British Journal of Urology (1994), 73, 683-686

Symptomatology of metastatic prostate cancer: prognostic significance A. RANA, G.D. CHISHOLM, H.M. RASHWAN, A . SALIM, M . V . MERRICK* and R.A. ELTONf University Department of SurgerylUrology, *Department of Nuclear Medicine, Western General Hospital and ?Medical Statistics Unit, University of Edinburgh, UK

Objective To identify the various presenting symptoms in patients with metastatic prostate cancer, quantify the metastatic load for each symptom group and compare their case-specific survival.

Patients and methods A prospective and consecutive series of 279 men with metastatic cancer of the prostate was analysed. Based on the symptom at presentation, six different groups were identified: blad- der outflow obstruction, bone pain, anaemia, weight loss, paraplegia and alteration of bowel habit.

Results Significant variations were observed in their metastatic load (Kruskal-Wallis test, P = 0.003 5) and in case-specific survival (log-rank test, P= 0.0038).

Conclusion Bladder outflow obstruction, bone pain and anaemia not only dictate treatment selection but we provide evidence that each of these symptoms has considerable prognostic significance in patients with metastatic cancer of the prostate.

Keywords Prostate cancer, bone metastasis, symptoms, prognosis, hormonal treatment

Introduction Approximately 50% of the men in our prostate cancer database have either occult or overt metastases, and 25% are already bone scan positive at presentation. They present with various metastatic symptoms, e.g. bone pain, weight loss, anaemia or exclusively with bladder outflow obstruction due to the primary tumour whilst their bony metastases remain quiescent.

Pain, performance status and anaemia are the recog- nized indicators of severity of disease and subsequent deterioration indicates poor response to treatment [l, 21. However, there has been no previous appraisal of the symptomatology of metastatic prostate cancer with particular reference to the underlying severity of the disease. This study identifies the various presenting symptoms, quanties the metastatic load for each symptom group and compares their case-specific survival.

Patients and methods A total of 279 men (mean age 70 years), 169 with bone metastases at presentation and 110 in whom they developed subsequently, were identied from a consecu- tive and prospective database of 614 men with newly diagnosed carcinoma of the prostate (Cap) from January

Accepted for publication 24 August 1993

1978 to December 1990. Their follow-up was continued to December 1991 for the present study. All had unequivocal bone metastases confirmed with a 99mTc- MDP bone scan and relevant skeletal radiographs. The presenting symptoms at the t i e of metastases were recorded and the metastatic load on bone scan was calculated as originally described by Soloway et al.

The primary hormonal treatment comprised subcapsu- lar orchidectomy (n = 266), cyproterone acetate (n = lo), leuteinizing hormone releasing hormone (LHRH)- analogues (n = 2) or oestrogens ( n = 1). Routine clinical assessment comprised detailed account of urinary symp- toms (with particular reference to flow rate, hesitancy, diurnal frequency and nocturia), digital rectal examin- ation and enquiry for the presence of bone pain requiring regular use of non-narcotic and/or narcotic analgesics. Debilitating weakness was considered to be due to anae- mia if the haemoglobin was less than 9 g/dl. Body weight was recorded and a weight loss of more than 10% in the preceding 12 months was considered significant. Neurological assessments were made for paraplegia, defmed as sensory and motor loss in the lower limbs with or without loss of sphincteric tone. Some patients with metastatic prostate cancer also presented with alteration in bowel habit, their disease masquerading as colorectal obstruction, later confirmed to be due either to locally extensive primary prostatic tumour or to lymphatic dissemination and compression of the bowel or its mesentery.

[31.

683

684 A. RANA e t al.

Clinical information was supplemented with haemato- logical and biochemical tests, repeated every 3 months. Follow-up bone scans and chest radiographs were per- formed every 6 months, or earlier if indicated. The follow-up period for the present study was until the end of December 1991 and the outcome of interest was disease-specific death, which was distinguished from non-cancer deaths.

Based on the predominant symptom at presentation, six groups were identified: bladder outnow obstruction (Group l), bone pain (Group 2), anaemia (Group 3), weight loss (Group 4), paraplegia (Group 5 ) and alter- ation in bowel habit (Group 6).

Statistical anulysis

The metastatic load was compared between groups by the Kruskal-Wallis test, and cancer-specific survival rates were calculated by the Kaplan-Meier method [4] and compared with the log-rank test. Cox's proportional hazards regression was used to test the prognostic significance of the presenting symptoms adjusted for difference in metastatic load.

Results A total of 159 (57%) patients presented with bladder outflow obstruction (Group 1) due to the primary tumour which required transurethral resection of the prostate (TURP) whilst their bone metastases remained quiescent. Ninety-three (33%) presented with metastatic bone pain (Group 2 ) which required regular use of non-narcotic or narcotic analgesics, nine (3%) presented with anaemia (Group 3), nine (3%) with weight loss (Group 4), six (2%) with paraplegia (Group 5 ) , and another six (2%) with alteration in bowel habit (Group 6) (Table 1). In the present series, only three patients had overlap of their symptoms.

The mean metastatic load differed significantly between the groups (P = 0.003 S), and was relatively

small for those with local symptoms (bladder outflow) when compared with manifestly disseminated disease (anaemia or weight loss). The Kaplan-Meier estimates of the median survival were 38, 26, 11, 16, 24 and 35 months respectively for Groups 1-6 (P-value of log-rank test = 0.0038).

The case-specific survival was significantly different between Groups 1 and 2 (P-value of log-rank test= 0.038) and between 2 and 3 (P-value of log-rank test = 0.003) (Fig. 1). The increasing metastatic load for various symptomatic groups correlated closely with their worsening prognosis (Table 1). However, Cox's regression showed a significant variation in prognosis amongst the symptom groups even after adjusting for differences in metastatic load (Chi-square = 20.66, 5 d.f., P<O.001). This was primarily explained by a worse prognosis in those with anaemia: the other five groups did not differ significantly in survival after adjusting for metastatic load.

Pvalue of log-rank: 1 vs 2 = 0.038 2 VS 3 = 0.003

I

Pvalue of log-rank: 1 vs 2 = 0.038 2 VS 3 = 0.003

! F I , I / I I I I I I I I I

0 2 4 6 8 10 Year

Fig. 1. Survival estimates by Kaplan-Meier method for three different symptomatic groups of men with M1-disease. Presenting symptoms: Group 1. outflow obstruction (n= 159): Group 2, bone pain (n=93); Group 3, anaemia (n=9) .

Table 1 Presenting symptoms, metastatic load, cancer-related death and cause-specific Metastatic load Cancer-related

Median surviva' survival in M1-disease Symptom Patients mean* death group n (%) (95% CL) n (%) (months) f

outflow 159 (57) 20(15-24) 97 (61) 38 Bone pain 93 (33) 26(20-32) 61 (66) 26 Anaemia 9 (3) 37(14-61) 9 11 Weight loss 9 (3) 40(21-58) 7 16 Paraplegia 6 (2) 26 (1-51) 4 24 Change in bowel habit 6 (2) 19 (1-39) 4 35 ~~

*P-value of Kruskal-Wallis test = 0.003 5. tP-value of log-rank=0.0038.

British Journal o j Urology (1994). 73

SY MP TO MAT0 LO G Y OF METASTATIC PROSTATE CANCER: PROGNOSTIC SIGNIFICANCE 685

Discussion Identification of prognostic factors in metastatic prostate cancer has become increasingly important [ 5-71. Following treatment, subsequent deterioration in clinical parameters such as pain, performance status, weight, bladder outflow symptoms and anaemia have been recognized as objective features of progression [ 2 , 81.

Bony metastasis is generally expected to manifest with bone pain. This study, however, has shown that only 3 3 % of patients with metastatic prostate cancer have bone pain at the time of diagnosis. The majority present with local symptoms of bladder outflow obstruction whilst their bone metastases remain quiescent. Disseminated disease manifests as bone pain, anaemia or weight loss, has a high metastatic load and these patients have a poor prognosis. The difference in their prognosis was significant amongst cohorts with bladder outflow obstruction, bone pain or anaemia: differences were not observed between the rest.

This study supports the view that pain and perform- ance status are strong indicators of the severity of disease [ l ] and this is reflected by a shorter median survival (by 12 months) in those who present with bone pain when compared with those who present with bladder outflow obstruction. However, this is largely explained by differ- ences in metastatic load.

Patients with prostate cancer may lose weight because of multiple factors, e.g. crippling severity of bone metast- ases, malignant cachexia, poor socio-economic status or mental status of old age. In the present series, the patients who presented with weight loss had a mean metastatic load of 40 which indicates that dissemination of the disease makes the predominant contribution. Anaemia was the most ominous sequela of widespread tumour dissemination in bone (mean metastatic load), and these patients had 100% disease-specific mortality with a median survival of 11 months in the present series. They had the worst prognosis even after adjust- ment for metastatic load. These results add support to Mulders et aZ.’s [9] report that an optimal level of haemoglobin ( > 8.5 mmol/l) is a good prognostic index in M1-disease.

Spinal metastases from prostate cancer rarely present with paraplegia (2%) but when this occurs it is a surgical emergency. With treatment, the median survival was 24 months in the present series compared with the median survival of 7 months from Massachusetts General Hospital [lo]. A high index of clinical suspicion is necessary and should be supported by myelo/radiculogram or magnetic resonance imaging, if available, at the earliest opportunity.

Prostate cancer can masquerade as rectal cancer [ l l ] . In the present series, six patients (2%) presented with

colorectal symptoms, two of whom required laparotomy and proximal colostomy and two were treated with local radiotherapy. All had received primary hormonal manipulation. Despite the fact that these patients had associated bone metastases at presentation, their prog- nosis was favourable with a median survival of 3 5 months.

In conclusion, patients with bony metastases from prostate cancer have a poor prognosis: but even within this group it has been possible to identify prognostic subgroups defined by their symptoms at presentation. Bladder outflow symptoms, bone pain or anaemia not only dictate treatment selection but each of these symp- toms has been found to have considerable prognostic significance in patients with metastatic prostate cancer.

Acknowledgements

The authors thank Mrs Elizabeth Brunton for her expert secretarial assistance.

References 1

2

3

4

5

6

7

8

9

10

Crawford ED, Eisenberger MA, McLeod DG et al. A controlled trial of Leuprolide with and without Flutamide in prostatic carcinoma. New Engl J Med 1989: 321: 419-24 Newliig DWW. Parameters of response and progression in prostate cancer. In Schroeder FH, ed. EORTC GU Monograph 8: Treatment of Prostatic Cancer - Facts and Controversies. New York: Wiley-Liss. 1990: 25-48 Soloway MS, Hardeman SW, Hickey D et al. Stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. Cancer 1988; 61: 195-202 Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. ] Am Statist Assoc 1958; 53:

Soloway MS, Ishikawa S , Zwaag RVD, Todd B. Prognostic factors in patients with advanced prostate cancer. Urology

Ernst DS, Hanson J, Venner PM and Uro-oncology group of Northern Alberta. Analysis of prognostic factors in men with metastatic prostate cancer. J Urol 1991: 146: 372-6 Johansson J-E. Andersson S-0, Holmberg L, Bergstrom R. Prognostic factors in progression-free survival and corrected survival in patients with advanced prostatic cancer: results from a randomised study comprising 150 patients treated with orchiectomy or oestrogens. ] Urol 1991; 146:

Slack NH, Murphy GP, NPCP. Criteria for evaluating patient responses to treatment modalities for prostatic cancer. Urol Clin N Am 1984: 11: 337-42 Mulders PFA, Dijkman GA, del Moral PF, Theeuwes AGM, Debruyne FMJ and members of the Dutch Southeastern Urological Cooperative Group. Analysis of prognostic factors in disseminated prostatic cancer. Cancer 1990; 65:

Flynn DF, Shipley WU. Management of spinal cord

457-81

1989; 33: (Suppl) 53-6

132 7-33

2758-61

British Journal of Urology (1994), 73

686 A. RANA e t a l .

compression secondary to metastatic prostatic carcinoma. Urol Clin N Am 1991: 18: 145-52

11 Foster MC, O’Reilly PH. Carcinoma of the prostate masquer- ading as rectal carcinoma. Report of 3 cases and review of the literature. Br J Urol 1990; 66: 193-5

H.M. Rashwan, MD, Visiting Consultant. A. Salim, FRCS(E), Honorary Clinical Fellow. M.V. Merrick, FRCR, FRCP(E), Consultant. R.A. Elton, PhD, Senior Lecturer. Correspondence: Mr A. Rana, Department of Urology, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.

Authors A. Rana, MS. FRCS(G), FRCS(I), D Urol (London), Registrar. G.D. Chisholm, CBE, ChM, FRCS, PPRCSE, Professor.

British Journal of Urology (1994). 73