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Ovarian cancer in the octogenarian: Does the paradigm of aggressive cytoreductive surgery and chemotherapy still apply?
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Gynecologic Oncology 110 (2008) 133 – 139 www.elsevier.com/locate/ygyno
Ovarian cancer in the octogenarian: Does the paradigm of aggressive cytoreductive surgery and chemotherapy still apply? ☆ Kathleen N. Moore ⁎, Monica S. Reid, Daniel N. Fong, Tashanna K.N. Myers, Lisa M. Landrum, Katherine M. Moxley, Joan L. Walker, D. Scott McMeekin, Robert S. Mannel University of Oklahoma Health Sciences Center, Division of Gynecologic Oncology, Oklahoma City, Oklahoma, USA Received 19 February 2008 Available online 20 May 2008
Abstract Objective. The cornerstone of therapy for advanced ovarian cancer is cytoreductive surgery (CRS) followed by platinum based chemotherapy. Optimal management for very elderly women (N 80) is unclear. This study sought to review the experience with treating ovarian cancer in this population. Materials and methods. This is a retrospective analysis of patients treated between 1991 and 2006. Outcomes included post-operative complications, chemotherapy received and overall survival. Statistical analysis was performed with SAS v.9.1. Results. 85 patients were identified with a mean age of 84 years. 86% of patients presented with advanced disease. Primary CRS was performed on 80%. Among patients with advanced disease who underwent either primary (68) or interval debulking (2), 74% were left with b 1 cm residual disease. Post-operative complications were common with 15% of patients suffering cardiac or pulmonary complications, over 10% with prolonged ileus, wound complications or mental status changes and over 30% requiring transfusion or antibiotics. Death prior to hospital discharge and within 60 days of surgery occurred in 13% and 20%. Among patients who underwent CRS, 13% were unable to receive indicated adjuvant therapy. Among those who were treated, 25% were treated with single agent platinum and 43% completed b3 cycles. Two-year overall survival for those who underwent CRS followed by adjuvant therapy is 51%. Conclusions. Our data suggests that patients N 80 may not tolerate combination surgery and chemotherapy. The extremely high proportion of post-operative complications and relatively high proportion of post-operative deaths argues for a more prudent approach to this group of patients. © 2008 Elsevier Inc. All rights reserved. Keywords: Gero-oncology; Ovarian cancer; Elderly; Complications
Introduction In 2007 it is estimated that 22,430 women will be diagnosed with epithelial ovarian cancer (EOC) and 15,280 women will die [1]. Over 25% of patients are diagnosed and 40% of deaths occur over age 75 [2]. As advanced age has been previously identified as the most important risk factor for development of ☆
Presented as Oral Main Plenary Presentation: Society of Gynecologic Oncologists Annual Meeting, 2007. ⁎ Corresponding author. Division of Gynecologic Oncology, University of Oklahoma, 920 SL Young Blvd., WP 2470, Oklahoma City, OK 73103, USA. Fax: +1 405 271 2976. E-mail address: [email protected] (K.N. Moore). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.03.008
EOC and the proportion of women living into their 8th and 9th decade is increasing, the number of women presenting with advanced EOC who are also elderly can be expected to increase as well. The current paradigm for primary treatment in advanced EOC includes primary surgical cytoreduction followed by combination platinum/taxane chemotherapy. Multiple studies have demonstrated the survival benefit obtained by achieving cytoreduction to no residual disease. This goal may require certain “radical procedures” such as splenectomy, and resection of the diaphragm, bowel or liver [3–9]. Complication rates for the addition of these radical procedures vary in the literature and depending on the population studied. The reported morbidities
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range from 32 to 50% with the majority being minor complications. The reported 30-day mortality rate ranges from 1.5 to 6% with deaths occurring in patients with significant pre-operative or disease related morbidity or age greater than 75. [4,6,9] The survival advantage in cytoreduction to no gross residual disease presumes that the primary surgical effort does not result in such morbidity that it significantly delays or prevents administration of combination platinum/taxane based chemotherapy. The standard of care for adjuvant chemotherapy in advanced EOC is also in flux. The recent collaborative group study evaluating intravenous and intraperitoneal chemotherapy demonstrated a significantly prolonged survival among those patients who received even some of their chemotherapy via an intraperitoneal route [10]. This survival advantage was accompanied by significantly more neuropathy among the intraperitoneal group which persisted to one year post completion of therapy. As the incidence of neuropathy among chemotherapy patients increases with age, will we be able to use a regimen with known high prevalence of significant neuropathy among a more aged population? Will they need a separate standard of care? Little data exists to guide physicians on whether elderly patients should receive the same management as younger patients who present with advanced EOC. Multiple studies have demonstrated poorer overall survival among patients greater than 65. This poorer survival persisted even when corrected for stage, residual disease and performance status [11,12]. One explanation for this outcome is that patients considered to be elderly often do not receive the same standard of care as their younger counterparts [13–19]. This may be a result of bias that they will not tolerate the extensive cytoreductive procedures and combination chemotherapy required to treat advanced EOC. Evaluating patients over 65, studies have reported an increased length of hospital stay, peri-operative mortality, chemotherapy toxicity and decreased survival as compared to younger patients [20,21]. The counter point to the above is that multiple studies have reported that if elderly patients receive the same therapy, their outcomes are equivalent to younger patients [22–25]. In general, our institutional practice is to offer primary cytoreductive surgery followed by adjuvant platinum/taxane based chemotherapy to all patients without an age triage. In cases of significant medical co-morbidities or patient choice, treatment plans are individualized. We sought to evaluate our experience with patients who presented with EOC at age 80 or greater in terms of primary therapy offered, operative complications, ability to receive chemotherapy and disease specific survival. It is important to know if this subset of elderly patients should be managed in a conventional manner. Methods Study approval was obtained from the University of Oklahoma Institutional Review Board. Records for patients who presented with EOC between 1991 and 2006 were identified and information abstracted. All patients who were treated with primary surgery underwent their procedure by one of the faculty gynecologic oncologists at the University of Oklahoma. Abstracted data included age at diagnosis, Karnofsky's performance status, primary treatment modality, residual tumor after cytoreductive effort, use of radical procedures, post-operative complications to include; myocardial infarction, congestive heart failure, arrhythmias not previously diagnosed, re-intubation, pulmonary embolus or deep venous thrombosis, prolonged
ileus, need for post-operative blood transfusion, re-operation within 30 days, readmission to hospital within 30 days of discharge and death within 60 days of primary surgery. Based on age and abstracted medical co-morbidities, combined condition and age related Charlson co-morbidity scores were calculated. A score of 10 was assigned to any patient in this cohort based on age alone. A score of 11 indicated the presence of one co-morbid condition and scores N11 were assigned for 2 or more co-morbid conditions and advancing age. We also collected data on patient disposition after cytoreductive surgery, time to initiation of chemotherapy and details regarding primary chemotherapy including agent selection, number of cycles, toxicity and response. At our institution, the initial chemotherapeutic regimen and dose is at the discretion of the attending gynecologic oncologist. In the event of grade 3 or 4 hematologic toxicity or neuropathy, chemotherapy is typically delayed one week. If the toxicity resolves or decreases to grade 1, chemotherapy is resumed. If chemotherapy is delayed for two weeks, at the resumption of therapy one or both agents are typically reduced by one dose level. Patients are asked to self report their toxicities by circling the grade (0–4) and type of toxicity on a pre-printed chart that is incorporated into their visit record. Statistical analysis was performed with Fisher exact test and Student t test. Survival analysis was performed with the Kaplan–Meier method. All statistical tests were performed with SAS v 9.1 (Cary, NC).
Results From a database of over 600 consecutive patients treated at a single institution between 1991 and 2006, 85 patients diagnosed with EOC at age 80 or greater were identified. The median age of diagnosis for this group was 83 years with a range of 80 to 95. Ninety-five percent of patients were Caucasian. At least one coexisting medical co-morbidity was recorded for 70% of this cohort and 30% carried a diagnosis of two or more medical conditions. The most common medical co-morbidity identified was hypertension (36/85); followed by coronary or cerebrovascular disease (18/85) and diabetes (10/85). History of a prior malignancy was reported for nine patients (11%) and the majority of these were breast carcinomas. Karnofsky's performance status (KPS) was recorded at the initial visit for each patient and ranged from 0 to 3. Eighty percent of patients had a KPS score of b 2 while the remainder were 2–3. Charlson co-morbidity scores were also calculated for the cohort. Combined condition and age related scores ranged from 10 to 13 with the vast majority of patients having a score of 10 (41%) or 11 (52%). Approximately 85% of patients presented with advanced (FIGO Stage III/IV) disease. This includes patients who did not undergo primary surgery but were diagnosed with Stage IV disease by virtue of positive pleural fluid, or who had evidence of at least Stage III disease on imaging studies. The majority of patients were found to have serous histology (81%) with only 5% endometriod and the remainder clear cell, mixed or undifferentiated. Primary cytoreductive surgery with anticipated chemotherapy to follow was attempted for 70 patients (80%). Chemotherapy alone was given to 15 patients (18%) and neoadjuvant therapy with interval cytoreductive surgery for 2 patients (2%). Evaluating only patients with advanced disease who underwent primary cytoreductive surgery (n = 61) and the two patients who underwent cytoreductive surgery after 3– 4 cycles of chemotherapy; optimal cytoreduction was achieved in 74% of cases. Radical cytoreductive procedures were utilized in 25 of these patients (41%) and included splenectomy (1), diaphragm stripping/resection (4) and bowel resection (23). (Table 1).
K.N. Moore et al. / Gynecologic Oncology 110 (2008) 133–139 Table 1 Demographic and primary treatment information for cohort n = 85 Age Median Range Race Caucasian PMHa HTN CAD/CEVD DM Prior malignancy COPD Dementia KPS 0–1 N2 Charlson score 10 11 12–13 Stageb Stage I Stage II Stage III Stage IV Unstaged Histology Serous Endometriod Other Primary treatment Chemotherapy only Neoadjuvant chemotherapy/surgery Surgery/chemotherapy Surgical outcomec (n = 61) Optimal cytoreduction Radical proceduresd Splenectomy Diaphragm surgery Bowel resection
83 80–95 94% 36 (42%) 18 (21%) 10 (12%) 9 (11%) 4 (5%) 2 (2%) 68 (80%) 17 (20%) 35 (41%) 44 (52%) 6 (7%) 9 (11%) 3 (4%) 55 (65%) 6 (7%) 12 (14%) 68 (81%) 5 (6%) 12 (13%) 15 (18%) 2 (2%) 68 (80%) 45 (74%) 25 (41%) 1 (4%) 4 (16%) 23 (92%)
HTN = hypertension; CAD/CEVD = coronary artery/cerebrovascular disease; DM = diabetes mellitus; COPD = chronic obstructive pulmonary disease; KPS = Karnofsky's performance status. a 19% of patients reported N1 medical co-morbidity, 10% reported two or more. b Unstaged patients received primary chemotherapy and had no evidence of Stage IV disease. c Surgical outcome is determined for patients with Stage III–IV disease. d Proportions for individual radical procedures are based on n = 25.
Post-operative complications were frequent among this cohort of patients. Arrhythmias were the most frequent post-operative medical complication (14%). Pleural effusions necessitating prolonged oxygen requirement occurred in 13% and extended mechanical ventilation (beyond the first 24 h after surgery) was reported in 9%. Inability to initiate oral feedings due to prolonged ileus beyond 6 days occurred in 11% and resulted in the use of total parenteral nutrition. Mental status changes significant enough to warrant septic and metabolic evaluation occurred in 10% of patients. Post-operative blood transfusion was required in 33% of patients for symptomatic anemia and antibiotics were initiated in 29% of patients for post-operative fever. Wound complications occurred in 10% of patients including one fascial
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dehiscence. Among the 23 patients who underwent bowel resection, anastomotic leak was identified in 2 (9%) requiring return to the operating room. The median length of hospital stay was 8 days with a range of 2 to 54 days. Among patients for whom disposition location was specified and who survived to discharge (n = 48), 50% were discharged to home and the remainder to skilled nursing or rehabilitation facilities. Thirteen percent of patients (9) who underwent primary surgical evaluation died during their primary hospitalization. (Table 2) On review of the medical records, one of these patients experienced a post-operative myocardial infarction resulting in cardiovascular collapse and her demise. A second patient developed an aspiration pneumonia requiring re-intubation and was similarly unable to recover. The remaining 7 patients experienced post-operative courses marked by delirium and oliguria, and transferred to intensive care for worsening overall status, however, no clear etiology for their failure to recover from surgery and ultimate demise was recorded. Among the 70 patients who underwent primary surgical exploration, two were Stage IA and required no further therapy. Eight patients (12%) received no adjuvant therapy after surgery; four of these patients died during their post-operative course Table 2 Post-operative complications for the 70 patients who underwent primary surgical evaluation or surgery after 3–4 cycles of chemotherapy n = 70 Cardiac Arrhythmias CHF MI Pulmonary Pleural effusions Aspiration pneumonia Prolonged ventilatory requirement¤ Pulmonary embolus Gastrointestinal Ileus N 6 days TPN requirement Hematologic/infectious Transfusion Antibiotic use Mental status changes Surgical site complications Wound infections Dehiscence Bowel anastomotic leak⁎ Return to OR Length of hospital stay Mean Median Range Disposition° Home Nursing facility Died prior to discharge
10 (14%) 2 (3%) 1 (1%) 9 (13%) 2 (3%) 6 (9%) 1 (1%) 8 (11%) 8 (11%) 23 (33%) 20 (29%) 7 (10%) 6 (9%) 1 (1%) 2 (9%) 3 (4%) 12 days 8 days 2–54 days 19 (50%) 19 (50%) 9 (13%)
⁎Proportion of anastomotic leaks was calculated with n = 23; number of bowel resections performed. °Information about disposition was available for 38 patients. Death rate prior to discharge is calculated for the entire surgical cohort (n = 70). ¤Prolonged ventilatory requirement refers to patients who remained intubated post-operatively N24 h.
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Fig. 1. Kaplan–Meier survival curve for patients N80 years old who present with advanced epithelial ovarian cancer and who underwent primary cytoreductive surgery. Median follow-up is 17 months. Two-year survival for Stage III is 51% and 0% for Stage IV.
and an additional four patients never recovered enough to tolerate adjuvant therapy and were placed on hospice. The majority of patients who received some adjuvant therapy were treated with combination paclitaxel and a platinum agent (73%). Two percent of patients were treated with platinum and cyclophosphamide and 25% were treated with single agent platinum. Seventeen percent of patients were treated as part of a clinical trial. For patients who initiated chemotherapy, 43% completed 3 or fewer cycles. Thirty-six percent of these patients discontinued therapy after one cycle due to demise and 56% discontinued prior to cycle number four due to toxicity. Six or more cycles were completed in 51% of patients. Looking more closely at the chemotherapy experience of patients who initiated therapy found no clear etiology for the high rate of discontinuation. Combination therapy with paclitaxel and
platinum was initiated in 73%. Anticipating increased toxicity, 76% of patients who received combination therapy were started at a dose reduction of 135 mg/m2 paclitaxel and an AUC of 5 for carboplatin. Patients treated with combination paclitaxel and cisplatin were started at 110 mg/m2 and 50 mg/m2. Even for patients treated with single agent therapy, 83% were started at a reduced dose. Despite this, there was no difference in the ability to complete 4 or more cycles based on starting dose of chemotherapy with 56% of those at reduced dose versus 43% of those at standard doses completing 4 or more cycles (p = ns). Hematologic toxicities were relatively common in this age group with 73% of patients experiencing common toxicity criteria version 4.0 grade 3 or 4 neutropenia, 14% experienced grade 3 or 4 anemia and 16% experienced grade 3 or 4 thrombocytopenia. Neutropenic fever requiring admission was reported in 18% and
Fig. 2. Kaplan–Meier survival curves for patients presenting with stage III or IV ovarian cancer who underwent primary cytoreductive surgery (n = 61) as compared to those treated with primary chemotherapy (n = 15). Two-year overall survival for those who underwent primary surgery is 51% versus 27% for those who received primary chemotherapy.
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neupogen or neulasta was used 27%. Transfusion during chemotherapy was required by 40% of the cohort and epogen used in 20%. Self reported toxicities were relatively uncommon in this age group. The most commonly recorded grade 3 or 4 toxicities were fatigue (25%), abdominal pain (14%) and extremity numbness (7%). Nausea, emesis, constipation, diarrhea, depression, extremity paresthesia and tinnitus were all recorded less than 5% of the time. Due to either hematologic or self-reported toxicities, chemotherapy was delayed at least once during therapy in 57% of patients. Median follow-up for patients who underwent primary surgical staging was 17.5 months. Two-year survival for Stage III is 51%. No patients with Stage IV disease who underwent primary surgery lived beyond one month. (Fig. 1) Twenty percent of patients who underwent primary surgical evaluation were deceased by two months. Factors which were evaluated as possibly associated with post-operative death and failure to complete more than 3 cycles of chemotherapy included age greater than and less than 85, presence of any medical co-morbidity, presence of 2 or more medical co-morbidities, KPS and Charlson co-morbidity score as well as performance of radical procedures at the time of cytoreduction. None of these factors was significantly associated with either outcome. A Charlson score of 12 or 13 as compared to b11 may be related to post-operative death at 20% vs. 12% (p = .5) as well as failure to complete N 3 cycles of chemotherapy at 80% vs. 44% (p = .09). The limited number of patients with a Charlson score N 11 limited this analysis. Fifteen patients were treated with primary chemotherapy. Their mean age was 86, median 87 and range of 80 to 94. As compared to patients who underwent primary surgical evaluation, patients who were treated with primary chemotherapy were significantly older (p = .027). Medical co-morbidities were reported in 87% of patients treated with primary chemotherapy. Fifty-three percent of patients reported two or more concomitant medical conditions. This was a significantly higher proportion with two or more medical co-morbidities than patients treated with primary surgery. Combination therapy with paclitaxel and platinum was used in 60% of patients with the remainder treated with single agent platinum. Median follow-up for patients treated with primary chemotherapy is 16 months. Estimated two-year overall survival is 27% as compared to 51% among those patients treated with primary surgery (p = .08). (Fig. 2) Twenty-six percent of patients treated with primary chemotherapy are deceased by two months after diagnosis. Discussion In this retrospective evaluation of patients with advanced ovarian cancer presenting over the age of 80, we demonstrate, at least among those who underwent primary cytoreductive surgery, a high rate of achieving minimal residual disease. This surgical success, however, comes at a price with complicated post-operative courses and, of most concern, death prior to hospital discharge and within 60 days of surgery in 13% and
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20% respectively. Further, among patients who underwent CRS, 13% were unable to receive any indicated adjuvant therapy and among those who were treated, only 57% completed N3 cycles. The most effective and acceptable sequence of therapies for elderly patients who present with advanced EOC has yet to be defined. The poorer prognosis seen in elderly patients has been attributed to sub-standard primary therapy. A large proportion of elderly patients are operated on by non-gynecologic oncologists, do not undergo primary surgery with intent to perform optimal cytoreductive surgery and may not receive combination or full dose cytotoxic chemotherapy [14]. Poorer outcome may not entirely be due to less aggressive primary therapy. Survival data from lymphoma, lung cancer and breast cancer all demonstrate a less robust response rate among patients greater than 65, even when given full dose chemotherapy [26,27]. This suggests that elderly patients may have some inherent chemoresistance contributing to their outcome. Other studies have found that if elderly patients are offered what is considered standard of care for younger patients, their outcome in terms of disease specific survival and complications are similar [22–25]. The most compelling data regarding treatment of the elderly comes from Gynecologic Oncology Group (GOG) trial 182 in which enrolled patients greater than 80 years of age had a 30% mortality rate within 6 months of study entry as compared to 6.8% in patients between 70 and 79. Similarly, in GOG trial 158 patients over 80 years of age had a 6 month death rate of 33% [28]. These are two trials in which optimally debulked patients were given standard dose chemotherapy and had an unacceptably high 6 month mortality rate. Patients then, who present with advanced EOC at an advanced age may run the risk of being undertreated if their physicians deem them too frail by age alone to undergo cytoreductive surgery followed by combination chemotherapy and modify this regimen, or potentially overtreated if their preoperative fitness is overestimated and aggressive up front surgery and chemotherapy is administered. Neither option provides optimal care for this growing patient population [28]. At our institution, the majority of patients who presented with a suspected ovarian malignancy (70/85) were offered primary surgical cytoreduction with anticipated adjuvant chemotherapy. The few patients for whom primary chemotherapy was recommended were older and carried more medical co-morbidities. The outcome data for those patients who underwent primary cytoreductive surgery is very similar to that reported for the same age groups in GOG 158 and 182. The death rate prior to hospital discharge was 13% and rose to 20% within 60 days of surgery. Over 40% of patients who initiated adjuvant chemotherapy discontinued prior to cycle 4 either due to toxicity (56%) and remainder due to patient demise. Our evaluation of both hematologic and non-hematologic toxicities did not reveal a clear etiology as to why so few patients are able to complete chemotherapy. Although the majority of patients experienced grade 3 or 4 neutropenia, only 18% developed neutropenic fever requiring admission. More uniform use of colony-stimulating factors in this age group may impact this finding. Among selfreported toxicities, only fatigue and abdominal pain were
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reported in more than 15% of patients. Prospective evaluation is needed to definitively link fatigue and or abdominal pain to an elderly patient's desire to discontinue therapy, however, as these are both modifiable toxicities, they may be targets of increased clinician attention and supportive care. There are limitations to this analysis including the retrospective collection of data and inherent selection bias in that this study only includes those patients who were ever referred to our center. In addition, the relatively small number of patients makes predictive modeling of post-operative risk difficult. Despite this, these data provide information on how to counsel patients greater than 80 years of age who elect to undergo cytoreductive surgery. Despite an attempt to select patients who appeared fit enough to undergo standard of care cytoreductive surgery and adjuvant chemotherapy, our data demonstrates a very high frequency of post-operative morbidity, post-operative mortality and disposition to a site other than the patient's own home. This would suggest a different algorithm for evaluating and treating patients who present with EOC in this age group is needed. It is important to define goals of therapy. With elderly patients is the goal cure, reduction of symptoms, preservation of independence or some combination of these? Adjusting therapy towards these goals may be reasonable. Unlike much of the literature addressing issues in gerooncology, the issues in management of ovarian malignancies in an elderly population are far more complex. Balducci et al. describes aging as a loss of functional reserve, stress tolerance and cognition all within a framework of increasing medical co-morbidities, high prevalence of depression and often inadequate social support [29,30]. If one follows standard of care, our patients will undergo cytoreductive surgery with intent to optimally debulk tumor, recover from this surgical procedure and have enough fitness to receive combination chemotherapy in a relatively short time interval following surgery. All within the setting of compromised functional reserve. Future prospective studies which focus on fitness assessment may help triage patients more appropriately to primary surgery or primary chemotherapy. Further, issues of altered pharmacokinetics with age, including decreased gastrointestinal absorption, changes in volume of distribution and alterations in metabolism, specifically decreases in the presence of cytochrome P450, and urinary excretion all need to be evaluated to best determine appropriate chemotherapeutic regimen and dose. Treatment of advanced EOC with cytoreductive surgery followed by adjuvant platinum/taxane based chemotherapy provides the best change of cure or long term survival among all comers. This strategy in patients greater than 80 years of age appears to come with a significant cost in terms of post-operative morbidity and mortality. Patients and their families should be counseled as to these risks and also to the potential of loss of independence prior to embarking on this treatment paradigm. Future research will help clinicians better determine which patients in this age group are fit enough to tolerate the standard of care — which is primary surgery followed by adjuvant therapy, versus those patients for whom palliation of symptoms and shorter term maintenance of quality of life are more important
priorities. For these patients, some variation in the current paradigm is warranted. Conflict of interest statement The authors declare that there are no conflicts of interest.
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Gynecologic Oncology 110 (2008) 133 – 139 www.elsevier.com/locate/ygyno
Ovarian cancer in the octogenarian: Does the paradigm of aggressive cytoreductive surgery and chemotherapy still apply? ☆ Kathleen N. Moore ⁎, Monica S. Reid, Daniel N. Fong, Tashanna K.N. Myers, Lisa M. Landrum, Katherine M. Moxley, Joan L. Walker, D. Scott McMeekin, Robert S. Mannel University of Oklahoma Health Sciences Center, Division of Gynecologic Oncology, Oklahoma City, Oklahoma, USA Received 19 February 2008 Available online 20 May 2008
Abstract Objective. The cornerstone of therapy for advanced ovarian cancer is cytoreductive surgery (CRS) followed by platinum based chemotherapy. Optimal management for very elderly women (N 80) is unclear. This study sought to review the experience with treating ovarian cancer in this population. Materials and methods. This is a retrospective analysis of patients treated between 1991 and 2006. Outcomes included post-operative complications, chemotherapy received and overall survival. Statistical analysis was performed with SAS v.9.1. Results. 85 patients were identified with a mean age of 84 years. 86% of patients presented with advanced disease. Primary CRS was performed on 80%. Among patients with advanced disease who underwent either primary (68) or interval debulking (2), 74% were left with b 1 cm residual disease. Post-operative complications were common with 15% of patients suffering cardiac or pulmonary complications, over 10% with prolonged ileus, wound complications or mental status changes and over 30% requiring transfusion or antibiotics. Death prior to hospital discharge and within 60 days of surgery occurred in 13% and 20%. Among patients who underwent CRS, 13% were unable to receive indicated adjuvant therapy. Among those who were treated, 25% were treated with single agent platinum and 43% completed b3 cycles. Two-year overall survival for those who underwent CRS followed by adjuvant therapy is 51%. Conclusions. Our data suggests that patients N 80 may not tolerate combination surgery and chemotherapy. The extremely high proportion of post-operative complications and relatively high proportion of post-operative deaths argues for a more prudent approach to this group of patients. © 2008 Elsevier Inc. All rights reserved. Keywords: Gero-oncology; Ovarian cancer; Elderly; Complications
Introduction In 2007 it is estimated that 22,430 women will be diagnosed with epithelial ovarian cancer (EOC) and 15,280 women will die [1]. Over 25% of patients are diagnosed and 40% of deaths occur over age 75 [2]. As advanced age has been previously identified as the most important risk factor for development of ☆
Presented as Oral Main Plenary Presentation: Society of Gynecologic Oncologists Annual Meeting, 2007. ⁎ Corresponding author. Division of Gynecologic Oncology, University of Oklahoma, 920 SL Young Blvd., WP 2470, Oklahoma City, OK 73103, USA. Fax: +1 405 271 2976. E-mail address: [email protected] (K.N. Moore). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.03.008
EOC and the proportion of women living into their 8th and 9th decade is increasing, the number of women presenting with advanced EOC who are also elderly can be expected to increase as well. The current paradigm for primary treatment in advanced EOC includes primary surgical cytoreduction followed by combination platinum/taxane chemotherapy. Multiple studies have demonstrated the survival benefit obtained by achieving cytoreduction to no residual disease. This goal may require certain “radical procedures” such as splenectomy, and resection of the diaphragm, bowel or liver [3–9]. Complication rates for the addition of these radical procedures vary in the literature and depending on the population studied. The reported morbidities
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range from 32 to 50% with the majority being minor complications. The reported 30-day mortality rate ranges from 1.5 to 6% with deaths occurring in patients with significant pre-operative or disease related morbidity or age greater than 75. [4,6,9] The survival advantage in cytoreduction to no gross residual disease presumes that the primary surgical effort does not result in such morbidity that it significantly delays or prevents administration of combination platinum/taxane based chemotherapy. The standard of care for adjuvant chemotherapy in advanced EOC is also in flux. The recent collaborative group study evaluating intravenous and intraperitoneal chemotherapy demonstrated a significantly prolonged survival among those patients who received even some of their chemotherapy via an intraperitoneal route [10]. This survival advantage was accompanied by significantly more neuropathy among the intraperitoneal group which persisted to one year post completion of therapy. As the incidence of neuropathy among chemotherapy patients increases with age, will we be able to use a regimen with known high prevalence of significant neuropathy among a more aged population? Will they need a separate standard of care? Little data exists to guide physicians on whether elderly patients should receive the same management as younger patients who present with advanced EOC. Multiple studies have demonstrated poorer overall survival among patients greater than 65. This poorer survival persisted even when corrected for stage, residual disease and performance status [11,12]. One explanation for this outcome is that patients considered to be elderly often do not receive the same standard of care as their younger counterparts [13–19]. This may be a result of bias that they will not tolerate the extensive cytoreductive procedures and combination chemotherapy required to treat advanced EOC. Evaluating patients over 65, studies have reported an increased length of hospital stay, peri-operative mortality, chemotherapy toxicity and decreased survival as compared to younger patients [20,21]. The counter point to the above is that multiple studies have reported that if elderly patients receive the same therapy, their outcomes are equivalent to younger patients [22–25]. In general, our institutional practice is to offer primary cytoreductive surgery followed by adjuvant platinum/taxane based chemotherapy to all patients without an age triage. In cases of significant medical co-morbidities or patient choice, treatment plans are individualized. We sought to evaluate our experience with patients who presented with EOC at age 80 or greater in terms of primary therapy offered, operative complications, ability to receive chemotherapy and disease specific survival. It is important to know if this subset of elderly patients should be managed in a conventional manner. Methods Study approval was obtained from the University of Oklahoma Institutional Review Board. Records for patients who presented with EOC between 1991 and 2006 were identified and information abstracted. All patients who were treated with primary surgery underwent their procedure by one of the faculty gynecologic oncologists at the University of Oklahoma. Abstracted data included age at diagnosis, Karnofsky's performance status, primary treatment modality, residual tumor after cytoreductive effort, use of radical procedures, post-operative complications to include; myocardial infarction, congestive heart failure, arrhythmias not previously diagnosed, re-intubation, pulmonary embolus or deep venous thrombosis, prolonged
ileus, need for post-operative blood transfusion, re-operation within 30 days, readmission to hospital within 30 days of discharge and death within 60 days of primary surgery. Based on age and abstracted medical co-morbidities, combined condition and age related Charlson co-morbidity scores were calculated. A score of 10 was assigned to any patient in this cohort based on age alone. A score of 11 indicated the presence of one co-morbid condition and scores N11 were assigned for 2 or more co-morbid conditions and advancing age. We also collected data on patient disposition after cytoreductive surgery, time to initiation of chemotherapy and details regarding primary chemotherapy including agent selection, number of cycles, toxicity and response. At our institution, the initial chemotherapeutic regimen and dose is at the discretion of the attending gynecologic oncologist. In the event of grade 3 or 4 hematologic toxicity or neuropathy, chemotherapy is typically delayed one week. If the toxicity resolves or decreases to grade 1, chemotherapy is resumed. If chemotherapy is delayed for two weeks, at the resumption of therapy one or both agents are typically reduced by one dose level. Patients are asked to self report their toxicities by circling the grade (0–4) and type of toxicity on a pre-printed chart that is incorporated into their visit record. Statistical analysis was performed with Fisher exact test and Student t test. Survival analysis was performed with the Kaplan–Meier method. All statistical tests were performed with SAS v 9.1 (Cary, NC).
Results From a database of over 600 consecutive patients treated at a single institution between 1991 and 2006, 85 patients diagnosed with EOC at age 80 or greater were identified. The median age of diagnosis for this group was 83 years with a range of 80 to 95. Ninety-five percent of patients were Caucasian. At least one coexisting medical co-morbidity was recorded for 70% of this cohort and 30% carried a diagnosis of two or more medical conditions. The most common medical co-morbidity identified was hypertension (36/85); followed by coronary or cerebrovascular disease (18/85) and diabetes (10/85). History of a prior malignancy was reported for nine patients (11%) and the majority of these were breast carcinomas. Karnofsky's performance status (KPS) was recorded at the initial visit for each patient and ranged from 0 to 3. Eighty percent of patients had a KPS score of b 2 while the remainder were 2–3. Charlson co-morbidity scores were also calculated for the cohort. Combined condition and age related scores ranged from 10 to 13 with the vast majority of patients having a score of 10 (41%) or 11 (52%). Approximately 85% of patients presented with advanced (FIGO Stage III/IV) disease. This includes patients who did not undergo primary surgery but were diagnosed with Stage IV disease by virtue of positive pleural fluid, or who had evidence of at least Stage III disease on imaging studies. The majority of patients were found to have serous histology (81%) with only 5% endometriod and the remainder clear cell, mixed or undifferentiated. Primary cytoreductive surgery with anticipated chemotherapy to follow was attempted for 70 patients (80%). Chemotherapy alone was given to 15 patients (18%) and neoadjuvant therapy with interval cytoreductive surgery for 2 patients (2%). Evaluating only patients with advanced disease who underwent primary cytoreductive surgery (n = 61) and the two patients who underwent cytoreductive surgery after 3– 4 cycles of chemotherapy; optimal cytoreduction was achieved in 74% of cases. Radical cytoreductive procedures were utilized in 25 of these patients (41%) and included splenectomy (1), diaphragm stripping/resection (4) and bowel resection (23). (Table 1).
K.N. Moore et al. / Gynecologic Oncology 110 (2008) 133–139 Table 1 Demographic and primary treatment information for cohort n = 85 Age Median Range Race Caucasian PMHa HTN CAD/CEVD DM Prior malignancy COPD Dementia KPS 0–1 N2 Charlson score 10 11 12–13 Stageb Stage I Stage II Stage III Stage IV Unstaged Histology Serous Endometriod Other Primary treatment Chemotherapy only Neoadjuvant chemotherapy/surgery Surgery/chemotherapy Surgical outcomec (n = 61) Optimal cytoreduction Radical proceduresd Splenectomy Diaphragm surgery Bowel resection
83 80–95 94% 36 (42%) 18 (21%) 10 (12%) 9 (11%) 4 (5%) 2 (2%) 68 (80%) 17 (20%) 35 (41%) 44 (52%) 6 (7%) 9 (11%) 3 (4%) 55 (65%) 6 (7%) 12 (14%) 68 (81%) 5 (6%) 12 (13%) 15 (18%) 2 (2%) 68 (80%) 45 (74%) 25 (41%) 1 (4%) 4 (16%) 23 (92%)
HTN = hypertension; CAD/CEVD = coronary artery/cerebrovascular disease; DM = diabetes mellitus; COPD = chronic obstructive pulmonary disease; KPS = Karnofsky's performance status. a 19% of patients reported N1 medical co-morbidity, 10% reported two or more. b Unstaged patients received primary chemotherapy and had no evidence of Stage IV disease. c Surgical outcome is determined for patients with Stage III–IV disease. d Proportions for individual radical procedures are based on n = 25.
Post-operative complications were frequent among this cohort of patients. Arrhythmias were the most frequent post-operative medical complication (14%). Pleural effusions necessitating prolonged oxygen requirement occurred in 13% and extended mechanical ventilation (beyond the first 24 h after surgery) was reported in 9%. Inability to initiate oral feedings due to prolonged ileus beyond 6 days occurred in 11% and resulted in the use of total parenteral nutrition. Mental status changes significant enough to warrant septic and metabolic evaluation occurred in 10% of patients. Post-operative blood transfusion was required in 33% of patients for symptomatic anemia and antibiotics were initiated in 29% of patients for post-operative fever. Wound complications occurred in 10% of patients including one fascial
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dehiscence. Among the 23 patients who underwent bowel resection, anastomotic leak was identified in 2 (9%) requiring return to the operating room. The median length of hospital stay was 8 days with a range of 2 to 54 days. Among patients for whom disposition location was specified and who survived to discharge (n = 48), 50% were discharged to home and the remainder to skilled nursing or rehabilitation facilities. Thirteen percent of patients (9) who underwent primary surgical evaluation died during their primary hospitalization. (Table 2) On review of the medical records, one of these patients experienced a post-operative myocardial infarction resulting in cardiovascular collapse and her demise. A second patient developed an aspiration pneumonia requiring re-intubation and was similarly unable to recover. The remaining 7 patients experienced post-operative courses marked by delirium and oliguria, and transferred to intensive care for worsening overall status, however, no clear etiology for their failure to recover from surgery and ultimate demise was recorded. Among the 70 patients who underwent primary surgical exploration, two were Stage IA and required no further therapy. Eight patients (12%) received no adjuvant therapy after surgery; four of these patients died during their post-operative course Table 2 Post-operative complications for the 70 patients who underwent primary surgical evaluation or surgery after 3–4 cycles of chemotherapy n = 70 Cardiac Arrhythmias CHF MI Pulmonary Pleural effusions Aspiration pneumonia Prolonged ventilatory requirement¤ Pulmonary embolus Gastrointestinal Ileus N 6 days TPN requirement Hematologic/infectious Transfusion Antibiotic use Mental status changes Surgical site complications Wound infections Dehiscence Bowel anastomotic leak⁎ Return to OR Length of hospital stay Mean Median Range Disposition° Home Nursing facility Died prior to discharge
10 (14%) 2 (3%) 1 (1%) 9 (13%) 2 (3%) 6 (9%) 1 (1%) 8 (11%) 8 (11%) 23 (33%) 20 (29%) 7 (10%) 6 (9%) 1 (1%) 2 (9%) 3 (4%) 12 days 8 days 2–54 days 19 (50%) 19 (50%) 9 (13%)
⁎Proportion of anastomotic leaks was calculated with n = 23; number of bowel resections performed. °Information about disposition was available for 38 patients. Death rate prior to discharge is calculated for the entire surgical cohort (n = 70). ¤Prolonged ventilatory requirement refers to patients who remained intubated post-operatively N24 h.
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Fig. 1. Kaplan–Meier survival curve for patients N80 years old who present with advanced epithelial ovarian cancer and who underwent primary cytoreductive surgery. Median follow-up is 17 months. Two-year survival for Stage III is 51% and 0% for Stage IV.
and an additional four patients never recovered enough to tolerate adjuvant therapy and were placed on hospice. The majority of patients who received some adjuvant therapy were treated with combination paclitaxel and a platinum agent (73%). Two percent of patients were treated with platinum and cyclophosphamide and 25% were treated with single agent platinum. Seventeen percent of patients were treated as part of a clinical trial. For patients who initiated chemotherapy, 43% completed 3 or fewer cycles. Thirty-six percent of these patients discontinued therapy after one cycle due to demise and 56% discontinued prior to cycle number four due to toxicity. Six or more cycles were completed in 51% of patients. Looking more closely at the chemotherapy experience of patients who initiated therapy found no clear etiology for the high rate of discontinuation. Combination therapy with paclitaxel and
platinum was initiated in 73%. Anticipating increased toxicity, 76% of patients who received combination therapy were started at a dose reduction of 135 mg/m2 paclitaxel and an AUC of 5 for carboplatin. Patients treated with combination paclitaxel and cisplatin were started at 110 mg/m2 and 50 mg/m2. Even for patients treated with single agent therapy, 83% were started at a reduced dose. Despite this, there was no difference in the ability to complete 4 or more cycles based on starting dose of chemotherapy with 56% of those at reduced dose versus 43% of those at standard doses completing 4 or more cycles (p = ns). Hematologic toxicities were relatively common in this age group with 73% of patients experiencing common toxicity criteria version 4.0 grade 3 or 4 neutropenia, 14% experienced grade 3 or 4 anemia and 16% experienced grade 3 or 4 thrombocytopenia. Neutropenic fever requiring admission was reported in 18% and
Fig. 2. Kaplan–Meier survival curves for patients presenting with stage III or IV ovarian cancer who underwent primary cytoreductive surgery (n = 61) as compared to those treated with primary chemotherapy (n = 15). Two-year overall survival for those who underwent primary surgery is 51% versus 27% for those who received primary chemotherapy.
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neupogen or neulasta was used 27%. Transfusion during chemotherapy was required by 40% of the cohort and epogen used in 20%. Self reported toxicities were relatively uncommon in this age group. The most commonly recorded grade 3 or 4 toxicities were fatigue (25%), abdominal pain (14%) and extremity numbness (7%). Nausea, emesis, constipation, diarrhea, depression, extremity paresthesia and tinnitus were all recorded less than 5% of the time. Due to either hematologic or self-reported toxicities, chemotherapy was delayed at least once during therapy in 57% of patients. Median follow-up for patients who underwent primary surgical staging was 17.5 months. Two-year survival for Stage III is 51%. No patients with Stage IV disease who underwent primary surgery lived beyond one month. (Fig. 1) Twenty percent of patients who underwent primary surgical evaluation were deceased by two months. Factors which were evaluated as possibly associated with post-operative death and failure to complete more than 3 cycles of chemotherapy included age greater than and less than 85, presence of any medical co-morbidity, presence of 2 or more medical co-morbidities, KPS and Charlson co-morbidity score as well as performance of radical procedures at the time of cytoreduction. None of these factors was significantly associated with either outcome. A Charlson score of 12 or 13 as compared to b11 may be related to post-operative death at 20% vs. 12% (p = .5) as well as failure to complete N 3 cycles of chemotherapy at 80% vs. 44% (p = .09). The limited number of patients with a Charlson score N 11 limited this analysis. Fifteen patients were treated with primary chemotherapy. Their mean age was 86, median 87 and range of 80 to 94. As compared to patients who underwent primary surgical evaluation, patients who were treated with primary chemotherapy were significantly older (p = .027). Medical co-morbidities were reported in 87% of patients treated with primary chemotherapy. Fifty-three percent of patients reported two or more concomitant medical conditions. This was a significantly higher proportion with two or more medical co-morbidities than patients treated with primary surgery. Combination therapy with paclitaxel and platinum was used in 60% of patients with the remainder treated with single agent platinum. Median follow-up for patients treated with primary chemotherapy is 16 months. Estimated two-year overall survival is 27% as compared to 51% among those patients treated with primary surgery (p = .08). (Fig. 2) Twenty-six percent of patients treated with primary chemotherapy are deceased by two months after diagnosis. Discussion In this retrospective evaluation of patients with advanced ovarian cancer presenting over the age of 80, we demonstrate, at least among those who underwent primary cytoreductive surgery, a high rate of achieving minimal residual disease. This surgical success, however, comes at a price with complicated post-operative courses and, of most concern, death prior to hospital discharge and within 60 days of surgery in 13% and
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20% respectively. Further, among patients who underwent CRS, 13% were unable to receive any indicated adjuvant therapy and among those who were treated, only 57% completed N3 cycles. The most effective and acceptable sequence of therapies for elderly patients who present with advanced EOC has yet to be defined. The poorer prognosis seen in elderly patients has been attributed to sub-standard primary therapy. A large proportion of elderly patients are operated on by non-gynecologic oncologists, do not undergo primary surgery with intent to perform optimal cytoreductive surgery and may not receive combination or full dose cytotoxic chemotherapy [14]. Poorer outcome may not entirely be due to less aggressive primary therapy. Survival data from lymphoma, lung cancer and breast cancer all demonstrate a less robust response rate among patients greater than 65, even when given full dose chemotherapy [26,27]. This suggests that elderly patients may have some inherent chemoresistance contributing to their outcome. Other studies have found that if elderly patients are offered what is considered standard of care for younger patients, their outcome in terms of disease specific survival and complications are similar [22–25]. The most compelling data regarding treatment of the elderly comes from Gynecologic Oncology Group (GOG) trial 182 in which enrolled patients greater than 80 years of age had a 30% mortality rate within 6 months of study entry as compared to 6.8% in patients between 70 and 79. Similarly, in GOG trial 158 patients over 80 years of age had a 6 month death rate of 33% [28]. These are two trials in which optimally debulked patients were given standard dose chemotherapy and had an unacceptably high 6 month mortality rate. Patients then, who present with advanced EOC at an advanced age may run the risk of being undertreated if their physicians deem them too frail by age alone to undergo cytoreductive surgery followed by combination chemotherapy and modify this regimen, or potentially overtreated if their preoperative fitness is overestimated and aggressive up front surgery and chemotherapy is administered. Neither option provides optimal care for this growing patient population [28]. At our institution, the majority of patients who presented with a suspected ovarian malignancy (70/85) were offered primary surgical cytoreduction with anticipated adjuvant chemotherapy. The few patients for whom primary chemotherapy was recommended were older and carried more medical co-morbidities. The outcome data for those patients who underwent primary cytoreductive surgery is very similar to that reported for the same age groups in GOG 158 and 182. The death rate prior to hospital discharge was 13% and rose to 20% within 60 days of surgery. Over 40% of patients who initiated adjuvant chemotherapy discontinued prior to cycle 4 either due to toxicity (56%) and remainder due to patient demise. Our evaluation of both hematologic and non-hematologic toxicities did not reveal a clear etiology as to why so few patients are able to complete chemotherapy. Although the majority of patients experienced grade 3 or 4 neutropenia, only 18% developed neutropenic fever requiring admission. More uniform use of colony-stimulating factors in this age group may impact this finding. Among selfreported toxicities, only fatigue and abdominal pain were
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reported in more than 15% of patients. Prospective evaluation is needed to definitively link fatigue and or abdominal pain to an elderly patient's desire to discontinue therapy, however, as these are both modifiable toxicities, they may be targets of increased clinician attention and supportive care. There are limitations to this analysis including the retrospective collection of data and inherent selection bias in that this study only includes those patients who were ever referred to our center. In addition, the relatively small number of patients makes predictive modeling of post-operative risk difficult. Despite this, these data provide information on how to counsel patients greater than 80 years of age who elect to undergo cytoreductive surgery. Despite an attempt to select patients who appeared fit enough to undergo standard of care cytoreductive surgery and adjuvant chemotherapy, our data demonstrates a very high frequency of post-operative morbidity, post-operative mortality and disposition to a site other than the patient's own home. This would suggest a different algorithm for evaluating and treating patients who present with EOC in this age group is needed. It is important to define goals of therapy. With elderly patients is the goal cure, reduction of symptoms, preservation of independence or some combination of these? Adjusting therapy towards these goals may be reasonable. Unlike much of the literature addressing issues in gerooncology, the issues in management of ovarian malignancies in an elderly population are far more complex. Balducci et al. describes aging as a loss of functional reserve, stress tolerance and cognition all within a framework of increasing medical co-morbidities, high prevalence of depression and often inadequate social support [29,30]. If one follows standard of care, our patients will undergo cytoreductive surgery with intent to optimally debulk tumor, recover from this surgical procedure and have enough fitness to receive combination chemotherapy in a relatively short time interval following surgery. All within the setting of compromised functional reserve. Future prospective studies which focus on fitness assessment may help triage patients more appropriately to primary surgery or primary chemotherapy. Further, issues of altered pharmacokinetics with age, including decreased gastrointestinal absorption, changes in volume of distribution and alterations in metabolism, specifically decreases in the presence of cytochrome P450, and urinary excretion all need to be evaluated to best determine appropriate chemotherapeutic regimen and dose. Treatment of advanced EOC with cytoreductive surgery followed by adjuvant platinum/taxane based chemotherapy provides the best change of cure or long term survival among all comers. This strategy in patients greater than 80 years of age appears to come with a significant cost in terms of post-operative morbidity and mortality. Patients and their families should be counseled as to these risks and also to the potential of loss of independence prior to embarking on this treatment paradigm. Future research will help clinicians better determine which patients in this age group are fit enough to tolerate the standard of care — which is primary surgery followed by adjuvant therapy, versus those patients for whom palliation of symptoms and shorter term maintenance of quality of life are more important
priorities. For these patients, some variation in the current paradigm is warranted. Conflict of interest statement The authors declare that there are no conflicts of interest.
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