Prognostic Value of Bone Scan in Patients With Metastatic Prostate Cancer Treated Initially With Androgen Deprivation Therapy

0022-5347/02/1684-1423/0 THE JOURNAL OF UROLOGY® Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 168, 1423–1426, October 2002 Printed in U.S.A.

DOI: 10.1097/01.ju.0000030900.55714.76

PROGNOSTIC VALUE OF BONE SCAN IN PATIENTS WITH METASTATIC PROSTATE CANCER TREATED INITIALLY WITH ANDROGEN DEPRIVATION THERAPY ´ OME ˆ ¨ LE NORMAND, GEORGES KARAM, PASCAL GLEMAIN, JER RIGAUD, RABI TIGUERT, LOIC JEAN-MARIE BUZELIN AND OLIVIER BOUCHOT From the Clinique Urologique, CHU Hoˆtel Dieu, Nantes, France

ABSTRACT

Purpose: We analyzed whether classifying bone prostate cancer metastases correlates with survival in patients treated primarily with androgen deprivation. Materials and Methods: We identified 86 patients with bone metastases who were followed between September 1988 and September 1999. Only those treated initially with androgen deprivation as monotherapy were included in this study. Clinical, pathological and radiological information were obtained by patient chart review. The 86 patients were divided into 2 groups according to metastasis grade on bone scan at diagnosis. Group 1 included patients with metastases on the axial skeleton and group 2 included those with bone metastases on the appendicular skeleton. In addition to our classification, we stratified patients according to the Soloway and Crawford et al classifications, and analyzed survival. Results: There were no statistical differences in the groups with axial versus appendicular metastases in terms of patient age, biopsy Gleason score, serum prostate specific antigen or clinical stage. Median survival was 53 and 29 months in patients with axial and appendicular bone metastases, respectively. Those with axial disease had better survival than those with appendicular bone metastases (p ⫽ 0.048). No statistical difference was observed when grading bone scan according to the Soloway and Crawford et al classifications. Conclusions: Classifying bone scans according to the site of metastases (axial versus appendicular) had many advantages. It is easy to understand and helps urologist better predict the patient prognosis. Axial metastases carries a better prognosis than appendicular metastasis. KEY WORDS: prostate, prostatic neoplasms, neoplasm metastasis, bone and bones, androgens

To determine the natural history of prostate cancer its clinical and pathological parameters must be defined. Prostate cancer is a slow growing tumor with nonlinear progression. It has been identified in autopsy series. The most common site of hematogenous spread of prostate cancer is bone. Isolated bone metastases were noted in 65% of patients with metastatic prostate cancer. Of men with metastatic prostate cancer 50% die of the disease within 30 months.1 On the other hand, 85% to 100% of patients who die of prostate cancer have bone metastases.2 The predilection sites of bone metastases are the spine, pelvis, ribs and limbs.3 Since the pioneering studies of Huggins and Hodges 60 years ago, it has been known that prostate cancer cells, like certain normal prostate epithelial cells, can chronically depend on a critical level of androgenic stimulation for net continuous growth and survival.4 It is on this basis that androgen deprivation therapy was used as a standard systemic therapy for metastatic prostate cancer.4 Androgen deprivation is not curative, but rather palliative treatment for prostate cancer. However, it can effectively control symptoms and prolong life. It also provides better quality of life and longer survival in treated patients.5 Nevertheless, metastatic prostate cancer remains incurable. Up to 80% of patients have a clinical response to androgen deprivation therapy and they become hormone refractory in a mean of 18 to 36 months. However, 10% of the men with advanced prostate cancer live 10 years. We analyzed whether disease extent on bone scan correlates with survival in patients with prostate cancer metastases treated initially with androgen deprivation. Accepted for publication May 17, 2002.

MATERIALS AND METHODS

Patient population. We retrospectively analyzed the records of 86 patients newly diagnosed with prostate cancer and bone metastases who were followed at our institution between September 1988 and September 1999. Clinical records were reviewed to identify patient age at diagnosis, prostate specific antigen (PSA), clinical stage, biopsy Gleason score, followup, survival and type of androgen deprivation therapy. None of these patients underwent orchiectomy, previous or subsequent aggressive therapy, such as radiation or surgery. They all received androgen deprivation as primary treatment. Of the 86 patients 7 (8%) received antiandrogen alone, 53 (62%) received luteinizing hormone-releasing hormone (LH-RH) analogue, 23 (27%) received LH-RH analogue with antiandrogen and 3 (3%) received estrogen. Androgen deprivation therapy was started just after proved prostate cancer was histologically and it was continued until death. Because PSA was not measured in all patients during monitoring, accurate assessments of biochemical progression was not available on all. The end point was survival. Bone scan. Bone scan was done at our institution in all patients before the initiation of androgen deprivation therapy. Total body scans were performed 3 to 4 hours after the intravenous administration of 20 mCi. 99mtechnetiummethylene diphosphonate. An area of increased radionuclide uptake was considered metastasis. If there was a question about an area of increased uptake, complementary x-rays were done to rule out benign disease. Based on the location of metastases scans in the 86 patients were divided into 2 groups. Group 1 included axial metastases located only on the axial skeleton, such as the

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PROGNOSTIC VALUE OF BONE SCAN FOR METASTATIC PROSTATE CANCER

spine, pelvis and/or skull. Group 2 included appendicular metastases located on the appendicular skeleton, such as the ribs and/or limbs. Patients with axial and appendicular metastases were included in group 2. In addition to our classification, we also graded each stratified bone scan according to the classifications of Soloway6 and Crawford7 et al (see Appendix). We compared survival in the groups. Followup. Followup examinations consisted of serum PSA, digital rectal examination and bone scintigraphy. Bone scintigraphy was performed when PSA increased or when clinically indicated. Plain x-ray and computerized tomography were performed to assess distant metastases. Statistical analysis. Patients were followed until January 2000. At this date they were considered alive, dead or lost to followup, defined as no followup in the last year. Patient overall survival was determined by the Kaplan-Meier method with differences measured by the log rank test. To study the various clinical factors we used the chi-square test for categorical variables and the Student t test for continuous variables. Tests results were considered statistically significant at p ⬍0.05. RESULTS

The table lists the characteristics of the 86 patients treated with androgen deprivation for metastatic prostate cancer. There were no statistical differences in the groups with axial versus appendicular metastases in terms of age, biopsy Gleason score, serum PSA, clinical stage and visceral metastases. Of the 44 patients with bone pain at diagnosis 6 had spine compression. When comparing survival in patients with and without bone pain, no statistical difference was noted (p ⫽ 0.362). Of the 86 patients 58 (68%) died during the study, 26 (30%) were alive at the end of the study and 2 (2%) were lost to followup. Overall survival in 50% of the 86 patients was 32 months at a median followup of 23 months (range 2 to 108). The survival rate at 1, 3 and 5 years was 81%, 46% and 25%, respectively, in the 86 patients (fig. 1). As described by Soloway et al, on bone scan extent of disease was grades 1 to 3 in 33 (38%), 40 (47%) and 13 (15%) cases, respectively (see Appendix).6 There was no grade 0

FIG. 1. Overall survival in 86 patients with metastatic prostate cancer treated with androgen deprivation.

since all patients had bone metastases according to that classification. In addition, no grade 4 disease extent was observed. There was no statistical difference in terms of survival when we compared the groups (p ⫽ 0.181). The 5-year survival rate was 32%, 20% and 0% for extent of disease grades 1 to 3, respectively. Of the patients 50% with grades 1 to 3 disease extent were alive at 46, 29 and 25 months, respectively. However, there was a trend when comparing survival in patients with 6 or fewer (grade 1) and greater than 6 (grades 2 and 3) metastases (p ⫽ 0.081, fig. 2). When we stratified patients according to the Crawford et al classification,7 25 (29%) had minimal and 61 (71%) had severe disease. There was a trend in the groups with minimal versus severe disease in terms of survival (p ⫽ 0.061, fig. 3). The 5-year survival rate was 42% and 17% for minimal and severe disease, respectively. Of the patients 50% with minimal and severe disease were alive at 38 and 32 months, respectively.

Patient characteristics before androgen deprivation therapy Overall No. pts. Age: Mean (range) Median No. biopsy Gleason score: 2–6 7 8–10 Unknown PSA (ng./ml.): Mean (range) Median No. clinical stage: T1c T2 T3a T3b T4 No. stage N: N1 Nx No. visceral metastases: Yes No No. Eastern Cooperative Oncology Group score: 0 1 2 3 No. initial treatment: Antiandrogen alone Analogue LH-RH alone Analogue LH-RH ⫹ antiandrogen Estrogen

86

Axial 23

Appendicular

p Value

63 0.4331

71.3 72

(47–93)

72.7 72

(52–88)

70.8 73

(47–93) 0.4152

16 28 37 5

3 10 9 1

13 18 28 4 0.3413

975 (3.4–12,420) 147.5

582 57

(11–7,586)

1,118 195

(3.4–12,420) 0.8124

5 14 24 40 3

1 2 7 12 1

4 12 17 28 2

4 82

1 22

3 60

5 81

1 22

4 59

16 42 27 1

5 12 6 0

11 30 21 1

7 53 23 3

1 15 6 1

6 38 17 2

0.7073 0.7418 0.8292

0.8751

PROGNOSTIC VALUE OF BONE SCAN FOR METASTATIC PROSTATE CANCER

FIG. 2. Survival by extent of disease on initial bone scan according to classification of Soloway et al (extent of disease 1 versus 2 to 3).6

FIG. 3. Survival by extent of disease on initial bone scan according to classification of Crawford et al (minimal versus severe disease).7

When using our classification, 23 patients (27%) had axial (group 1) and 63 (73%) had appendicular (group 2) bone metastases. All patients with appendicular metastases had axial metastases. There was a mean plus or minus standard deviation of 4.2 ⫾ 2.8 and 11.3 ⫾ 6.9 metastases in the axial and appendicular groups, respectively (p ⫽ 0.0001). Patients with axial disease had better survival than those with appendicular disease (p ⫽ 0.048, fig. 4). The 5-year survival rate was 47% and 16% in those with axial and appendicular metastases, and 50% of patients were alive at 53 and 29 months, respectively. DISCUSSION

Bone metastasis is a known poor prognosis factor. Androgen deprivation therapy provides a better response rate in patients without versus with bone metastases.8 –11 Bone scan is useful for determining the distribution of bone metastases because it evaluates the whole skeleton at once. We observed in our study that bone scan had prognostic value in patients with metastatic prostate cancer treated initially with androgen deprivation. This significant difference in survival was observed when we stratified patients according to the distribution of metastases on initial bone scan. Thus, patients with appendicular metastases had a worse outcome than those with axial bone metastasis. The advent of serum PSA testing and implementation of screening programs for detecting prostate cancer has led to a

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FIG. 4. Survival rate in patients with appendicular versus axial bone metastases.

pathological stage shift in patients undergoing radical prostatectomy. More patients are diagnosed with small tumor volume and there is a dramatically decreased rate of metastatic disease. The combination of serum PSA, Gleason score and clinical stage can help select patients not requiring bone scan. However, bone scan cannot be safely omitted in patients with poor prognostic factors, including high serum PSA, high Gleason score and advanced clinical stage.12 It is well known that prostate cancer has a predilection to metastasize to bone, resulting in a marked increase in bone turnover. Two hypotheses were postulated. 1) Prostate cancer cells tend to reach bone more easily than other organs. 2) Bone tissue may be a favorable, rich medium, allowing prostate cancer cells to grow.13 By injecting the venous plexus of the prostate Batson observed that the latter drained directly into the vertebral venous plexus, which may explain the early spread of prostate cancer to the spine.14 On the other hand, Rana et al reported that bone prostate cancer metastases were more often located on the axial than the appendicular skeleton.15 Soloway et al suggested a classification for prostate cancer bone metastases according to the number of metastatic sites discovered on bone scan.6 They reported a 2-year survival rate of 96%, 76%, 62% and 43% for grades 1 to 4 disease, respectively, after androgen deprivation therapy. They also noted a difference in terms of survival for grades 1 and 4. However, there was no difference in grades 2 and 3. Jorgensen et al reported the same results as Soloway et al when comparing grade 1 versus grades 2 to 4 but there was no difference in survival for grades 2 versus 3 and 3 versus 4.16 Ishikawa et al analyzed that series and stratified patients into 2 groups according to the number of bone metastases using a cutoff of 6 metastases (grades 1 versus 2 to 4).17 When stratifying patients into 2 groups, they noted a distinct difference in survival by eliminating overlap in the groups. In our study there was no difference in survival when we compared grades 1 to 3. This finding may have been the result of small sample size. Nevertheless, there was a trend when using a cutoff of 6 metastases. Patients with 6 or fewer metastases had better survival than those with greater than 6. Crawford et al reported that patients with minimal disease had better survival than those with severe disease.7 When using this classification, we identified a trend in the 2 groups in disease survival. Their classification is similar to ours except they incorporated visceral metastases in their classification. In addition, metastases to the skull were included in the severe disease group. Our classification was based only on bone scan findings. Skull metastases were included in

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axial group that had a better prognosis, in contrast to the Crawford et al classification. Classifying bone scans by the number of metastatic sites is not always easy, especially when a large nonhomogenous single metastasis is difficult to differentiate from 2 small metastases. The classification of prostate cancer metastases used in our study (appendicular versus axial skeleton location) had an advantage because it considers only the location and not the number or volume of metastases. Also, we noted a significant difference in survival when comparing patients by bone metastasis location. In 2 previous studies metastases outside of the pelvis and lumbar spine (also called peripheral metastases) were associated with the worst prognosis.18, 19 Our study was retrospective and included a small sample of patients who received androgen deprivation as initial treatment for prostate cancer. Thus, a lack of data, such as serum PSA, may explain the limitations of this study. Biochemical failure could not be assessed. A prospective study including a larger number of patients is needed to validate our results. Why patients with appendicular bone metastases had a worse outcome than those with axial metastases is not clear. However, all those with appendicular metastases had axial metastases. Is it because patients with appendicular metastases had more tumor volume or do those with axial metastases respond better to androgen deprivation therapy? The first hypothesis is more plausible. Furthermore, Messing et al reported prolonged disease survival in patients with low volume metastatic disease on androgen deprivation therapy.20 According to the natural history of prostate cancer appendicular metastases appear at the end of disease evolution. This centrifugal spread starts at the pelvis and spine before extending to the ribs and limbs. This hypothesis can explain why patients with appendicular metastases have a poor prognosis. CONCLUSIONS

Bone scan is valuable for identifying and grading bone metastases in patients with prostate cancer. When adopting the axial versus appendicular bone classification, a significant difference in survival was observed. This classification, which is easy to understand, is more sensitive and may help urologists better counsel patients on their prognosis. Identifying patients with a short life expectancy is important for early effective treatment and also for quantifying the results of new drugs. Patients enrolled in various clinical trials should be stratified by the location of bone metastases since the site of prostate cancer bone metastases has an impact on disease survival. APPENDIX: PROSTATE CANCER METASTASES CLASSIFICATIONS

Soloway et al6 0—Normal or abnormal due to benign disease 1—Less than 6 metastases, of which each is less than 50% the size of a vertebral body 2—Between 6 and 20, size of lesion as described 3—More than 20 but less than a super scan 4—Super scan or its equivalent (more than 75% of the ribs, vertebrae and pelvic bones) Crawford et al7 Minimal disease—Absent disease in the ribs, long bones, skull or soft tissue other than lymph node involvement Severe disease—disease in the ribs, long bones, skull or soft tissue other than lymph node involvement Present series Axial—metastases located only on the spine, pelvis and/or skull

Appendicular—metastases located on the ribs and/or limbs with or without axial metastases REFERENCES

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