Patterns of care of cervical cancer in the elderly: A qualitative literature review

JGO-00399; No. of pages: 9; 4C: Journal of Geriatric Oncology xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Journal of Geriatric Oncology

Patterns of care of cervical cancer in the elderly: A qualitative literature review Venkatesulu Bhanu Prasad 1, Supriya Mallick ⁎,1, G.K. Rath 1 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi

a r t i c l e

i n f o

Article history: Received 31 July 2016 Received in revised form 3 October 2016 Accepted 1 December 2016 Available online xxxx Keywords: Elderly Cervix Pattern of care Radiotherapy Chemotherapy Surgery

a b s t r a c t Introduction: Cancer of the uterine cervix is the fourth most common cancer worldwide among women. However, there is limited data about elderly cervical cancer patients and gross underrepresentation of elderly patients in clinical trials. Hence, the optimal therapy of such patients is not well formulated. Methodology: We conducted this systematic review of evidence to assess patterns of care in elderly patients with cervical cancer. Results: A total of 17,338 publications are reported in PubMed until July, 2016 pertaining to cervical cancer. Out of these, only 24 publications (full length papers or meeting proceedings) reported about clinical outcomes of elderly patients with cervical carcinoma. These publications report data from as early as 1949 to the present. In these publications, out of 14,479 patients aged ≥60 years of age, 11,279 (77.89%) received external beam radiation. Concurrent chemotherapy has been used in 11 publications. Brachytherapy usage has been reported in 19 publications. In a few studies, brachytherapy was not used because of fear of toxicity. Overall, low dose rate (LDR) was the most common modality, followed by high dose rate (HDR). The authors have showed technical reasons (48.7%), comorbidities (69.4%) and patient refusal (38.3%) as causes for not delivering brachytherapy. Five-year overall survival (OS) has been found to be inferior to the non-elderly cohort and ranges from 27%–69% for elderly patients compared to 58%–75% in the non-elderly population. An 11% 5 year OS has been reported for patients treated with suboptimal radiation dose compared to 74% in those treated with chemo radiotherapy followed by brachytherapy. Conclusion: Gross underrepresentation of patients above 65 years in clinical trials has resulted in treatment dilemmas in the elderly. Newer advances like immunotherapy, hypoxic modifiers, image guided radiation, image guided brachytherapy are promising approaches to reduce treatment complications and optimize outcome in elderly patients in cervical cancer. © 2016 Elsevier Ltd. All rights reserved.

1. Introduction Cancer of the uterine cervix is the fourth most common cancer among women worldwide and seventh overall with an estimated 528,000 new cases in 2012. Eighty-five percent of the global burden occurs in less developed countries with an estimated 266,000 deaths from cervical cancer worldwide in 2012 [1]. Cervical cancer most commonly occurs in the 30–40 year age group but a bimodal increase occurs after the age of 70 with increased mortality [2]. The treatment protocols for elderly patients are difficult to formulate since there is gross underrepresentation of elderly patients in clinical trials [3]. Presence of comorbidities, hormonal changes, changes in bone mineral density, alteration in lean body mass, reduction in functional reserve of kidneys and heart causes changes in drug distribution leading to increased drug

⁎ Corresponding author at: Department of Radiation Oncology, All India Institute of Medical Sciences, India. Tel.: +91 9899448450; fax: +91 11 26589243. E-mail address: [email protected] (S. Mallick). 1 Concept, Literature Search, Analysis, Manuscript Writing.

toxicity. Psychosocial aspects, absence of caregivers, nutritional and swallowing problems, and cognitive decline cause issues of compliance to therapy [4,5]. Comprehensive geriatric assessment (CGA) tools are available to assess frailty and acts as a pointer towards biological age. CGA assess a patients functional capacity, polypharmacy, nutritional status, cognitive function, geriatric syndromes and comorbidities, but are cumbersome and time consuming [6,7]. With the advances in healthcare and an increase in the lifespan, the population above 65 years is around 524 million worldwide and constitutes 8% of world's population in 2010 according to National Institute of Aging, USA. According to current estimates, this subgroup will increase 3 times to reach 1.5 billion by 2050. Between 2010 and 2050, the number of older population in less developed countries is estimated to increase by 250% compared to the 71% increase in developed countries [8]. Hence, cancer therapy in elderly patients is a pertinent issue in developing countries as it is in the developed world. In a SEER analysis conducted between 1988 to 2005 assessing patterns of care in carcinoma cervix, it was found that 26.9% of patients were above 60 years [9]. This systematic review of evidence has been done to assess patterns of care in elderly patients with cervical cancer.

http://dx.doi.org/10.1016/j.jgo.2016.12.004 1879-4068/© 2016 Elsevier Ltd. All rights reserved.

Please cite this article as: Bhanu Prasad V, et al, Patterns of care of cervical cancer in the elderly: A qualitative literature review, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.12.004

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2. Materials and Methods 2.1. Date Source and Search Method Two authors (BP and SM) independently searched PubMed, Google search, and Cochrane library for eligible studies using the following search words: Cervical cancer AND elderly, from 1950 to July 1, 2016 published in the English language and proceedings from the American Society of Radiation Oncology (ASTRO), the American Society of Clinical Oncology (ASCO), the European Society of Radiation Oncology (ESTRO), and the European Society of Medical Oncology (ESMO) from 2000 to 2016 were also searched for potentially eligible studies. The details of the search strategy in PubMed have been mentioned in the supplementary digital content. References from the primary search result were also manually searched for potentially eligible studies. 2.2. Study Selection We included only published articles describing cervical cancer management with surgery, radiotherapy or chemotherapy in the ≥65 years

age group or comparing patients ≥65 years with a younger cohort. Articles on pathology and genetics alone without report on treatment and clinical outcomes were excluded from the analysis. Two independent authors (BP and SM) selected the eligible trials. Any disagreement between two authors was solved by discussing with a third author (GKR). Study selection has been depicted in Fig. 1 PRISMA flow diagram [10]. 2.3. Data Collection and Data Items Two authors independently (BP and SM) extracted all data from the eligible trials. The following data were collected from each of the study: name of the first author, year of publication, age group described, TNM staging, and treatment received, associated disease, disease free interval, overall survival, toxicity grading, interruption of treatment, usage of brachytherapy. Initially, all data were tabulated in a Microsoft Excel spread sheet. We neither asked the author(s) nor contacted the publishers for any unpublished data. A quantitative meta-analysis was not done in view of differing age groups reported and usage of different radiation doses and brachytherapy schedules in the eligible studies. Primary endpoint of our review was to assess whether the survival

Fig. 1. PRISMA flow chart depicting the selection of publications.

Please cite this article as: Bhanu Prasad V, et al, Patterns of care of cervical cancer in the elderly: A qualitative literature review, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.12.004

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Fig. 2. Use of different treatment modality for the elderly patients.

Fig. 3. The frequency of publication in each decade.

outcomes in elderly are different from younger cohort, secondary endpoints were to assess treatment modalities that were used and to assess toxicity profile.

3. Results A total of 17,338 publications were reported in PubMed until July, 2016 pertaining to cervical cancer, out of which 48 publications represented cervical cancer in the elderly population. Out of the 48

publications, only 24 publications (full length papers or meeting proceedings) reported about clinical outcomes of elderly patients with cervical carcinoma. Forty-one percent of these publications were from 2001 to 2010 [Fig. 1]. This highlights minimal attention to the growing problem of elderly cervical cancer worldwide. The age cut-off of elderly also varied across publications and few considered age of ≥60 years as elderly; however, few articles have set age 70 or 80 as the cut-off to be considered elderly. These varied criteria increased heterogeneity in data interpretation and made it difficult to put a real picture of pattern of care in elderly patients. Treatment options have also varied across different studies from surgery only, to concurrent chemo-radiotherapy depending on stage and institutional protocol. Thirty-nine percent and 36% patients received only radiotherapy and radio-chemotherapy, respectively [Fig. 2]. These publications report data for a long period of time and as early as 1949. Hence, treatment modality varied widely. Among the available data for treatment modality, 4 publications reported use of Cobalt 60 tele-therapy or Orth voltage radiation or Radium and Roentgen therapy. However, newer series have reported use of conventional treatment with linear accelerator and even intensity modulated radiotherapy [Fig. 3]. In these publications, out of 14,479 patients aged ≥60 years, 11,279 (77.89%) received external beam radiation. Concurrent chemotherapy has been used in 11 publications. Brachytherapy usage has been reported in 19 publications. In few studies brachytherapy was not used because of fear of toxicity. Overall, low dose rate (LDR) was the most common modality followed by high dose rate (HDR) [Fig. 4]. One study reports pulse dose rate (PDR) with interstitial technique as well. Interestingly, the series where brachytherapy has been reported as high as 30% did not receive the treatment [11]. The authors have showed technical reasons (48.7%), comorbidities (69.4%) and

Fig. 4. Use of different radiation machine for the elderly patients.

Please cite this article as: Bhanu Prasad V, et al, Patterns of care of cervical cancer in the elderly: A qualitative literature review, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.12.004

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Fig. 5. Comparison of survival in younger and older patients.

patient refusal (38.3%) as causes for not delivering brachytherapy. 5 year OS have been found to be inferior to the non-elderly cohort and ranged from 27%–69% for elderly compared to 58%–75% in the nonelderly population [Fig. 5]. Meng et al. reported a dismal 11% 5 year OS for patients treated with suboptimal radiation dose compared to 74% treated with chemo radiotherapy followed by brachytherapy [12]. Survival outcome and treatment details of all published literature have been tabulated in Table 1. These results shows a possibility of achieving equivalent or near equivalent results even in elderly patients when adequate dose of radiation along with chemotherapy followed by radiation. Acute and late toxicity of radiation has been reported in different studies and are tabulated in Table 2. 4. Discussion 4.1. Challenges of Treatment Delivery in Elderly Patients with Cervical Cancer Cervical cancer can present as early or locally advanced. In early cervical cancer, the treatment of choice is surgery followed by adjuvant radiation or chemo radiation based on the risk factors. In locally advanced cervical cancers the treatment of choice is radical chemo radiation. Brachytherapy forms an integral component of treatment in early as well as locally advanced cervical cancer. 4.2. Challenges with Surgery Radical vaginal or abdominal hysterectomy by open or laparoscopic route is the most common surgical procedure performed in patients with early stage cervix cancer. Patients require spinal or general anesthesia. Comorbidities, like diabetes mellitus, hypertension, coronary artery disease, metabolic syndrome act as risk factors for anesthetic clearance. Normal physiological aging causes reduction in reserve in organ systems causing increased risk of perioperative and postoperative complication. Post-operative complications like bleeding requiring blood transfusion, paralytic ileus, bladder dysfunction, fistula, lymphocele, and wound healing secondary to infection, sexual dysfunction secondary to nerve damage and vaginal shortening and pulmonary embolus are known events [13–16]. Choi et al. compared outcomes of radical hysterectomy in age groups of 41–50 (group A) and N 65 years (group B). Medical comorbidities in group B were higher than group A, primarily due to hypertension (23.3 vs. 56.5%, p = 0.014);

additionally, no significant differences were reported in post-operative complications with 1 mortality in group B due to bleeding [17]. Susini et al. compared post-operative morbidity in age group N70 in two different time periods from 1985 to 1990 and 1991 to 1995 and found that patients free from post-operative complications were greater in 1991– 1995 (76%) compared to 1985–1990 (52%) (p = 0.001). Among the 213 patients analyzed, 76% had a preexisting illness like hypertension 40% and DM 18% and two or more associated diseases were found in 48% of patients [18]. These studies show that the incidence of associated comorbidities is higher and post-operative complications are similar to the younger cohorts. However, it should be taken into account that both studies reported patients eligible for radical surgery. In a SEER database analysis of 28,902 patients, 3879 (13.4%) were aged 60 to 69, 2543 (8.8%) were 70 to 79 years of age, and were 1364 (4.7%) 80 years of age. Among women with early stage (IB1-IIA) tumors, primary surgery was performed in 82.0% of women b 50 years of age, compared with 54.5% of women aged 70–79 and 33.2% of those above 80 years of age (P b .0001). For those women who underwent primary surgery, use of radical hysterectomy, the procedure of choice, decreased with age from 58.9% of patients b50 years old to 20.4% in those above 80 years of age (P b .0001). Among the patients treated with surgery, lymphadenectomy was undertaken in 66.8% of women b 50 years of age versus 29.0% of those aged 70–79 years and 9.1% of patients 80 years old (P b .0001). In patients with locally advanced cervical cancer (IIB to IVA), no cancer directed therapy was done to 138 (3.9%) women less than 50 years of age, compared with 80 (7.3%) of those aged 70– 79 years and 74 (12.1%) of the women above age 80 (P b .0001). This SEER analysis clearly shows disparities in surgical treatment among patients with cervical cancer with regards to age [9]. Shortcoming of this analysis is comorbidity profile and reason of suboptimal treatment was not documented. Fuchtner et al. compared morbidity outcomes in patients b 65 and N 65 of age undergoing radical hysterectomy for carcinoma cervix found that the incidence of surgery-related complications was 5 (11.1%) in the N65 years group and 9 (9.9%) in the younger group (p = 0.825). Early postoperative medical complications occurred more frequently in the N65 years age group (11.1%) than in the younger group (5.6%) (p = 0.238), but no statistical significance was seen [19]. 4.3. Challenges with Chemo Radiation The National Cancer Institute in the United States issued an alert in the year 1999 recommending chemo-radiation with cisplatin as the

Please cite this article as: Bhanu Prasad V, et al, Patterns of care of cervical cancer in the elderly: A qualitative literature review, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.12.004

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Table 1 Studies describing overall and disease free survival outcomes in different studies. Author

Study period

Age group defined

Frickle et al., 1957 [65] 1940–1949 N60 years Salinska et al., 1979 [66] 1963–1968 N70 years Grant et al., 1989 [67] Kennedy et al., 1989 [68] Chapman et al., 1992 [69] Mitsuhashi et al., 1995 [70]

1979–1984 N75 years 1972–1984 N75 years

Comparator

n

Overall survival

None 40–49 N70 years None None

217 515 85 22 27

5 year OS 45.4% 5 year OS 57.4% 5 year OS 45.9% NA 5-year OS 34.5%

363

5-year OS 27.1%. 5-year CCS stages I, II, III, or IV 100%, 92%, 74%, and 32%.(b70) 5-year CCS stages I, II, III, or IV 100%, 81%, 73%, and 54% (N70) 5 year OS 58.0% 5 year OS 46.4 % 5-year OS 70% for entire cohort 75% b 65, 69% 65–74, N75 years 42% (p 0.001) 5-year OS 70.4% 5 year OS 40.9% (p 0.001),

1951–1985 N65 years 1970–1987 N70 years

b70 ≥70 years

167 126

Mitchell et al., 1998 [71] 1975–1993 N70 years

35–69, N70 b65 N65 b70 years N70 years

338 60 221 87 163 109

Brun et al., 2003 [72]

1976–1996 N65 years

Low et al., 2005 [73]

1990–2004 N70 years

Coker et al., 2006 SEER analysis [74]

1992–1999 N65 years

No

1251

Ikushima et al., 2007 [75]

1969–1997 N65 years

Fox et al., 2008 [76] Goodheart et al., 2008 [77]

1993–2003 N60 years 1997–2001 N65 years

b64, 65–74 N75 None N65 b65

337 258 132 100 27 69

Wang et al., 2009 [78]

1993–2007 N70 years

Park et al., 2010 [79]

1998–2007 N65 years

b70 years 70–79 years N80 years RT VS CTRT None Group 1 b45 Gy or no RT Group 2 45 Gy ± BT Group 3 CTRT + BT

552 226 56 61 44 40 29 53 31

b50, 50–59 60–69 70–79 N80 N65 years b65 years None None b70 years ≥70 years

15,790 5326 3879 2543 1364 52 107 30 25 1385 197

b70 70–79 N80 years None

215 124 41 114

Yoshida et al., 2011 [80] 2000–2009 N75 years Meng et al., 2011 [12] 1999–2006 N75 years

Sharma et al., 2012 SEER analysis [9]

1988–2005 N60 years

Gao et al., 2013 [81]

2007–2009 N65

Hata et al., 2014 [82] Hansen et al., 2014 [83] Wright et al., SEER analysis [84]

1995–2012 N80 years 2000–2011 N80 years 1986–2003 N70 years

Sakurai et al., 1999 [85]

1970–1994 N70 years

Lindegaard et al., 2000 [86]

1987–1996 N70 years

Disease free survival

5 year DFS 57.6 % 5 year DFS 60.4%

5 year DFS 65.4% 5 year DFS 55.8% (p 0.015)

3 year cervical cancer morality and all-cause mortality Radiation [yes vs. no] 1.25 [0.90, 1.73]; 0.81 [0.66, 0.99] Chemotherapy [yes vs. no] 0.92 [0.64, 1.32]; 0.95 [0.74, 1.22] Surgery [yes vs. no] 0.35 [0.24, 0.51]; 0.27 [0.21, 0.35] Any treatment vs. no treatment 0.64 [0.45, 0.92]; 0.49 [0.39, 0.62] 5 year OS 59% 5 year OS 68% 5 year OS 49% Survival 80% year not specified All-cause mortality group 1 0.63 95% CI (0.18–1.55) Group 2 0.48 95% CI (0.21–1.07) Cancer-specific mortality group 1 0.87 (0.22, 3.47) group 2 0.45 (0.20, 1.02)

5-year OS 53.5%; 5-year CSS 66.6% 5-year OS 61.8%; 5 year CSS 68.8% 3 year OS 58% 5 year OS for group 1 11% 5 year OS for group 2 27%, 5 year OS for group 3 74%

3 year OS 73.1% 3 year OS 72.9% 2 year OS 75% NA HR for death from any cause N 70 years 2.1 (95% CI, 1.5–3.0). HR for death from cervical cancer N 70 years 1.6 (95% CI, 1.1–2.5). 5 year OS 59% 48% 36% 5 year OS 61% for stage I, 34% for stage II 25% for stage III

3 year DFS 80% 5 year DFS for group 1 11% 5 year DFS for group 2 24%, 5 year DFS for group 3 64%

3 year DFS 71.2% 3 year DFS 67.3% 2 year DFS 69% NA

Tumor control at 5 years were 80% for stage I, 53% for stage II 46% for stage III

[OS-overall survival, DFS-disease free survival, CCS-cervical cancer specific survival, SEER-Surveillance Epidemiology End Results Database].

standard of care in locally advanced cervical cancer [20]. Cisplatin has a wide array side effect profile ranging from severe emesis, electrolyte imbalance, ototoxicity, nephrotoxicity, volume overload due to hydration, myelosuppression, peripheral neuropathy, alopecia, infusion

related reactions, and local soft tissue irritant injury [21,22]. Radiation therapy has a side effect profile which includes dermatitis, cystitis, proctitis, myelosuppression due to pelvic bone marrow irradiation, vaginal dryness, vaginal stenosis, sacral insufficiency fractures,

Please cite this article as: Bhanu Prasad V, et al, Patterns of care of cervical cancer in the elderly: A qualitative literature review, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.12.004

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Table 2 Studies depicting with the toxicity profile described in younger and elderly cohort. Author

Comparator

Therapy received

Acute hematological toxicity

Acute GI and others

Acute GU

Chronic GI

Chronic GU

Grant et al,1989 [67] Mitsuhashi et al., 1995 [70]

None

RT

–

Grade 4–2

–

–

–

b70 ≥70 years

RT

Mitchell et al., 1998 [71]

35–69, N70

RT/CT

Sakurai et al, 1999 [85]

b70 70–79 N80 years of age

RT/surgery

Lindegaard et al, 2000 [86]

None

RT

Low et al., 2005 b70 years [73] N70 years

Ikushima et al., 2007 [75]

b64, 65–74 N75

–

Acute irradiation morbidity – 7 Vaginal perforation – 4 Uterine perforation – 10 Technical 10 Infection 4

–

RT

–

–

–

RT/CTRT

G2 16 (26.7), G3 5 (8.3), G4 11 (.7) G2 23 (52.3), G3 10 (22.7), G4 8 (18.2)

G2 23 (37.7) G3 0 G2 G2 31 (70.5) G3 0 7(11.5) G2 5 (11.4) Grade 3–3 Grade 3–3

RT

Yoshida et al., 2011 [80] Meng et al., 2011 [12]

None

CTRT

Group 1 b45 GY or no RT Group 2 45 Gy with or without brachy Group 3 CTRT + brachy N65 years b65 years

b45 GY or no RT 45 Gy with or without brachy CTRT with brachy

Hata et al., 2014 [82] Hansen et al, 2014 [83]

G2 and G3 Group 1 0% Group 2 0.5% –

–

RT/CTRT

Gao et al., 2013 [81]

G2and G3 Group 1 6% Group2 7% –

–

RT

N65 b65 b70 years 70-79 years N80 years Park et al., 2010 RT VS [79] CTRT

Goodheart et al., 2008 [77] Wang et al., 2009 [78]

Grade 3 or 4 10 (6.0%) 12 (9.5%)

Grade 2 2(1.2%) Grade 4 3 (1.8%) Grade 2 2(1.6%) Grade 4 1 (0.8%) G2 and G3 G2 and G3 Group 1 5.6% Group 1 6.8% Group 2 0% Group 2 8.1% Grade 2 26 (12.2%), G3 3 (1.4%), G4 11 (5.1%) Grade 2 20 (16.1%), G3 8 (6.5%), G4 6 (4.8%) Grade 2 1 (2.4%), G3 2 (4.8%), G4 1 (2.4%) Both GI and GU together Vagina Ulceration G1 27; G2 7 Agglutination G1 76; G2 40 Pelvis Fibrosis G1 66; G2 20 Lymphedema G2 21 Intestine Ulceration G1 6; G2 2 Stenosis G1 9; G2 4 Perforation G3 1 Bladder Fibrosis G1 1 Fistula G3 8 Death 1 Grade 2 both GI and GU (17.1% in Group 1and Group 2 27.7% Grade 3 Group 1 1 Group 2 2 Grade 2 24 (7.1); Grade 2 45 (13.4); Grade 3–4 16 Grade 3–4 2 (0.6) (4.7) Grade 2 15 (5.8); Grade 2 56 (21.7); Grade 3–4 8 Grade 3–4 0 (6.1) Grade 2 3 (2.3); Grade 2 16 (6.2); Grade 3–4 0 Grade 3–4 0 0 Grade 2 2 7.3% (Grade 3–4) Grade 3–4 3% G2 or more11.9%, G2 or more 20.3%, 16.0%, 16.2% 32.7% 27.9% G2 9(14.8) G3 4 (6.6) G2 4 (6.6), G3 2 G2 10 (22.7) G3 1 (2.3) (3.3) G2 5 (11.4), G3 0 Grade 3–1

Grade 3–1

Group 2 G2(0), Group 3 G2(5),G3(1)

Group 2 G2 (0) Group 3 G2 (5), G3 (1)

Group 2–0 Group 3 Grade 2–6, Grade 3–3

Group 2 G-2(3), G-3(1) Group 3 G2-(6), G3(7)

Group 2 G2 (1) Group 3 G2 (3)

CTRT

All grades-17 All grades-77

All grades-3 All grades-11

None

RT

Grade 2–6, Grade 3–1

Grade 2–3

None

RT

0

Grade 2–1

All grade-2 All grade-10 Grade Grade 2–2 2–1 Grade Grade 4–2 2–1

0 0

[RT-radiotherapy, CT-chemotherapy, Grade (G)-RTOG grading system, GI-gastrointestinal, GU-genitourinary].

lumbosacral plexopathy, lymphedema and secondary malignancies [23–26]. In older patients above 65 years of age, with comorbidities like hypertension, DM, CAD, the renal functional reserve could already be compromised and hence nephrotoxicity could be aggravated. In addition with negative nitrogen balance and reduction in lean body mass persistent emesis associated with cisplatin and small bowel toxicity by radiation would be an additive factor in causing nutritional imbalance. Percentage of bone marrow in pelvis can range from 30% to 50%. Pelvic radiation with cisplatin may cause significant myelosuppression especially in elderly patients [27–29]. Grade 2 and 3 hematological toxicity reported in study by Keys et al. was 10% in the radiotherapy group

alone and 50% in the combined modality group. Persistent myelosuppression can be seen up to 1 year after completion of therapy. Hormonal changes associated with menopause may lead to vaginal dryness, recurrent urinary tract infections, alteration in bone mineral density and physical limitation of movements, depression and loss of sexual drive [30–33]. Age related changes may cause difficulty in micturition and genital organ prolapse. Radiation may compound these problems by causing increased vaginal dryness, superadded infections secondary to mucosal injury reported in approximately 26%, and increase incidence of pelvic fractures up to 8.2% [34,35]. Sexual dysfunction secondary to vaginal dryness, vaginal stenosis, which may lead to

Please cite this article as: Bhanu Prasad V, et al, Patterns of care of cervical cancer in the elderly: A qualitative literature review, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.12.004

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dyspareunia is attributed to side effects of radiation, more so in elderly where post-menopausal hormonal changes and associated depression may be additive risk factors [36]. Cisplatin induced peripheral neuropathy was reported in 50% of patients which would be aggravate by coexisting DM [37]. Brachytherapy is an integral part of multimodality treatment of carcinoma cervix. Both low dose rates (LDR) and high dose rate (HDR) intra-cavitary radiation therapy (ICRT) has anesthetic requirements mainly spinal anesthesia. LDR requires prolonged immobilization up to 24–48 h and HDR requires multiple insertions ranging from 3 to 5 depending on dose fractionation schedules followed. Anesthetic clearance in view of comorbidities and prolonged immobilization leading to pulmonary embolism are issues specific in elderly patients. SEER analysis done by Sharma et al. showed that usage of brachytherapy declined by age 66. Seven percent in those b50 years old to 58.9% in patients aged 70 to 79 years and to 46.3% in women above 80 years old (P b .0001) [9]. Mitchell et al. also reported that usage of brachytherapy declined with age such that 11% of patients 60 to 69 years old, 20% aged 70 to 79 years, and 40% of those above 80 years of age did not receive (ICRT) [11].

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4.3.1.3. Modifications in Chemo Radiation Approaches. In patients without any comorbidity above 65 years of age radical chemo radiation with cisplatin should be the standard of care. Consideration should be made towards assessment of biological age in comparison to chronological age [9]. Ceccaroni et a.l in a retrospective analysis of 148 patients assessed tolerance of chemotherapy in patients of N 70 years. Eighty percent of patients had single comorbidity and standard schedule of chemotherapy was administered in 97.3% of patients. Only 6.8% of patients discontinued chemotherapy due to hematological toxicity. Chronological age was not found to adversely influence the ability to receive aggressive treatment [46]. Cetina et al. in a reviewed 59 patients with median age of 62 years with DM and HT, treated with weekly carboplatin and radiation. Seventy-nine percent of patients received 5 cycles of chemotherapy and very few side effects were reported in the study. Thirty month overall survival was 63%, slightly below historical controls. Patients with borderline renal dysfunction may be considered for carboplatin based chemotherapy [47].

4.3.1.1. Cervical Cancer Screening in Elderly. Cervical cancer screening is not a well-discussed topic and most guidelines recommend stopping cervical cancer screening at age 65 for women screened adequately defined by three consecutive negative cytology tests or two consecutive negative human papillomavirus (HPV)/Pap co-tests in the 10 years prior to stopping, with the most recent test within 5 years. These patients are considered not at increased risk for cervical cancer. In addition many reports suggest rarity of high grade lesions in older women. Point should be made that older women who have never been screened have the highest incidence of and mortality from cervical cancer and benefit the most from screening [38,39].

4.3.1.4. Immuno-radiotherapy, Monoclonal Antibody and Other Novel Approaches. Anti-PD-L1 enhances efficacy of radiation through a cytotoxic T cell-dependent mechanism. Radiation with concurrent Anti-PD-L1 induces tumor regression. Immunomodulatory drugs like nivolumab, pembrolizumab are being evaluated in recurrent or metastatic cervical patients. These agents hold promise in future for elderly patients with cervical cancer not fit for cytotoxic chemotherapy. Four ongoing trials are evaluating pembrolizumab and nivolumab in recurrent or metastatic patients. Both trials have enrolled patients above 65 years of age as well [42-44,48-50]. Bevacizumab has shown survival benefit in metastatic cervical cancer [51]. In a phase 2 study, RTOG 0417 of concurrent radiation with bevacizumab showed survival outcomes and toxicity profile similar to that of definitive CTRT [46,52]. In elderly patients, it may be considered as an alternative to cisplatin in patients with non HT comorbidities that preludes usage of cytotoxic chemotherapy. Cervical cancer is a hypoxic tumor [53]. Hypoxic cell modifiers like nimorazole can be explored in elderly patients with cervical cancer not fit for any form of chemotherapy or biological agents.

4.3.1.2. Modifications in Surgical Care. Recent surgical advances like nerve-sparing radical hysterectomy (RH), vaginal radical hysterectomy with laparoscopic lymphadenectomy, total laparoscopic radical hysterectomy (LRH), and robotic laparoscopic radical hysterectomy has shown significant reduction in perioperative and post-operative complications. Charoenkwan et al. reported 100% recovery in bladder function compared to 66% among historical controls after nerve sparing radical hysterectomy [40]. Park et al. compared laparoscopic versus open RH for elderly patients with early-stage cervical cancer and reported that operating time (253.8 vs 271.9 min, P = 0.035), estimated blood loss (375 mL vs 553 mL, P = 0.014), time interval to return of bowel movement (2.3 vs 2.9 days, P = 0.005) and the length of the postoperative hospital stay (9.8 vs 20 days, P = .001) were significantly shorter in the LRH group [41]. In patients with comorbidities radical chemo radiation can still be a credible alternative in early stage cervical cancer [42,43]. A robotic approach compared to conventional laparoscopic approaches provides better three-dimensional view, greater dexterity, and tremor limitation. Magrina et al. compared robotic, laparoscopic, and open abdominal approach. Blood loss and hospital stay were less with robotic approach compared to laparoscopic approaches with equivalent survival outcomes [44]. Nordin et al. did a study to assess desire for cure among elderly patients with cancer and found that elderly desire cure more even if treatment is associated with disfigurement (P = 0.029), elderly believe more strongly that physicians should make treatment decisions for them (P = 0.001). Hence the study concluded that elderly desire radical surgery and cure in a similar way as their young counterparts but are less likely to question physicians decision and hence prone to physician age bias [45].

4.3.1.5. Modifications in Radiation Therapy. Radiation is the primary modality in elderly patients that can be used in patients even with multiple comorbidities. With advances like intensity modulated radiation therapy (IMRT), image guided radiotherapy (IGRT), and proton therapy, bone marrow sparing IMRT toxicity reduction can be achieved especially in elderly patients. Prospective phase 2 study by Gandhi et al. evaluating IMRT vs conventional radiotherapy have shown IMRT arm had less grade 2 acute GI toxicity 31.8% vs 63.6% (P = 0.034) and grade 3 GI toxicity 4.5% vs 27.3% (p = 0.047) than patients receiving conventional radiotherapy [54]. In a phase 3 study by Chopra et al. comparing IGIMRT vs 3DCRT of 120 patients found no difference in grade 2 acute bowel toxicity but late grade 3 bowel toxicity was 3.2% in IMRT arm compared to 17.6% in 3DCRT arm with a significant P value (p = 0.02) [55]. Kidd et al. in a prospective cohort study comparing IMRT vs non IMRT cohort showed that grade 3 bowel and bladder complications were 6% and 17%, respectively, with a significant p value (p = .0017). These evidences form a strong basis for IMRT especially in elderly patients in whom less toxicity would mean better compliance and quality of life. There is very limited experience evaluating proton therapy in the form of case series. Proton with spread out Bragg peak may play an important role in toxicity limitation and enhancing quality of life in elderly patients. NCT01600040 is evaluating proton therapy in adjuvant setting in post hysterectomy patients of carcinoma endometrium and cervix [56]. Brachytherapy should be a part of the standard of care for elderly cervical cancers as well. Use of IMRT or stereotactic boost in place of brachytherapy has resulted in inferior overall survival with hazard ratio of 1.86 (95% CI, 1.35–2.55; P b 0.01) [57]. MRI-guided brachytherapy provides better conformal dose distribution and dose limitation to bowel and bladder [58,59]. Integration of functional imaging with brachytherapy

4.3.1. Means to Avoid Complications in Elderly Patients with Cervical Cancer

Please cite this article as: Bhanu Prasad V, et al, Patterns of care of cervical cancer in the elderly: A qualitative literature review, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.12.004

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V. Bhanu Prasad et al. / Journal of Geriatric Oncology xxx (2016) xxx–xxx

may further limit toxicity and enhance quality of life in elderly patients [60-62]. Patients with significant comorbidities where spinal or general anesthesia is a contraindication patients can be considered with sedation alone as shown by Sharma et al. where HDR ICRT dosimetry was similar for patients done under spinal anesthesia [63]. If patients are not suitable for brachytherapy then IMRT or stereotactic boost can be considered as a last resort to achieve the required tumoricidal doses [64]. 5. Conclusion Geriatric oncology is an evolving subspecialty in oncology. Gross underrepresentation of patients above 65 years in clinical trials has resulted in treatment dilemmas in the elderly. Most of the patients have received suboptimal treatment because of anticipated morbidity. Contemporary surgical options have significantly reduced postoperative morbidity in the elderly cohort. Optimal dose of EBRT with concurrent chemotherapy and brachytherapy is feasible without excess complications in this cohort of patients. Newer advances like immunotherapy, hypoxic modifiers, image guided radiation, and image guided brachytherapy are promising approaches to reduce treatment complications and optimize outcome in elderly patients in cervical cancer. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jgo.2016.12.004. Disclosures The authors have nothing to disclose. Meeting Presentation Not presented. Financial Support No financial support received. Compliance with Ethical Standards: ⁎ Disclosure of potential conflicts of interest: The authors have no conflict of interest. ⁎ Research involving human participants and/or animals: Not applicable. ⁎ Informed consent: Not applicable. Disclosures and Conflict of Interest Statements The authors have no conflicts of interest to disclose. Author Contributions Study Concept: B Prasad, S Mallick, GK Rath. Study Design: B Prasad, S Mallick, GK Rath. Data Acquisition: B Prasad, S Mallick, GK Rath Quality Control of Data and Algorithms: B Prasad, S Mallick, GK Rath. Data Analysis and Interpretation: B Prasad, S Mallick, GK Rath. Statistical Analysis: B Prasad, S Mallick, GK Rath. Manuscript Preparation: B Prasad, S Mallick, GK Rath. Manuscript Editing: B Prasad, S Mallick, GK Rath. Manuscript Review: B Prasad, S Mallick, GK Rath. References [1] GLOBOCAN cancer fact sheets: cervical cancer [Internet]. cited 2016 Jul 11, Available from: http://globocan.iarc.fr/old/FactSheets/cancers/cervix-new.asp.

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Please cite this article as: Bhanu Prasad V, et al, Patterns of care of cervical cancer in the elderly: A qualitative literature review, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.12.004