Netherlands, 1986–1996. Eur J Cancer 2002;38:2041–7. [17] Benson K, Balducci L, Aapro M. Anemia and cancer. In: Balducci L, Ershler WB, Bennett JM, editors. Anemia in the elderly. New York, NY: Springer; 2007. p. 99–113. [18] Caro JJ, Salas M, Ward A, Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: a systematic quantitative review. Cancer 2001;91:2214–21. [19] Sakurai H, Mitsuhashi N, Takahashi M, et al. Radiation therapy for elderly patient with squamous cell carcinoma of the uterine cervix. Gynecol Oncol 2000;77:116–20. [20] Mitchell PA, Waggoner S, Rotmensch J, Mundt AJ. Cervical cancer in the elderly treated with radiation therapy. Gynecol Oncol 1998;71: 291–8. [21] Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–53. [22] Goodheart M, Jacobson G, Smith BJ, Zhou L. Chemoradiation for invasive cervical cancer in elderly patients: outcomes and morbidity. Int J Gynecol Cancer 2008;18:95–103. [23] Nam EJ, Lee M, Yim GW, et al. Comparison of carboplatin- and cisplatin-based concurrent chemoradiotherapy in locally advanced cervical cancer patients with morbidity risks. Oncologist 2013;18:843–9.