Early Palliative Intervention for Patients with ...

Jpn J Clin Oncol 2013;43(8)788 – 794 doi:10.1093/jjco/hyt074 Advance Access Publication 4 June 2013

Early Palliative Intervention for Patients with Advanced Cancer Masatomo Otsuka1,*, Atsuko Koyama2, Hiromichi Matsuoka3, Minoru Niki2, Chihiro Makimura3, Ryo Sakamoto2, Kiyohiro Sakai2 and Masahiro Fukuoka4 1

Department of Palliative Care, Sakai Hospital, Kinki University Faculty of Medicine, 2Department of Psychosomatic Medicine, Sakai Hospital, Kinki University Faculty of Medicine, 3Department of Medical Oncology, Kinki University Faculty of Medicine and 4Department of Medical Oncology, Sakai Hospital, Kinki University Faculty of Medicine, Higashiosaka, Osaka, Japan

Received February 18, 2013; accepted April 29, 2013

Background: Early palliative intervention in advanced cancer patients with metastatic nonsmall-cell-lung cancer has been shown to improve survival time. Possibly, palliative intervention at the time of outpatient care further improves patient survival time. Objective: We performed a comparative study of late and early referrals of patients with advanced cancer to clarify the appropriate time for palliative intervention and the improvement in survival time. Methods: Two hundred and one cancer patients, all since deceased, who were treated in our department over a period of 4 years were divided into two groups: patients who experienced outpatient services for ,7 days (late referral group, 64 patients) and those who experienced outpatient services for 7 days (early referral group, 137 patients). Survival time, duration of chemotherapy and post-progression survival were retrospectively analyzed through examination of medical records. Results: Survival time of the early referral group was longer than that of the late referral group in all the cases (19.0 vs. 6.5 months, P , 0.001). Survival time in advanced non-small-cell lung cancer was 3.5 and 14.0 months (P ¼ 0.010) and 16.5 and 20.9 months (P ¼ 0.039) in advanced colorectal cancer, respectively. There was no significant difference in gastric cancer (P ¼ 0.310). Post-progression survival in each group was 0.7 and 2.7 months (P ¼ 0.018) in non-small-cell lung cancer. Conclusions: The results of this study suggested that early outpatient referral and palliative intervention leads to improvement of the outcome in patients with advanced non-small-cell lung cancer and colorectal cancer. A prospective comparative study is warranted. Key words: early palliative intervention – outpatient palliative care – survival time – post-progression survival – non-small-cell lung cancer

INTRODUCTION Recently, several effective medications, including moleculartargeted drugs, have been developed for the treatment of cancer, resulting in improved therapeutic results and prognosis. However, complete cure for all advanced cancer patients is still not feasible. According to the World Health Organization (WHO), palliative care targets patients whose

disease is not responsive to curative treatment (1). The sentence ‘Palliative care is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy’ was added to the WHO’s definition of palliative care in 2002 (1). From the standpoint of palliative care medicine, treatment that cures cancer is one of the most effective means of palliative

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*For reprints and all correspondence: Masatomo Otsuka, 2-7-1 Harayamadai, Minami-ku, Sakai, Osaka 590-0132, Japan. E-mail: [email protected]

Jpn J Clin Oncol 2013;43(8)

symptoms and end-of-life planning. Also, inpatients at our hospital cannot visit the OPCS; palliative care specialists from the OPCS visit their beds. The initial medical examination with the palliative care specialist lasts more than 60 min, during which the palliative care specialist conducts a full medical and psychosocial assessment, after which recommendations are made for symptom and palliative care treatment, education, counseling and home support. Referrals to home care and the community hospice are made as appropriate. Follow-up appointments at the OPCS are tailored to the needs of each patient. METHODS To clarify whether referral to palliative care was made in appropriate timing on advanced cancer patients, patients were divided into two referral groups: those who experienced the OPCS for ,7 days (patients were not able to visit the OPCS for symptom exacerbation within 6 days from palliative intervention: late referral) and those who experienced the OPCS for 7 days or more ( patients were able to visit the OPCS regularly: early referral). Duration of palliative care (from palliative intervention to death), duration of OPCS (from palliative intervention to hospitalization), survival time, prechemotherapy duration (from diagnosis of cancer to beginning of chemotherapy), duration of chemotherapy and postprogression survival (PPS)(from discontinuation of chemotherapy due to disease progression to death) (11,12) were retrospectively analyzed by the examination of medical records. The various durations are presented as months and median. Figure 1 shows the flow diagram of the study protocol. STATISTICAL ANALYSIS

PATIENTS AND METHODS PATIENT SELECTION A total of 201 inpatients treated at the Department of Palliative Care, Sakai Hospital, Kinki University Faculty of Medicine, in the 4 years from October 2007 to September 2011 were retrospectively assessed in this study. Patients with uncertain cancer diagnosis time and patients who were transferred to other hospitals were excluded. All the patients evaluated in this study are now deceased. This study was conducted according to the guidelines of the ethics committee of our hospital. As all the data assessed in this study were obtained as part of routine clinical assessments from the patients’ medical records, written consent was not obtained from the patients, in accordance with the guidelines of the Japanese Ministry of Health, Labor and Welfare. THE OUTPATIENT PALLIATIVE CARE SERVICE Although the OPCS is a component of our hospital, outpatients are referred to the OPCS from ours, as well as other hospitals and nearby clinics, for management of pain or other

Statistical analyses were performed with the use of SPSS software, version 19.0 (SPSS). Descriptive statistics were used to estimate confidence intervals, medians and standard deviations of the study variables. Mann – Whitney U-test was used for analysis of significant differences between median and 95% confidence interval between the two groups. Survival time rates were calculated according to the Kaplan – Meier method, and differences between groups were tested for significance using the log – rank test. A Cox proportional-hazards model was used to assess the effect of early referral on survival.

RESULTS PATIENTS’ CHARACTERISTICS Patient characteristics, including their primary tumor sites, duration of palliative care, duration of OPCS, survival time and duration of chemotherapy are shown in Table 1. Of the 201 patients analyzed, 117 were male and 84 were female, with a median patient age of 72.0 years. Sixty-four cases (31.8%) underwent OPCS for ,7 days (late referral group,


care. Hence, concurrent standard cancer care and palliative care are important when dealing with cancer patients (2,3). Unfortunately, however, in Japan, only few patients receive palliative care during anti-cancer treatment, many being referred to palliative care only after discontinuation of treatment. Patients should not be asked to choose between cancer treatment and palliative care, but rather, should receive both (4 – 7). Hence, concurrent palliative and standard oncology care is important, and early referral to palliative care is needed during anti-cancer treatment (4). Previous reports suggested that palliative intervention improve overall survival in advanced non-small-cell lung cancer (NSCLC) (8,9). However, it is unclear for how long early palliative intervention improves the survival time of cancers other than NSCLC. Also, the appropriate timing of palliative intervention and the elements of survival that benefit from these are unclear. The outpatient palliative care service (OPCS) of the Department of Palliative Care, Sakai Hospital, Kinki University Faculty of Medicine was established in September 2007. For outpatient palliative care, palliative intervention begins at an early stage. If the patient is hospitalized due to symptom exacerbation, palliative therapy continues to be provided by the same palliative care specialist, to treat the patient’s psychosocial problems at the same time as anti-cancer treatment is being provided. We performed a retrospective comparison of early versus late palliative interventions in patients with advanced cancer. The aims of this study were to evaluate the effect of early palliative intervention on survival in NSCLC and other cancers, and to clarify the elements affecting survival and the appropriate timing of palliative interventions (10).

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mean age 72.0 years) vs. 137 cases (68.2%, mean age 70.0 years) who received OPCS for 7 days or more (early referral group). Thirty-nine percent of patients in the late referral group were female when compared with 43.1% in the early referral group. Of the 201 cases, the primary tumor in 52 was NSCLC, 38 patients had gastric cancer, 31 had colorectal cancer, 23 had breast cancer, 22 had pancreatic or hepatobiliary malignancies and 35 had other malignancies. Sixteen of 52 NSCLC patients, 19 of 38 gastric cancer patients and 14 of 31 breast and gastrointestinal cancer patients were stage IV with chemotherapy. Median durations of palliative care in the late and early referral groups were 0.7 and 2.7 months, respectively (P , 0.001). Median durations of OPCS were 0.0 and 1.7 months, respectively (P , 0.001), with some patients being admitted and discharged several times during their treatment, as required. Survival times were 6.5 and 19.0 months, respectively (P , 0.001). Thirty-seven of 64 (57.8%) patients in the late referral group and 98 of 137 patients in the early referral group (71.5%) had a history of chemotherapy. Durations of chemotherapy were 14.0 and 18.0 months, respectively, in the late and early referral groups (P ¼ 0.210) (Table 1).

Kaplan – Meier estimates of survival in the study groups are shown in Fig. 2. Median estimates of survival were as follows: 16.0 months (95% confidence interval [CI] 15.7 – 22.3 months) in the entire sample (201 patients), 6.0 months (95% CI 0.0 – 12.2 months) in the late referral group (64 patients) and 19.0 months (95% CI 15.7 – 22.3 months) in the early referral group (137 patients) (P ¼ 0.002 by the log-rank test). After adjusting for age, sex and history of chemotherapy, hazard ratio for death in the outpatient group was 0.553 (95% CI 0.406 – 0.752) (P , 0.001) (Table 2). SURVIVAL TIME, PRE-CHEMOTHERAPY AND CHEMOTHERAPY DURATIONS AND PPS IN STAGE IV CANCERS WITH AND WITHOUT CHEMOTHERAPY To reduce the influence of cancer stage at the time of initial diagnosis and history of chemotherapy on survival time assessments, we have extracted patients with stage IV cancer and a history of chemotherapy (Table 3). Survival times in patients with stage IV NSCLC undergoing chemotherapy were 3.5 and 14.0 months in the late and early referral groups, respectively (P ¼ 0.010), which were significantly different.


Figure 1. Flow diagram of the study protocol.


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Table 1. Baseline characteristics of the study participants Variables

Late referral

Early referral

(n ¼ 64)

[95% CI]

Age (years)

72.0

[67.6–73.8]

Female no. (%)

25 (39.0%)

P value

(n ¼ 137)

[95% CI]

70.0

[68.3– 72.3]

59 (43.1%)

0.711 0.593

Primary tumor sites 15 (4)*

23.4%

37 (12)*

27.0%

Gastric cancer

13 (7)*

20.3%

25 (12)*

18.2%

Colorectal cancer

9 (5)*

14.1%

22 (9)*

16.1%

Breast cancer

7

10.9%

16

11.7%

Pancreatic cancer and hepatobiliary malignancies

7

10.9%

15

10.9%

Others

13

20.4%

22

16.1%

Duration of PC

0.7

[0.7– 1.1]

2.7

[3.9–5.7]

,0.001

Duration of the OPCS

0.0

[0.0– 0.1]

1.7

[3.0–4.8]

,0.001

Survival time

6.5

[11.1–34.2]

19.0

[25.2– 38.2]

,0.001

With CT

(n ¼ 37)

Duration of CT

14.0

[24.2– 40.5]

0.210

(n ¼ 98) [11.8–49.5]

18.0

P values were calculated with the U authorization of Mann– Whitney. Age (years), duration of PC, duration of the OPCS, survival time and duration of CT were shown by the median. Duration of PC, duration of the OPCS, survival time and duration of CT were shown in months. CI, confidence interval; PC, palliative care; OPCS, outpatient palliative care service; CT, chemotherapy. *( ) shows the number of stage IV cases with chemotherapies.

Table 2. Proportional hazards regression model of survival time in late and early referral groups Hazards ratio

Figure 2. Kaplan–Meier estimates of survival according to study groups.

Survival times in stage IV gastric cancer patients undergoing chemotherapy were 12.7 and 17.8 months in the late and early referral groups, respectively (P ¼ 0.310), which were not

95% CI

P value

Age

1.010

0.996–1.024

0.150

Sex

0.656

0.487–0.884

0.006

Early referral

0.553

0.406–0.752

,0.001

Chemotherapy

0.475

0.342–0.661

,0.001

significantly different. Survival times in patients with stage IV colorectal cancer undergoing chemotherapy were 16.5 and 20.9 months in the late and early referral groups, respectively (P ¼ 0.039), which were significantly different. Initial chemotherapies in the NSCLC patients were as follows: 13 cases received intravenous chemotherapy and 3 received oral epidermal growth factor receptor-tyrosine kinase inhibitor. All 19 gastric cancer patients received an oral fluoropyrimidine oxonate combination (S-1). Eleven of the colorectal cancer patients received intravenous chemotherapy, while three of them received oral S-1. Differences in the durations of the prechemotherapy period between late and early referral groups with NSCLC, gastric cancer and colorectal cancer were 20.1 month (P ¼ 1.000), 20.5 month (P ¼ 0.767) and 0.1 month (P ¼ 0.739), respectively. Further, differences in the durations of chemotherapy between late and early referral groups in the


Non-small-cell lung cancer

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Table 3. Survival time, duration of pre-CT, duration of CT and PPS in stage IV cancers with and without chemotherapy Primary tumor

CT

Referral timing

NSCLC

þ

Late

(4)

3.5 [0.3– 8.5]

Early

(12)

14.0 [9.5– 21.8]

Late

(3)

2

Gastric cancer

Colorectal cancer

Survival time [95% CI]

0.5 [218.9–31.3]

Early

(7)

4.9 [2.9– 6.6]

þ

Late

(7)

12.7 [3.9– 27.4]

Early

(12)

17.8 [13.2–38.9]

2

Late

(4)

2.5 [1.1– 3.6]

Early

(2)

Late

(5)

16.5 [2.6– 22.4]

Early

(9)

20.9 [13.7–36.7]

þ

Duration of pre-CT [95% CI]

P value

0.010

0.7 [20.1–1.3]

1.000

1.9 [21.6–7.0]

0.425

–

–

0.310

1.7 [22.2–10.6]

0.767

0.355

–

–

0.039

1.3 [0.5– 2.8]

0.739

0.6 [0.2– 1.3]

Duration of CT [95% CI]

P value

PPS [95% CI]

P value

0.115

0.7 [20.4– 2.1]

0.018

–

–

–

–

7.1 [1.8– 16.3]

0.237

0.8 [21.0– 5.8]

0.163

–

–

–

0.162

3.5 [1.2–5.5]

0.386

6.0 [3.5– 13.4]

1.2 [22.6–12.1]

2.7 [0.4–12.5]

14.9 [7.5– 29.4] –

2.6 [1.1–4.7]

1.7 [28.2–11.7]

Late

(2)

4.4 [221.7–30.4]

Early

(4)

7.4 [1.3– 13.1]

1.4 [0.9– 2.6] 0.355

–

10.0 [20.9–15.8] 15.9 [6.7– 28.3]

–

–

4.0 [2.5–9.4] –

–

–

Survival time, duration of pre-CT, duration of CT and PPS are represented as median. PPS was calculated from the end of chemotherapy to death. P values were calculated by Mann–Whitney’s U-test. ( ) shows the number of cases. PPS, post-progression survival.

three types of cancers were 4.1 months (P ¼ 0.115), 7.8 months (P ¼ 0.237) and 5.9 months (P ¼ 0.162), respectively, which were not statistically significantly different. Differences in PPS between late and early referral groups were 2.0 months (P ¼ 0.018), 1.8 months (P ¼ 0.163) and 0.5 month (P ¼ 0.386), respectively, the difference being statistically significant only in NSCLC patients. In all cases, chemotherapy was discontinued by the medical oncologist due to disease progression. There were 10 cases of NSCLC, 6 of gastric cancer and 6 of colorectal cancer in patients of stage IV not receiving chemotherapy. The difference of survival time was 4.4 months (P ¼ 0.425), 20.8 month (P ¼ 0.355) and 3.0 months (P ¼ 0.355) in the late and early referral groups, respectively, which were not statistically significantly different.

KAPLAN – MEIER ESTIMATES OF SURVIVAL IN THE TWO STUDY GROUPS Figure 3 shows Kaplan – Meier estimates of survival in the three kinds of cancers. Survival was calculated from the time of diagnosis of cancer to the time of death. Median estimates of survival were as follows: 2.7 months (95% CI 0.2 – 5.2) in the late referral group and 13.6 months (95% CI 7.8 – 19.4) in the early referral group with NSCLC (P ¼ 0.007 with the use of the log-rank test); 12.0 months (95% CI 0.0 – 30.0) in the late referral group and 14.0 months (95% CI 9.4 – 18.6) in the early referral group with gastric cancer (P ¼ 0.305) and 16.5 months (95% CI 0.0 – 38.6) in the late referral group and 20.9 months (95% CI 20.2 – 21.7) in the early referral group with colorectal cancer (P ¼ 0.032).

DISCUSSION The primary objective of this study was to evaluate retrospectively the effect of palliative intervention on survival in NSCLC and other cancers. We found differences in the improvements in survival time resulting from early intervention in NSCLC, gastric cancer and colorectal cancers. The survival time increased by 10.5 months (P ¼ 0.010) in patients with NSCLC, 5.1 months (P ¼ 0.310) in patients with gastric cancer and 4.4 months (P ¼ 0.039) in patients with colorectal cancer with early palliative intervention. A significant difference was seen in the survival time in NSCLC and colorectal cancers. This finding suggests that early palliative intervention improves the survival time of cancers other than NSCLC. One of the secondary objectives of our study was to clarify the elements of improvement in survival time with palliative intervention. Survival time includes the pre-chemotherapy period, the duration of chemotherapy and post-progression survival. Differences in the duration of chemotherapy with early vs. late intervention in NSCLC, gastric cancer and colorectal cancer were 4.1 months (P ¼ 0.115), 7.8 months (P ¼ 0.237) and 5.9 months (P ¼ 0.162), respectively. Differences in the post-progression survival were 2.0 months (P ¼ 0.018), 1.8 months (P ¼ 0.163) and 0.5 month (P ¼ 0.386), in early vs. late referral groups, respectively. Thus, the effect of early palliative intervention on the improvement in survival of advanced cancers was different in types of cancer. Significant effects were seen in NSCLC and colorectal cancer. The durations of chemotherapy were also extended in the three kinds of cancer. Hence, it is possible that the apparent survival improvement with early palliative intervention is due to extension of the duration of chemotherapy by palliative support. However, the extension of survival time with early when


2

P value


793


Figure 3. Kaplan–Meier estimates of survival in the two study groups.

compared with late referral was also seen in the nonchemotherapy group, the difference being 4.4 months (P ¼ 0.425) in NSCLC and 3.0 months (P ¼ 0.355) in colorectal cancer. Hence, it suggests that early palliative intervention extends the survival time of advanced NSCLC and colorectal cancer.

Another secondary objective of our study was to explore the appropriate timing of palliative interventions. Regarding the appropriate timing of palliative intervention, early interventions result in enhanced care of patients and their families from an early stage. However, at this early stage, patients and their families need curative anticancer treatments (such as

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CONCLUSION The results of this study suggested that early outpatient referral and palliative intervention leads to improvement of the outcome in patients with advanced NSCLC and colorectal cancer. Hence, cancer patients should be referred for palliative care while they are still regularly visiting the hospital for outpatient chemotherapy.

Acknowledgements We thank both the patients who participated in this study and their families.

Conflict of interest statement None declared.

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surgery, chemotherapy and radiation therapy) and may not yet be feeling the symptoms that are being treated, meaning that they do not adequately appreciate the necessity for palliative care. Furthermore, palliative care is frequently misconstrued as synonymous with end-of life care, with some patients and families mistakenly believing that palliative care shortens the patient’s life. Conversely, if the timing of intervention is late, the patients’ symptoms and requirements may be significantly greater due to disease exacerbation. Palliative care specialists need to be sensitive to the patient’s psychosocial background while treating them, particularly the pain, both physical and emotional, felt by patients with a poor survival time. If the patient has cognitive impairment, the patient’s symptoms and feelings cannot be confirmed. Considering these two aspects, it is necessary to start palliative care for advanced cancer patients during standard oncology care. Further, the appropriate timing of intervention should be individualized in each case. However, medical oncologists are often not aware of the appropriate time for palliative care (13,14). The timing of palliative intervention should not be determined by the patient’s uncertain prognosis; rather, it should be decided based on the patient’s ability to cooperate with and benefit from the palliative care. Therefore, oncologists should refer patients for palliative care at the outpatient stage (15,16). At these early stages, when patients still do not have many symptoms, palliative medicine will have more of a supportive role. The present study has several limitations. First, it is that this study was a retrospective analysis; therefore, prospective studies are needed to confirm the survival benefit of early palliative intervention. Second, it is possible that there were some differences in performance status (PS) in both groups at initial cancer diagnosis, because it was impossible to clarify all patients’ PS from medical records or introduction letters. Hence, we analyzed the first-line chemotherapy, and confirmed that all patients received standard chemotherapy in both groups. Third, subgroup analysis of stage IV cancers could have been biased by small sample size. Hence, further prospective studies are necessary in the future.