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doi:10.1111/jog.12320
J. Obstet. Gynaecol. Res. Vol. 40, No. 5: 1399–1406, May 2014
Benefit of palliative chemotherapy and hospice enrollment in late-stage ovarian cancer patients Hiroshi Tsubamoto, Yoshihiro Ito, Riichiro Kanazawa, Ryu Wada, Yoko Hosoda, Okuto Honda, Ryu Takeyama, Riya Sakane, Yu Wakimoto and Hiroaki Shibahara Department of Obstetrics and Gynecology, Hyogo College of Medicine, Nishinomiya, Japan
Abstract Aim: The ideal timing for transition to best supportive care (BSC) for ovarian cancer patients is not clear. We retrospectively assessed the survival benefit of continuing chemotherapy and hospice enrollment in late-stage ovarian cancer patients. Materials and Methods: Eligibility criteria included platinum and taxane treatment, clinical progression within 6 months of the last platinum dose, and progression during chemotherapy. Results: Of the 55 eligible patients (median overall survival after first becoming refractory [1st Ref], 96 days), 22 received chemotherapy (Chemo group), two received radiation therapy, and 13 had medical contraindications for subsequent chemotherapy. The remaining 18 patients (BSC group) were compared with the Chemo group. The Chemo and BSC groups had similar background characteristics, except for the rate of consultation with a regional palliative care physician before or within 1 week of 1st Ref (9% vs 50%, respectively). In multivariate analysis, chemotherapy (hazard ratio 0.251, P = 0.005) and hospice enrollment (hazard ratio, 0.274, P = 0.023) were predictive factors of survival after 1st Ref. Conclusions: Chemotherapy after 1st Ref can be offered and hospice enrollment during the terminal stages is encouraged for recurrent ovarian cancer patients. Key words: chemotherapy, hospice, ovarian cancer, palliative care, refractory disease.
Introduction Ovarian cancer is an important cause of cancer-related deaths in women. In most cases, these patients present with advanced disease and initially respond to platinum-based chemotherapy, typically consisting of carboplatin and paclitaxel. However, the majority of women relapse and subsequently do not respond to chemotherapy. The real benefit of chemotherapy for late-stage recurrent patients is said to be the control of symptoms,1 and an emotional effect is also expected.2 However, limited information is available concerning the timing for discontinuation of chemotherapy.
For platinum-resistant disease, a clinical trial has showed the survival benefit of continuing chemotherapy.3 In the study, only 14% of patients had a history of disease progression during previous chemotherapy, and this disease was designated as ‘refractory disease’ and was associated with poor overall survival (OS).4 The National Comprehensive Cancer Network Clinical Practice Guidelines of 2013 recommend that chemotherapy be discontinued after two consecutive episodes of progression during chemotherapy in daily practice. To date, the survival advantage of continuing chemotherapy after the first episode of progression during chemotherapy (1st Ref) has not been reported.
Received: June 20 2013. Accepted: October 9 2013. Reprint request to: Dr Hiroshi Tsubamoto, Department of Obstetrics and Gynecology, Hyogo College of Medicine, Mukogawa 1-1, Nishinomiya, Hyogo 663-8501, Japan. Email: [email protected]
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1399
H. Tsubamoto et al.
On the other hand, patients with shorter predicted survival times were found to receive increased chemotherapy during their last 3 months of life.5 In another study in which 54.3% of enrolled patients had epithelial ovarian cancer, hospice enrollment, as recommended by each patient’s health-care provider, and discontinuing chemotherapy were significantly associated with prolonged survival.6 These findings suggested that continuing chemotherapy might be harmful and that hospice care should be recommended for patients with refractory disease. Therefore, we conducted this study to determine the survival time after 1st Ref in order to assess the survival benefit of continuing chemotherapy after 1st Ref and to elucidate the parameters that affect OS after 1st Ref, such as the quality of palliative care.
Methods The medical charts of patients with histologically confirmed diagnoses of ovarian cancer who were treated at our teaching hospital and died between January 2004 and June 2013 were retrospectively reviewed. Patients were included if they had received platinum and taxane chemotherapy, showed clinical (symptomatic or radiological) progression within 6 months of the last dose of platinum, and experienced progression during chemotherapy. Patients who progressed during firstline platinum and taxane treatment or during platinum-based chemotherapy at recurrence were also included. The decision concerning whether to re-treat after the first progression was based on a consensus among treating physicians, the patient, and the patient’s family, without fixed criteria. Because the Ministry of Health, Labour and Welfare had not approved any targeted drugs, including bevacizumab, for ovarian cancer, none of these patients received targeted therapy, and none were enrolled in any clinical trial involving targeted therapy. Patient demographics, palliative care status, and treatments were compared between groups of patients who did (Chemo group) and did not (BSC group) receive chemotherapy after 1st Ref. Both groups received supportive care mainly by treating physicians before 2008, and thereafter, by treating physicians and a palliative care team in our hospital. In 2008, the local government developed a plan to promote cancer control programs, and we have improved the quality of cancer care in accordance with these programs. The Chemo group and the BSC group were compared using the Student’s t-test, the χ2-test, or Fisher’s exact
1400
test, as appropriate. A P-value of < 0.05 was considered statistically significant. When the same regimen was administered at an interval of >6 months, the number of regimens was calculated as 2. When patients relapsed during first-line taxane and platinum chemotherapy, the time from the date of starting first-line chemotherapy until the date of progression was substituted for the interval between two consecutive relapses.7 OS was calculated from the date of 1st Ref until death. Survival curves were estimated using the Kaplan–Meier method and compared between groups using log–rank statistics. Factors other than the predictive factors of subsequent chemotherapy were analyzed using a Cox proportional hazards model to determine the factors associated with OS. The efficacy of subsequent chemotherapy in patients with measurable disease was evaluated according to the Response Evaluation Criteria In Solid Tumors ver. 1.1 criteria.8 Because computed tomography (CT) slices in routine clinical practice were 5–10 mm, measurable lesions were defined as those ≥20 mm in diameter. Lesions detected on positron emission tomography-CT were excluded when reliable or valid, repeated measurements using CT were difficult. Criteria for a status of unequivocal progression included increased frequency of paracentesis and unexpected or emergency admission to the hospital. When stable disease (SD) could not be confirmed radiologically at 8 weeks or more, progressive disease (PD) was diagnosed. Efficacy was also evaluated according to the Gynecologic Cancer InterGroup (GCIG) criteria.9 All statistical analyses were performed using the software XLSTAT 2012 (Addinsoft).
Results From 2004 to 2013, 55 patients experienced first progression during chemotherapy; their median OS was 96 days (95% confidence interval [CI], 68–134 days) (Fig. 1). Of these patients, two received radiotherapy after first progression, and 13 had medical contraindications to subsequent chemotherapy, including nine with an Eastern Cooperative Oncology Group (ECOG) performance status of 4, one with complete bowel obstruction, one with onset of brain infarction, one with aggravation of schizophrenia, and one with disseminated intravascular coagulation. In addition, 22 patients received chemotherapy after first progression (Chemo group), and the remaining 18 patients without medical contraindications for subsequent chemotherapy, received best supportive care (BSC group).
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Chemotherapy or best supportive care
Figure 1 Overall survival (OS) after first progression (n = 55). The median OS was 96 days (95% confidence interval [CI], 68–134 days).
patients, intravenous non-platinum combination chemotherapy in three, intravenous platinum-based chemotherapy in three, intraperitoneal docetaxel or cisplatin in five, and intrapleural cisplatin in two. Of the 14 patients with measurable disease, one (7.1%) showed a response, resulting in a response rate (RR) of 7.1% (Table 2). According to GCIG criteria, the RR among the 22 enrolled patients in the Chemo group was 9.0%, with one patient each showing a serological and radiological response. Six patients with partial response and SD received intravenous chemotherapy, with a clinical benefit rate at 8 weeks of 27% (95% CI, 8.7–45.9%). These patients discontinued chemotherapy because of disease progression, not because of chemotherapy-related toxicities. After adjusting for demographic and clinical factors among the 40 patients in the Chemo and BSC groups, a Cox proportional hazards model showed that chemotherapy (hazard ratio [HR] 0.251; 95% CI, 0.095–0.658; P = 0.005) and death at home or in a hospital-based hospice (HR, 0.240; 95% CI, 0.070–0.820; P = 0.023) were independent predictors of OS (Table 3).
Discussion
Figure 2 Schema of enrolled patients (n = 55), when first becoming refractory (1st Ref). BSC, best supportive care; OC, ovarian cancer.
The flowchart of the 55 enrolled patients is shown in Figure 2, and the demographic and clinical characteristics of the Chemo and BSC groups are shown in Table 1. A higher percentage of patients in the BSC group than in the Chemo group were referred to a palliative care physician (PCP) before or at 1st Ref (P = 0.004). All other variables were similar between the two groups. Median OS was significantly longer in the Chemo group (168 days; 95% CI, 102–248 days) than in the BSC group (68 days; 95% CI, 43–98 days; P < 0.001) (Fig. 3). Subsequent chemotherapy following 1st Ref consisted of intravenous non-platinum monotherapy in nine
The primary goal of treatment for patients with platinum-resistant disease is the maintenance of quality of life, achieved by preventing and alleviating symptoms.10 However, no randomized controlled trials have demonstrated that chemotherapy improves symptoms or quality of life in patients with relapsed ovarian cancer. A phase III trial comparing canfosfamide with pegylated liposomal doxorubicin or topotecan showed that the latter control regimens resulted in a longer OS of 13.5 months, with a progression-free survival (PFS) of 4.3 months.3 Refractory disease occurred in 14% of the patients. A phase III trial comparing tamoxifen with chemotherapy in patients with platinum-refractory or platinum-resistant ovarian cancer showed that the median PFS with chemotherapy was less than 3 months, although 44% of patients treated with chemotherapy were refractory to platinum-based therapy.11 Neither trial included subset analysis of refractory patients, and most patients enrolled in both trials had an ECOG performance status of 0 or 1. Because performance status and cancer-related symptoms are major predictors of patient prognosis,12,13 the results cannot be generalized to the routine clinical situation of refractory patients.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1401
H. Tsubamoto et al.
Table 1 Patient demographics (n = 40)
Era at 1st Ref. 2004–2008 2009–2013 Age, median (range) Races Japanese (Asian) Caucasians Histology Mucinous/clear Others Number of previous regimens 1 2 3 ≥4 ECOG performance status 0 1 2 3 Cancer related symptom Yes No Paracentesis or thoracocentesis† Yes No Platinum free interval
doi:10.1111/jog.12320
J. Obstet. Gynaecol. Res. Vol. 40, No. 5: 1399–1406, May 2014
Benefit of palliative chemotherapy and hospice enrollment in late-stage ovarian cancer patients Hiroshi Tsubamoto, Yoshihiro Ito, Riichiro Kanazawa, Ryu Wada, Yoko Hosoda, Okuto Honda, Ryu Takeyama, Riya Sakane, Yu Wakimoto and Hiroaki Shibahara Department of Obstetrics and Gynecology, Hyogo College of Medicine, Nishinomiya, Japan
Abstract Aim: The ideal timing for transition to best supportive care (BSC) for ovarian cancer patients is not clear. We retrospectively assessed the survival benefit of continuing chemotherapy and hospice enrollment in late-stage ovarian cancer patients. Materials and Methods: Eligibility criteria included platinum and taxane treatment, clinical progression within 6 months of the last platinum dose, and progression during chemotherapy. Results: Of the 55 eligible patients (median overall survival after first becoming refractory [1st Ref], 96 days), 22 received chemotherapy (Chemo group), two received radiation therapy, and 13 had medical contraindications for subsequent chemotherapy. The remaining 18 patients (BSC group) were compared with the Chemo group. The Chemo and BSC groups had similar background characteristics, except for the rate of consultation with a regional palliative care physician before or within 1 week of 1st Ref (9% vs 50%, respectively). In multivariate analysis, chemotherapy (hazard ratio 0.251, P = 0.005) and hospice enrollment (hazard ratio, 0.274, P = 0.023) were predictive factors of survival after 1st Ref. Conclusions: Chemotherapy after 1st Ref can be offered and hospice enrollment during the terminal stages is encouraged for recurrent ovarian cancer patients. Key words: chemotherapy, hospice, ovarian cancer, palliative care, refractory disease.
Introduction Ovarian cancer is an important cause of cancer-related deaths in women. In most cases, these patients present with advanced disease and initially respond to platinum-based chemotherapy, typically consisting of carboplatin and paclitaxel. However, the majority of women relapse and subsequently do not respond to chemotherapy. The real benefit of chemotherapy for late-stage recurrent patients is said to be the control of symptoms,1 and an emotional effect is also expected.2 However, limited information is available concerning the timing for discontinuation of chemotherapy.
For platinum-resistant disease, a clinical trial has showed the survival benefit of continuing chemotherapy.3 In the study, only 14% of patients had a history of disease progression during previous chemotherapy, and this disease was designated as ‘refractory disease’ and was associated with poor overall survival (OS).4 The National Comprehensive Cancer Network Clinical Practice Guidelines of 2013 recommend that chemotherapy be discontinued after two consecutive episodes of progression during chemotherapy in daily practice. To date, the survival advantage of continuing chemotherapy after the first episode of progression during chemotherapy (1st Ref) has not been reported.
Received: June 20 2013. Accepted: October 9 2013. Reprint request to: Dr Hiroshi Tsubamoto, Department of Obstetrics and Gynecology, Hyogo College of Medicine, Mukogawa 1-1, Nishinomiya, Hyogo 663-8501, Japan. Email: [email protected]
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1399
H. Tsubamoto et al.
On the other hand, patients with shorter predicted survival times were found to receive increased chemotherapy during their last 3 months of life.5 In another study in which 54.3% of enrolled patients had epithelial ovarian cancer, hospice enrollment, as recommended by each patient’s health-care provider, and discontinuing chemotherapy were significantly associated with prolonged survival.6 These findings suggested that continuing chemotherapy might be harmful and that hospice care should be recommended for patients with refractory disease. Therefore, we conducted this study to determine the survival time after 1st Ref in order to assess the survival benefit of continuing chemotherapy after 1st Ref and to elucidate the parameters that affect OS after 1st Ref, such as the quality of palliative care.
Methods The medical charts of patients with histologically confirmed diagnoses of ovarian cancer who were treated at our teaching hospital and died between January 2004 and June 2013 were retrospectively reviewed. Patients were included if they had received platinum and taxane chemotherapy, showed clinical (symptomatic or radiological) progression within 6 months of the last dose of platinum, and experienced progression during chemotherapy. Patients who progressed during firstline platinum and taxane treatment or during platinum-based chemotherapy at recurrence were also included. The decision concerning whether to re-treat after the first progression was based on a consensus among treating physicians, the patient, and the patient’s family, without fixed criteria. Because the Ministry of Health, Labour and Welfare had not approved any targeted drugs, including bevacizumab, for ovarian cancer, none of these patients received targeted therapy, and none were enrolled in any clinical trial involving targeted therapy. Patient demographics, palliative care status, and treatments were compared between groups of patients who did (Chemo group) and did not (BSC group) receive chemotherapy after 1st Ref. Both groups received supportive care mainly by treating physicians before 2008, and thereafter, by treating physicians and a palliative care team in our hospital. In 2008, the local government developed a plan to promote cancer control programs, and we have improved the quality of cancer care in accordance with these programs. The Chemo group and the BSC group were compared using the Student’s t-test, the χ2-test, or Fisher’s exact
1400
test, as appropriate. A P-value of < 0.05 was considered statistically significant. When the same regimen was administered at an interval of >6 months, the number of regimens was calculated as 2. When patients relapsed during first-line taxane and platinum chemotherapy, the time from the date of starting first-line chemotherapy until the date of progression was substituted for the interval between two consecutive relapses.7 OS was calculated from the date of 1st Ref until death. Survival curves were estimated using the Kaplan–Meier method and compared between groups using log–rank statistics. Factors other than the predictive factors of subsequent chemotherapy were analyzed using a Cox proportional hazards model to determine the factors associated with OS. The efficacy of subsequent chemotherapy in patients with measurable disease was evaluated according to the Response Evaluation Criteria In Solid Tumors ver. 1.1 criteria.8 Because computed tomography (CT) slices in routine clinical practice were 5–10 mm, measurable lesions were defined as those ≥20 mm in diameter. Lesions detected on positron emission tomography-CT were excluded when reliable or valid, repeated measurements using CT were difficult. Criteria for a status of unequivocal progression included increased frequency of paracentesis and unexpected or emergency admission to the hospital. When stable disease (SD) could not be confirmed radiologically at 8 weeks or more, progressive disease (PD) was diagnosed. Efficacy was also evaluated according to the Gynecologic Cancer InterGroup (GCIG) criteria.9 All statistical analyses were performed using the software XLSTAT 2012 (Addinsoft).
Results From 2004 to 2013, 55 patients experienced first progression during chemotherapy; their median OS was 96 days (95% confidence interval [CI], 68–134 days) (Fig. 1). Of these patients, two received radiotherapy after first progression, and 13 had medical contraindications to subsequent chemotherapy, including nine with an Eastern Cooperative Oncology Group (ECOG) performance status of 4, one with complete bowel obstruction, one with onset of brain infarction, one with aggravation of schizophrenia, and one with disseminated intravascular coagulation. In addition, 22 patients received chemotherapy after first progression (Chemo group), and the remaining 18 patients without medical contraindications for subsequent chemotherapy, received best supportive care (BSC group).
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Chemotherapy or best supportive care
Figure 1 Overall survival (OS) after first progression (n = 55). The median OS was 96 days (95% confidence interval [CI], 68–134 days).
patients, intravenous non-platinum combination chemotherapy in three, intravenous platinum-based chemotherapy in three, intraperitoneal docetaxel or cisplatin in five, and intrapleural cisplatin in two. Of the 14 patients with measurable disease, one (7.1%) showed a response, resulting in a response rate (RR) of 7.1% (Table 2). According to GCIG criteria, the RR among the 22 enrolled patients in the Chemo group was 9.0%, with one patient each showing a serological and radiological response. Six patients with partial response and SD received intravenous chemotherapy, with a clinical benefit rate at 8 weeks of 27% (95% CI, 8.7–45.9%). These patients discontinued chemotherapy because of disease progression, not because of chemotherapy-related toxicities. After adjusting for demographic and clinical factors among the 40 patients in the Chemo and BSC groups, a Cox proportional hazards model showed that chemotherapy (hazard ratio [HR] 0.251; 95% CI, 0.095–0.658; P = 0.005) and death at home or in a hospital-based hospice (HR, 0.240; 95% CI, 0.070–0.820; P = 0.023) were independent predictors of OS (Table 3).
Discussion
Figure 2 Schema of enrolled patients (n = 55), when first becoming refractory (1st Ref). BSC, best supportive care; OC, ovarian cancer.
The flowchart of the 55 enrolled patients is shown in Figure 2, and the demographic and clinical characteristics of the Chemo and BSC groups are shown in Table 1. A higher percentage of patients in the BSC group than in the Chemo group were referred to a palliative care physician (PCP) before or at 1st Ref (P = 0.004). All other variables were similar between the two groups. Median OS was significantly longer in the Chemo group (168 days; 95% CI, 102–248 days) than in the BSC group (68 days; 95% CI, 43–98 days; P < 0.001) (Fig. 3). Subsequent chemotherapy following 1st Ref consisted of intravenous non-platinum monotherapy in nine
The primary goal of treatment for patients with platinum-resistant disease is the maintenance of quality of life, achieved by preventing and alleviating symptoms.10 However, no randomized controlled trials have demonstrated that chemotherapy improves symptoms or quality of life in patients with relapsed ovarian cancer. A phase III trial comparing canfosfamide with pegylated liposomal doxorubicin or topotecan showed that the latter control regimens resulted in a longer OS of 13.5 months, with a progression-free survival (PFS) of 4.3 months.3 Refractory disease occurred in 14% of the patients. A phase III trial comparing tamoxifen with chemotherapy in patients with platinum-refractory or platinum-resistant ovarian cancer showed that the median PFS with chemotherapy was less than 3 months, although 44% of patients treated with chemotherapy were refractory to platinum-based therapy.11 Neither trial included subset analysis of refractory patients, and most patients enrolled in both trials had an ECOG performance status of 0 or 1. Because performance status and cancer-related symptoms are major predictors of patient prognosis,12,13 the results cannot be generalized to the routine clinical situation of refractory patients.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1401
H. Tsubamoto et al.
Table 1 Patient demographics (n = 40)
Era at 1st Ref. 2004–2008 2009–2013 Age, median (range) Races Japanese (Asian) Caucasians Histology Mucinous/clear Others Number of previous regimens 1 2 3 ≥4 ECOG performance status 0 1 2 3 Cancer related symptom Yes No Paracentesis or thoracocentesis† Yes No Platinum free interval
