IMPACT OF HIGH AGE ON CANCER TREATMENT
Annamaria Ferrero
Gynaecological Oncology
Academic Department of Gynaecology and Obstetrics Mauriziano Hospital, Torino, Italy
Oslo, 04.06.18
GYNAECOLOGICAL CANCERS IN ELDERLY PATIENTS
• Incidence increases with age to reach a peak during the 7th decade of life
• Median age at first diagnosis is currently 63 years
One third of patients are aged 70 or older
OVARIAN CANCER OVARIAN CANCER
• Life expectancy is rising
• The higher the age, the higher the risk of malignancy
• Women aged 65 and above represent the fastest-growing population
• Increase of gynaecological malignancies
Howlader N et al, SEER Cancer Statistics Review 1975-2012, Bethesda National Cancer Institute 2015
Current International Standard of Care for ovarian cancer
I. Cytoreductive Surgery
The ultimate goal is optimal cytoreduction. The term “optimal” cytoreduction should be reserved for those with no macroscopic residual disease.
II. Systemic Treatment
The standard arm must contain a taxane and a platinum agent administered for six cycles. The recommended regimen is paclitaxel (175 mg/m2) and carboplatin (AUC 5-6) intravenously every 3 weeks.
Acceptable additions or variations in dose, schedule, and route of delivery include:
Dose-dense paclitaxel intravenously (JGOG 3016)
Intraperitoneal chemotherapy in patients < 1 cm residual disease (GOG 172)
Biological Agent: Bevacizumab (GOG 218 -Arm 3)
Int J Gynecol Cancer 2011: 21; 756-762
UNDER-TREATMENT
OF ELDERLY PATIENTS
The prognostic role of age in ovarian cancer is controversially discussed
Elderly patients are less likely to receive standard antineoplastic treatments
• Treatment guidelines less frequently applied than for younger patients
• Less aggressive therapy in elderly patients , even in the absence of comorbidity
Trillsch F et al, J Ovarian Res 2013; Sabatier R et al, Int J Gynecol Cancer 2015; Fourcadier E et al, BMC Cancer 2015
UNDER-TREATMENT AND UNDER- REPRESENTATION
IN CLINICAL TRIALS
Surveillance, Epidemiology, End Results (SEER) Medicare data:
retrospective cohort study, 1995 – 2008
7,938 women older than 65 years,
stage III - IV ovarian cancer, treatment and overall survival
2.9% no treatment, 15.4% surgery only, 24.8% chemotherapy only
41.8% primary debulking surgery and chemotherapy in an optimal timeframe
15.1% primary debulking surgery and chemotherapy but not optimal timing or not all six cycles of chemo completed
In a SEER survey, only 9% of patients with cancer older than 75 were included in clinical trials
Lin JJ et al, Obstet Gynecol 2016;127:81–9; Talarico L et al, J Clin Oncol. 2004; Hilpert F et al, Onkologie 2012;
Freyer G, Ovarian Cancer in Elderly Patients, Springer International Publishing Switzerland 2016
Optimal cytoreduction (residue < 1cm) is associated with better survival benefit compared to residue > 1cm. Presently, the goal has shifted towards obtaining no gross residual disease (0 cm) at conclusion of surgery with better survival benefit.
A debulking surgery with the intent of complete tumor resection frequently requires radical surgical steps: bowel resection, upper abdominal surgery, pelvic and para- aortic lymphadenectomy.
SURGICAL TREATMENT OF ELDERLY PATIENTS WITH OVARIAN CANCER
RESIDUAL TUMOR RESIDUAL TUMOR
Patients older than 65 years more seldom achieved macroscopic complete resection in advanced disease in comparison to younger patients,
accompanied with significantly shorter survival.
Wimberger et al, Gynecol Oncol 2006
SURGICAL TREATMENT OF ELDERLY PATIENTS WITH OVARIAN CANCER
• Elderly women with advanced ovarian cancer have the best survival if they are able to
undergo optimal therapy with primary debulking surgery and chemotherapy
• Given the morbidity of cytoreductive surgery, neoadjuvant chemotherapy followed by
interval surgery has been proposed as an alternative treatment strategy
• Elderly women 3.6 less likely to have surgical treatment (OR = 0.28 [0.19– 0.41])
• Elderly had poorer survival than younger
patients (p< 0.001), more when no guidelines- recommended
Vergote et al, N Engl J Med 2010, Kehoe et al, Lancet 2015 Fourcadier et al, BMC Cancer 2015
Octogenarians have an increased risk of pulmonary and septic complications
UNDER-TREATMENT
OF ELDERLY PATIENTS
Primary treatment:
• nearly all patients <70 years (97%)
• 54% of the patients aged ≥80 years
Combination therapy (debulking surgery and chemotherapy):
• 85% of the patients aged <70 years
• 61% of patients aged 70–79 years
• 22% of patients aged ≥80 years
Over the time in patients aged 70–79:
• PDS + ACT decreased with 22 %
• NACT + IDS increased by 27%
• 5% more patients received chemotherapy only
Schuurman MS et al, Gynecol Oncol 2018
UNDER-REPRESENTATION IN CLINICAL TRIALS
Standard drug combination, dosing and expected side effect profile primarily derived from a younger cohort of patients
Under-representation of elderly patients in prospective ovarian cancer phase III trials
even if eligible
(AGO OVAR-3 trial only 13% ≥ 70 years)
To increase the number of elderly patients in conventional trials for adult
To design specific trials for elderly people not candidates for conventional therapies
POSSIBLE FUTURE STRATEGIES POSSIBLE FUTURE
STRATEGIES
Talarico L et al, J Clin Oncol. 2004; Hilpert F et al, Onkologie 2012;
Freyer G, Ovarian Cancer in Elderly Patients, Springer International Publishing Switzerland 2016
CARBOPLATIN AUC 5 + PACLITAXEL 175 mg/m2 is the standard of care STRATEGIES FOR ELDERLY PATIENTS: 1. Weekly Carboplatin and Paclitaxel
2. Single agent Carboplatin
MITO-5 phase II: WEEKLY DOSING OF CARBOPLATIN AUC2 AND PACLITAXEL 60 mg/m2 for 6 cycles on vulnerable patients 70 and older:
• RECIST response rate: 38.5% ; median OS: 32 months
• Lower toxicity (89% of patients without any unacceptable toxicity)
MITO-7 phase III: 6 cycles of TRI-WEEKLY CARBOPLATIN-PACLITAXEL versus 18 cycles of WEEKLY CARBOPLATIN-PACLITAXEL (older age subgroup):
• Similar progression free survival
• Lower haematological toxicity and higher quality of life with the weekly schedule
EWOC-1 phase II: PACLITAXEL WITH CARBOPLATIN every 3 weeks versus CARBOPLATIN MONOTHERAPY every 3 weeks versus WEEKLY PACLITAXEL WITH CARBOPLATIN (ongoing):
completion of 6 courses of chemotherapy without premature termination for progression, death or unacceptable toxicity in elderly patients with a Geriatric Vulnerability Score ≥ 3
FIRST LINE CHEMOTHERAPY FIRST LINE CHEMOTHERAPY
MEDICAL TREATMENT OF
ELDERLY PATIENTS WITH
OVARIAN CANCER
DELAY OF
CHEMOTHERAPY IN ELDERLY
• 184 patients (average age 73)
• 67.5% of patients able to complete 6 cycles of chemotherapy
• 34% of these a dose reduction
• 45% of these ≥ 1 dose delay
• Any dose delay associated with a decrease in overall survival (p = 0.02)
STRATEGIES
- Pre-treatment scoring systems to identify frailer populations with decreased tolerance to
chemotherapy
- Appropriate starting dose reductions and design of preventive interventions to decrease toxicity
Treatment completed without delay
Joseph N et al, Gynecol Oncol.2015
INTRAPERITONEAL CHEMOTHERAPY
GOG 172 trial (39% of 205 women who received IP cisplatin-paclitaxel were elderly):
• 16 month survival advantage
• Health-related quality of life significantly worse before the fourth cycle and in the weeks after treatment, especially in regards to abdominal pain and neurotoxicity
• Less than half of patients able to complete ≥ 4 cycles
RESULTS:
• 133 patients: 100 <70 years, 33 ≥70 years
• Older patients received fewer cycles of therapy (6.4 vs 5.8, p=0.002)
• Similar dose delays (0.9 vs 0.7, p=0.72) and modifications (0.9 vs 0.36 ,p= 0.11)
• Median PFS (27 vs 31 months) and OS (71 and 62 months) not statistically different
• Grade3/4 neutropenia significantly worse in the older patients (82% vs 100%, p=0.04
• Neuropathy grade ≥2 and other non-hematologic toxicities not different between age groups
Crim A et al, Gynecol Oncol 2017; Armstrong DK et al, NEnglJMed. 2006
100 90 80 70 60 50 40 30 20 10 0
PFS estimate (%)
0 5 10 15 20 25
Time (months)
No. of patients at risk
<70 years
≥70 years 492 345 205 96 29 1
179 124 70 35 6 0
<70 years
≥70 years
ECOG PS 0 ECOG PS ≥1
100 90 80 70 60 50 40 30 20 10 0
0 5 10 15 20 25
Time (months)
No. of patients at risk ECOG PS 0
ECOG PS ≥1
242 167 102 44 12 1
397 283 161 86 23 0
Age Performance status
OTILIA multicentre observational study of bevacizumab-containing therapy in women with newly diagnosed ovarian cancer in Germany
PFS estimate (%)
Clinical outcome: similar PFS irrespective of age and performance status
Wimberger P et al, ESGO 2015
All (n=808) Cardiovascular
comorbidities (n=445) Pre-existing hypertension
(n=406) Diabetes mellitus (n=83)
Median duration of BEV therapy, months
(95% CI) 13.4
(12.8–13.8) 13.4
(12.5–13.8) 13.5
(12.5–13.8) 11.3
(8.1–13.6)
BEV discontinuation, n (%) 433 (54) 233 (52) 209 (51) 50 (60)
All grade AEs, n (%) 599 (74) 348 (78) 318 (78) 67 (81)
Grade 3/4 AEs, n (%) 301 (37) 189 (42) 177 (44) 42 (51)
PFS, months (95% CI) 21.3 (20.3–22.5) 21.3 (20.1–23.1) 21.3 (20.0–23.1) 20.2 (16.8–26.2)
• Age and ECOG performance status do not influence efficacy and tolerability of BEV in newly diagnosed stage IIIB-IV OC
• Patients with comorbidities had similar PFS to the overall population, despite older age and worse ECOG PS
• Grade 3/4 AEs were slightly more common, particularly in patients with diabetes mellitus
• Cardiovascular comorbidities and pre-existing hypertension were not associated with increased risk of BEV treatment discontinuation
• With appropriate care, BEV is an option in patients with comorbidities
OTILIA: Influence of comorbidities on clinical outcome
Mustea A et al, ESMO 2016; Sehouli J et al, IGCS 2016; Woopen et al, ESMO 2017
Safety and Efficacy of Extended Bevacizumab Therapy in Elderly (Q70 Years) Versus Younger Patients Treated for Newly Diagnosed Ovarian Cancer in the International ROSiA Study
Frederic Selle, Nicoletta Colombo, Jacob Korach, Cesar Mendiola, Andres Cardona, Youssef Ghazi, and Amit M. Oza
Int J Gynecol Cancer 28, 4, May 2018
Safety and Efficacy of Extended Bevacizumab Therapy in Elderly (Q70 Years) Versus Younger Patients Treated for Newly Diagnosed Ovarian Cancer in the International ROSiA Study
Frederic Selle, Nicoletta Colombo, Jacob Korach, Cesar Mendiola, Andres Cardona, Youssef Ghazi, and Amit M. Oza
Int J Gynecol Cancer 28, 4, May 2018
Older patients experienced higher incidences of all grade anemia (44% vs 32%), diarrhea (35% vs 25%), and asthenia (22% vs 12%), and grade Q3 hypertension (41% vs 22%) and thromboembolic events (7% vs 2%)
ROC Treatment Algorithm (ESMO Guidelines)
Adapted from Ledermann J, et al. Ann Oncol. 2013;24(suppl 6):vi24-vi32
ROC: Recurrent ovarian cancer; PR: Platinum Resistant;
PS: Platinum Sensitive; PPS: Platinum Partially Sensitive
ROC
PS
Fully PS
- Carboplatin-doublet - Carboplatin + paclitaxel - Carboplatin +
gemcitabine (± bevacizumab) - Carboplatin + PLD
PPS
- Carboplatin-doublet - Trabectedin + PLD
PR
Sequential single agent therapy - Paclitaxel - Topotecan - PLD
- Gemcitabine
CHEMOTHERAPY FOR RECURRENT DISEASE
Patients ≥70 years experienced more neuropathy, with a higher incidence in the C–P arm.
Similar to all study patients, C–PLD provided a better therapeutic index with less toxicity than C–P in elderly women
ANTIANGIOGENIC AGENTS:
BEVACIZUMAB PLATINUM-RESISTANT RECURRENT DISEASE PLATINUM-RESISTANT
RECURRENT DISEASE
Post-hoc exploratory analyses of efficacy, safety and patient-reported outcomes according to age <65 versus
≥ 65 years RESULTS:
PFS and response rate improvement with
bevacizumab were consistent in older and younger patients
Grade ≥ 3 hypertension was more common in elderly bevacizumab-treated patients
Bevacizumab-containing therapy was well tolerated, suggesting a favourable benefit/risk profile
Geriatric assessments are needed to improve selection of elderly patients
Sorio R et al, Gynecol Oncol 2017
Oza A M, ESMO 2017
OLAPARIB IN
ELDERLY PATIENTS
398 patients aged 65 years and older stratified into age groups by 5 year increments and compared to those <65
No differences between age group cohorts and the need for dose reductions while receiving olaparib therapy and dose interruption.
No occurrences of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in any of the older cohorts.
No significant differences in toxicities across age groups.
NCCN, ASCO and SGO guidelines all endorse offering testing for germline BRCA mutations in all women with epithelial ovarian cancer regardless of age
Dockery LE et al, Gynecol Oncol 2017
ENDOMETRIAL CANCER ENDOMETRIAL CANCER
A disease primarily affecting elderly women: mean age at diagnosis 68 years
The greater majority of patients have acquired comorbidities (diabetes, obesity, metabolic syndrome, hypertension, cardiovascular diseases, pulmonary dysfunction)
More aggressive disease in terms of hystology (type 2), histological grade leading to a poor prognosis
Surgery is the main treatment approach at any age:
• laparotomy (historically)
• laparoscopy and robotic surgery (in the last decade several studies have demonstrated feasibility and advantages)
• vaginal approach (chosen especially the elderly)
Siegel R et al, Cancer statistics, CA Cancer J Clin 2015;
US Cancer Statistics Working Group, 1999–2008 incidence and mortality web-based report, US Cancer Statistics 2012
GYNAECOLOGICAL CANCERS IN
ELDERLY PATIENTS
SURGICAL TREATMENT OF ELDERLY PATIENTS WITH ENDOMETRIAL CANCER
For a given surgical approach,
elderly patients do not have more perioperative complications than younger patients
In elderly women, laparotomic approach is associated with more morbidity in terms of blood loss, peri-operative complications and longer hospital stay, thus mini- invasive surgery appears to be a valid option for vulnerable women
Which surgical approach?
Which surgical approach?
Bourgin et al, EJSO 2016
Lymphadenectomy: an integral part of the comprehensive surgical staging of endometrial cancer, but its role in early endometrial cancer still unclear
• Number of lymph nodes removed by laparoscopy or robotic surgery compared to laparotomy: no significant difference as function of patient age
• Lymphadenectomy extend the operative time: a morbidity risk factor for a elderly woman (in elderly every increase of 30 minutes in the operating room causes a 17% increase in the complication rate)
• Lymphadenectomy is associated with perioperative (vascular and neural) and postoperative (lymphedema and neurological) risks
LIMPHADENECTOMY LIMPHADENECTOMY
Bourgin et al, EJSO 2016
In view of the higher severity of endometrial cancer in elderly patients, it would be legitimate to perform lymphadenectomies more often
Further studies are required in order to determine whether nodal staging has to be
performed in this age group.
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER
Radiotherapy:
fractionated radiotherapy and brachytherapy
• less side effects
• meaningful in the treatment of elderly patients
BUT…
women aged 75–84 years and 85 years or older are
significantly less likely to receive radiotherapy than younger women
Rauh-Hain JA et al, Obstet Gynecol 2015; Wright JD et al, Gynecol Oncol 2011
MEDICAL TREATMENT OF ELDERLY PATIENTS WITH ENDOMETRIAL CANCER
6 CYCLES OF THREE-WEEKLY CARBOPLATIN AND PACLITAXEL 6 CYCLES OF THREE-WEEKLY CARBOPLATIN AND PACLITAXEL
Palaia I et al, Oncology 2013; Rauh-Hain JA et al, Obstet Gynecol 2015
• More adjuvant treatment is recommended in the elderly patients because of a higher incidence of advanced disease and aggressive histopathology
• Chemotherapy in very elderly patients is feasible with an acceptable toxicity profile
BUT…
Women aged 75–84 years and ≥ 84 years were significantly less likely to receive chemotherapy
Approximately 50% of elderly patients who were recommended treatment
actually received it
CONCLUSIONS
The number of elderly patients with gynaecological cancers is rising
Elderly patients are less likely to receive standard antineoplastic treatments despite beeing able to tolerate stronger treatments
Elderly patients are under-represented in clinical trials; older age should not be an exclusion criterion in cancer trials
Fraily assessments are needed both in clinical practice and clinical trials
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