Definitive radiotherapy of prostate cancer: the possible role of staging lymphadenectomy

Int. J. Radiation Oncology Biol. Phys., Vol. 57, No. 1, pp. 33– 41, 2003 Copyright © 2003 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/03/$–see front matter

doi:10.1016/S0360-3016(03)00428-0

CLINICAL INVESTIGATION

Prostate

DEFINITIVE RADIOTHERAPY OF PROSTATE CANCER: THE POSSIBLE ROLE OF STAGING LYMPHADENECTOMY SOPHIE D. FOSSÅ, PH.D.,* WOLFGANG LILLEBY, M.D.,† HÅKON WÆHRE, M.D.,‡ AASMUND BERNER, PH.D.,§ GORAN TORLAKOVIC, M.D.,§ ELISABETH PAUS, PH.D.,储 AND DAG RUNE OLSEN, PH.D.¶ Departments of *Clinical Research, †Radiotherapy, ‡Surgical Oncology, §Pathology, 储Central Laboratory, and ¶Medical Physics, The Norwegian Radium Hospital, Oslo, Norway Purpose: To evaluate the postradiotherapy 5-year cancer-specific (CSS), clinical progression-free (cPFS), and overall (OS) survival rates in patients with pN0 M0 prostate cancer (PC). Methods: Between 1989 and 1996, 203 consecutive pN0 M0 PC patients (T1–2, 66; T3– 4, 137) received conformal prostatic four-field radiotherapy (median target dose 66 Gy). Any hormone manipulation was delayed until clinical progression (growth of the primary tumor or development of distant metastases). Results: After a median observation time of 87 months (range 11–156), 99 patients had relapsed clinically and 70 patients were dead, 37 of them as a result of prostate cancer. Five-year CSS, cPFS, and OS rates were, respectively, 90% (95% CI 86 –94%), 64% (95% CI 57–71%), and 82% (95% CI 77– 87%), with no difference of OS compared with age-matched males from the general population. Gleason score (<7A vs. >7B) and the T category predicted cPFS, whereas CSS was associated with Gleason score only. Preradiotherapy PSA failed to predict survival. Patients with T1–2 Gleason score <7A had a 97% 5-year CCS, as compared with 89% for all other patients. A median of eight lymph nodes (range 0 –29) were described in the specimens from pelvic lymphadenectomy (LA). Conclusion: Despite still preliminary observations, our 5-year results challenge the use of combined hormone radiotherapy in patients who are proven to be pN0 by preradiotherapy LA; in particular, in patients with T1–2/Gleason score <7A, whereas the survival in all other patients with pN0 M0 prostate cancer may be improved by adjuvant androgen deprivation. © 2003 Elsevier Inc. Prostate cancer, Radiotherapy, Lymphadenectomy, Survival.

INTRODUCTION Radical prostatectomy and high-dose (definitive) radiotherapy (RT) are accepted as curative treatment options in patients with prostate cancer confined to the prostatic gland T1–T2 (1, 2). Patients with ⱖT3 prostate cancer are usually deemed to be inoperable. They may be referred to high-dose RT, although the role of RT in such cases is controversial and competes with other treatment options. In a recent study, the 5-year overall survival rate in patients with locally advanced disease was about 62% after RT alone, but increased to 78% if combined with prolonged androgendeprivation 3 years after irradiation (3). A significant benefit of combined hormone RT in locally advanced M0 prostate cancer was also found in a Swedish study (4) and in American RT series (5–7). The beneficial effect of combined treatment is particularly evident in the subgroup of patients with high Gleason score (7). In many RT centers, combined hormone RT has become

the standard local treatment in locally advanced M0 prostate cancer not suitable for radical prostatectomy. The optimal duration of androgen deprivation is, however, not defined, and hormone treatment has varied from 2– 4 months to 3 or more years. Several years’ androgen deprivation is not without side effects and may have a negative impact on a man’s quality of life. Although the Leydig cell function probably recovers in most patients with short-term androgen deprivation, this may be more doubtful in elderly men after long-term Leydig cell suppression. Both the doctor and the patient have thus to balance the side effects of long-term androgen deprivation against a prolonged life expectancy. It is, therefore, not surprising that other methods of hormone manipulation are considered for use in combination with RT; for example, nonsteroidal anti-androgens (8) or the short-time use of cytostatics. Radiotherapists may even question whether all patients with pelvis-confined prostate cancer need medical adjuvant hormone treatment together with curatively in-

Reprint requests to: Sophie D. Fosså, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway. Tel: ⫹47 22 93 40 00; Fax: ⫹47 22 93 45 53; E-mail: [email protected]

Supported by The Norwegian Cancer Society. Received Nov 18, 2002, and in revised form Mar 7, 2003. Accepted for publication Mar 18, 2003. 33

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between the external and internal iliac arteries up to the iliac bifurcation and along the obturator nerve. The T category was based on digital rectal examination (11). All patients had at least one determination of serum prostate-specific antigen (PSA) before RT. The level of preradiotherapy serum PSA did not represent a criterion of exclusion. For the purpose of this analysis, the preradiotherapy PSA levels were categorized as ⱕ10 ␮g/L vs. 11–20 ␮g/L vs. ⬎20 ␮g/L. Histology was originally based on World Health Organization grading, but was subsequently revised according to Gleason’s recommendation and furthermore divided in two groups: low-risk Gleason scores (ⱕ7a: Gleason score 2– 6 or Gleason score 3⫹4 vs. high-risk Gleason scores (ⱖ7b: Gleason score 4⫹3 or Gleason score 8 –10) (12). All patients displayed a performance status 0 or 1 with a life expectancy of at least 5 years. Fig. 1. Number of patients per year referred to curatively intended radiotherapy of pN0 M0 prostate cancer.

tended RT. Subgroups of patients may exist who achieve favorable 5-year survival rates without the use of adjuvant androgen deprivation. Patients who were proven to be of pN0 by preradiotherapy staging lymphadenectomy (LA) would hypothetically represent such a group with particularly favorable survival. In these patients, adjuvant systemic treatment could probably be omitted if truly high-dose RT is applied by modern radiation techniques. The present exploratory report attempts to substantiate this hypothesis by a descriptive analysis of patients with T1–3 pN0 M0 prostate cancer treated with definitive RT. Any systemic hormone treatment was delayed until progression. PATIENTS AND METHODS Patients Curative RT of prostate cancer was introduced in Norway in the 1980s, based on the favorable reports by Bagshaw et al. (9). Late in the 1980s, shortage of RT resources and a relatively high rate of radiation-induced toxicity during the initial experience (10) caused some reluctance among Norwegian urologists to refer patients for curatively intended RT. The referral rate increased gradually after 1989 (Fig. 1), when four-field RT was introduced and radiation to the pelvic lymph nodes was omitted in patients who were proven to be pN0 by preradiotherapy pelvic staging LA. To be eligible for the present analysis, patients with histologically verified prostate cancer had been treated at the Norwegian Radium Hospital (NRH) between 1989 and 1996 (February). They had been deemed to be inoperable either because of the extent of the primary tumor or they had opted for RT after having been informed about the therapeutic options. All patients were of pN0 M0 category, as demonstrated by pelvic LA and bone scan. All LAs were to be done bilaterally, with the aim of resecting lymph nodes

Radiotherapy Until 1994, definitive RT was applied with a four-field box technique (opposing anterior-posterior fields and two opposing lateral fields) using multiple customized shielding as previously described (13). In August 1994, a modification of this semiconformal technique was introduced by using a multileaf collimator instead of customized Cerrobend blocks. Briefly, the gross target volume (GTV) was defined by a three-dimensional computed tomography planning system (Helax, Uppsala, Sweden) and covered the prostate and the seminal vesicles (Fig. 2). The clinical target volume encompasses the GTV and an additional margin of 10 mm to account for potential microscopic disease. Furthermore, a margin of 10 mm is added to account for organ motion and set-up errors; this volume is then the planning target volume (PTV). The irradiation field encompasses the PTV and a margin of 5 mm to account for the penumbra. In patients with ⱕT3b tumors, the PTV was reduced after 50 Gy to cover the prostate only, whereas patients with ⱖT3c tumors continued RT to an unchanged PTV. All patients received megavolt photon energy, 15 MV, with daily fractions of 2 Gy, 5 days per week, with a target dose of median 66 Gy (range 64 –70 Gy). The dose was prescribed on the central axis at the projected center of the target volumes, and from 1992 in regard to the ICRU 50 reference point. Follow-up All patients were seen at the NRH’s outpatient department 3 months after completion of RT. Thereafter, further follow-up was individualized according to geographic conditions and regulations by the Norwegian health care service, which prioritizes routine follow-up at local hospitals. The patient should thus be followed-up at the department of urology at the local hospital or—as a secondary alternative— by the patient‘s general practitioner. The type and frequency of follow-up examinations were left up to the responsible clinician, but annual reports had to be sent to the NRH reporting on clinical progression, eventual side ef-

Radiotherapy of pN0 M0 prostate cancer

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Fig. 2. Anterior and lateral (left) view of digitized X-ray field.

fects, and death. All patients were followed-up to death or to June 1, 2002, by a specially designed case record form sent to local hospitals and general practitioners to determine the latest survival status, date and type of clinical progression, and the cause of death. Progression Serum PSA was not a routine tumor marker in the early 1990s. Therefore, only clinical progression was considered in the present study. Local recurrence was defined as symptomatic and clinically detectable growth of the prostate tumor. Distant metastases were detected either by X-ray or bone scan, most often after the development of clinical symptoms.

Side effects Because of the previously described follow-up routines, there were considerable reasons to suspect underreporting of side effects by the responsible clinicians. Because the evaluation of radiation-induced toxicity is not within the primary aim of this study and 154 of the 203 patients had been previously studied by a Quality of Life survey (13), side effects were not further analyzed. Statistics All analyses were done by the PC-based SPSS, version 10.1, using descriptive parametric or nonparametric tests, as appropriate. The primary endpoint was cancer-specific survival (CSS), with overall survival (OS) and clinical progres-

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Table 1. Demographics of 203 pN0M0 patients receiving definitive radiotherapy for prostate cancer Age at diagnosis (years) T category T1-2 T3-4 Histology (Gleason) ⱕ7a ⱖ7b PSA [␮g/L] ⱕ10 11–20 ⬎20 Intervals (months) Diagnosis 3 Radioth. Diagnosis 3 LA LA 3 Radioth. Number of described lymph nodes Radiotherapy, target dose (Gy) Observation time (months)

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Norwegian Cancer Registry provided overall survival figures for age-matched men from the general population.

66 (48–81)* 66 137

RESULTS

97 106 21 (1–187)* 51 49 103 5 (2–41)* 3 (0–38)* 2 (0.4–10)* 8 (0–29)* 66 (64–70)* 87 (11–156)*

Patients The 203 eligible patients had a median age of 66 years at the start of RT (Table 1). About two-thirds of the patients had T3 tumors with three T4 cancers (tumor adherent to the bladder wall). There were only three T1 tumors. About half of the patients belonged to the low-risk Gleason group. Only 25% of the patients had a preradiotherapy PSA serum level of ⱕ10 ␮g/L. A median of 5 months had elapsed from diagnosis to start of RT, though occasionally relatively long times elapsed from diagnosis to referral to RT. A total of 194 patients had received a target dose of 66 Gy during a 6.5 to 7 week period.

* Median (range).

sion-free survival (cPFS) being secondary endpoints. Survival analyses from the start of RT were done by the Kaplan-Meier procedure with the log–rank test for determination of statistical differences. Clinical progression-free survival covered the time from RT start to the date of first clinical relapse. The end point of cancer-specific survival was death resulting from progressing prostate cancer, excluding sudden deaths resulting from cardiovascular events in patients with stable prostate cancer. Overall survival evaluated deaths independent from their causes. Backward conditional Cox regression analyses determined independent parameters for cancer-specific survival. A p value of ⱕ0.05 was considered to be statistically significant. The

Lymphadenectomy Fourteen of the 203 patients had a laparoscopic LA, and 189 had an open LA as previously described (14). A total of 120 LAs were done by oncologic urologists at a cancer center (NRH, Table 2). The number of lymph nodes, routinely described in the LA specimen, varied from 0 to 29, with the lowest median value among the 14 patients with laparoscopic LA (Table 2). “Fatty tissue only” was described in the operation specimen of one laparoscopic and one open LA. No significant association was found between the T category and the pretreatment PSA level or the number of described lymph nodes. Patients with tumors of Gleason scores ⱖ7B had significantly higher PSA levels than those with Gleason scores ⱕ7A tumors (Table 2).

Table 2. Type of lymphadenectomy (LA) and number of described lymph nodes A: Type of LA Type of LA

Hospital

Cancer center (120) 91 (2–23)

No. lymph nodes

Open

Laparascopy

Total

Local hospital (69) 8 (0–29)

Local hosp. (14) 5 (0–10)

(203) 8 (0–29)

B: T category, Gleason score, preradiotherapy PSA T category T1/2

PSA ␮g/L No. lymph nodes

T3/4

Total

ⱕ7a

ⱖ7b

ⱕ7a

ⱖ7b

ⱕ7a

ⱖ7b

17† (3–95) 10 (0–23)

21 (3–74) 8 (2–24)

17 (4–124) 6 (1–20)

25 (1–188) 8 (0–29)

17‡ (3–124) 8 (0–23)

25‡ (1–188) 8 (0–29)

Abbreviation: PSA ⫽ prostate-specific antigen. * Median (range) of described lymph nodes. Open vs. laparascopic LA: p ⫽ 0.002. † Median (range). ‡ ⱕ7a vs. ⱖ7b: p ⫽ 0.01.

Radiotherapy of pN0 M0 prostate cancer

Table 3. Outcome Clinical progression (PD) Type of first progression Local* Distant* Local ⫹ distant* Time to PD (months) Status on 01-06-02 Alive Local progression*§ Distant metastases*§ Local ⫹ distant*§ Dead Of prostate cancer Of other diseases Local progression*㛳 Distant metastases*㛳 Local ⫹ distant*㛳

99* 36 48 15 45 (3–139)† 133 (51)‡ 27 16 8 70 37 33 3 7 1

* Number of patients. Median (range). ‡ Alive with postradiotherapy clinical progression. § First clinical progression in survivors. 㛳 First clinical progression of patients dead of other causes. †

Outcome After a median observation time of 87 months, clinical progression was reported in 99 patients (Table 3). Distant metastases as first progression with or without local tumor growth were described in 62 patients, whereas growth of the primary tumor without distant spread indicated the first progression in 36 patients (median time to progression 45 months). At the last observation, 133 patients were alive. In 51, clinical progression had been demonstrated. Thirtyseven patients were dead of prostate cancer and 33 were dead from other causes, including 11 patients with prior progression of their prostate cancer that was deemed, however, to be unrelated to the cause of death. Because all patients had been observed for at least 5 years or to death, final 5-year survival rates were available (Figs. 3–5). The 5-year prostate cancer-specific survival rate was

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90% (95% confidence interval [CI] 86 –94%) (Fig. 3), the comparable figures for progression-free survival and overall survival being, respectively, 64% (95% CI 57–71%) and 82% (95% CI 77– 87%), respectively. Within the first 5 years after RT, the curves for overall survival in prostate cancer patients and in men from the general population were almost identical. The two-tiered Gleason grouping, but not the T category, predicted cancer-specific survival, the curves separating after 5 years (Fig. 4). The Gleason score and the T category were significantly associated with cPFS. Patients with pretreatment PSA ⱕ10 ␮g/L tended to have a slightly better progression-free survival than all other patients (p ⫽ 0.13). The level of pretreatment PSA did, however, not have an impact on prostate cancer–specific survival. The T category (T1/T2 vs. T3/T4), the pretreatment PSA (ⱕ10 vs. ⬎10 ␮g/L), and the Gleason score (ⱕ7A vs. ⱖ7B) were entered into the Cox regression analyses with, respectively, cPFS and CSS as outcome parameters. The T category (p ⫽ 0.028) and the Gleason score (p ⬍ 0.001) remained independent predictors of progression-free survival, whereas prostate cancer-specific survival was determined by the Gleason score only (p ⫽ 0.05). Combining the T category and Gleason score, two prognostic groups were identified as to cancer-specific survival: Group 1, T1/T2, Gleason ⱕ7A; Group 2, all other patients (Fig. 5). For the first group (38 patients) the 5-year cancer-specific survival rate was 97% (95% CI 92–103%) with, so far, only one death resulting from prostate cancer during the fifth to tenth years. The comparable 5-year cancer-specific survival rate for the remaining 165 patients was 89% (95% CI 84 –94%) (p ⫽ 0.02), with steady decrease of the survival rates during the ensuing 5 years.

DISCUSSION Compared with published reports on overall survival in androgen-deprivated curatively irradiated patients (Table

Fig. 3. Cancer-specific, clinical progression-free, and overall survival after curative radiotherapy of prostate cancer (203 patients). Vertical markers indicate censored patients and percentages display 5-year survival rates. – – – survival curve of men from the age-matched general population. Figures below each graph indicate the number of patients at risk.

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Fig. 4. Cancer-specific (A-C) and clinical progression free (D-F) survival. (1) Gleason ⱕ7A. (2) Gleason ⱖ7B. (3) T1/2. (4) T3/4. (5) PSA ⱕ10 ␮g/L. (6) PSA 11–20 ␮g/L. (7) PSA ⬎ 20 ␮g/L.

4), our series of pN0 M0 prostate cancer patients displays a favorable 5-year overall survival rate of 82%, obtained without hormone manipulation. These results should particularly be viewed on the background that two thirds of our patients had ⱖT3 tumors. Our series thus emphasizes the important role of preradiotherapy LA for identification of pN0 patients. The two-tiered Gleason score was the most important prognostic factor for cancer-specific survival, but the two curves did not deviate before about 5 years have elapsed. This latter observation supports the view that observation times of more than 5 years are necessary in patients with pelvis-confined prostate cancer to define a treatment’s survival improving significance. Although all of our patients had been observed until death or for more than 5 years, we still consider our survival rates as preliminary. Our favorable results may be explained by the fact that all patients were considered to be pN0 after pelvic lymphadenectomy, limited to the obturator region. Based on the routine description of the LA specimen, there has been a considerable variability of the extent of LA or the patholo-

gist’s awareness when examining the surgical specimen. This may also explain the low overall number of described lymph nodes if compared with the series by Burkhard et al. (16) and Heidenreich et al. (17) on extended LA. These authors have pointed out that lymph node metastases can be found in pelvic regions outside the obturator triangle, even in patients with PSA ⬍ 10 ␮g/L or those with low-risk histology. The clinical importance of preprostatectomy LA is generally acknowledged. Urologists are reluctant to perform radical prostatectomy if pelvic lymph node metastases are found per-operatively. Biologically, this finding is believed to indicate the presence of hematogenous micrometastases even in clinically staged M0 patients. Patients with pelvic lymph node metastases are considered not to benefit from radical prostatectomy, but to represent candidates for systemic treatment. The same rationale is valid for curatively intended RT of prostate cancer. One cannot expect to eradicate all tumor tissue by high-dose prostatic irradiation in a patient with pelvic lymph node metastases. This statement does not exclude the possibility that RT combined with

Radiotherapy of pN0 M0 prostate cancer

Fig. 5. Cancer-specific survival in patients with pN0 prostate cancer. (1) T1/T2 Gleason ⱕ 7A. (2) T1/2 Gleason ⱖ 7B or T3/4 any Gleason score.

androgen deprivation may prolong survival in patients with pelvic lymph node metastases, as suggested by Lawton et al. (18).

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Because the risk of pelvic lymph node metastases increases with increasing T category, we suspect that some of our patients with ⱖT3 tumor did indeed have undetected pelvic lymph node metastases in other pelvic regions. These patients are at risk to rapidly develop distant metastases, explaining prostate cancer deaths during the first 5 years after RT. Another explanation for rapid postradiotherapy progression may be that existing lymphatic micrometastases were missed in a significant number of routinely described lymph nodes. However, we regard this risk as limited based on our previous review of 92 patients from the present series: only 4 patients had immunohistologically stained micrometastases (14). The greatest survival-improving effect of combined RT and androgen deprivation has been seen in patients with a considerable subclinical risk of micrometastatic disease, those of a high T category and a high Gleason grade (7), comparable with those with pelvic lymph node metastases. These patients with high-risk prostate cancer are increasingly treated by combination of androgen deprivation and high-dose RT. The long-term use of androgen deprivation is, however, not without problems, and should be avoided if possible. Together with published series (Table 4), the results of the present study indicate such a possibility for the subgroup of pN0 patients, even though limited target fields and relatively low target doses were applied. Our 5-year results in patients with T1/T2 tumors of Gleason ⱕ7A histology are also comparable with those reported after radical prostatectomy (1, 22). Our study results have to be confirmed in prospective studies before they can be regarded as conclusive, but so far we believe that preradiotherapy LA identifies patients (T1/T2 tumors of Gleason score ⱕ7A) in whom long-term hormone treatment safely

Table 4. Curatively intended radiotherapy for prostate cancer A: with adjuvant androgen deprivation A: with adjuvant androgen deprivation Study first author (ref)

n

T category

Type AD

Observation period (years)

Overall survival

Bolla (3) Granfors (4) Pilepich (5) Zagar (15)

415 91 945 84

T2-4 T2-4 pN ⫹ (43%) T2-4 T3,T4

Pilepich (6)

456

T2-4

LHRH Orchiectomy LHRH DES Orch/LHRH LHRH

5 9 7 5 15 8

78% 63% 75% 68% 25% 53%

B: in pN0M0 Study first author (ref)

No. of patients

PV:prostata only/pelvic field

T1-2

T3-4

Observation period (years)

OS (%)

CSS (%)

PFS (%)

Bagshaw (9) Eastham (19) Asbell (20) Gray (21) Present series

60 105 117 129 203

NA 105/0 58/59 NA 203/0

60 91 117 115 66

0 14 0 14 137

15 16.5 12 13.9 7.5

46 34 48 46 82

70 79 86 60 90

NA 60 50 NA 64

Abbreviations: AD ⫽ androgen deprivation; LHRH ⫽ ; DES ⫽ ; Orch ⫽ ; PV ⫽ planning volume; OS ⫽ overall survival; CSS ⫽ cancer-specific survival; PFS ⫽ progression-free survival; NA ⫽ not available.

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may be delayed without decreasing the outcome. On the other hand, the cancer-specific survival decreases steadily in patients with T1/T2 Gleason score ⱖ7B or in those with T3/T4 tumors, despite of being of pN0 category. These patients will probably benefit from adjuvant androgen deprivation. Histologic grading remained the most important independent prognostic factor for separating a high-risk group from a low-risk group. This has also been confirmed by Roach et al., who indicated that Gleason grading was the most reliable predictive factor for outcome (7). Despite all uncertainties associated with clinical T categorization, this parameter also had an impact on progression-free survival, whereas pretreatment serum PSA, surprisingly, had no prognostic value for the outcome in our series. In a recent report, Kupelian et al. (2) had been unable to correlate pretreatment serum PSA values to postradiation outcome (23). Neither could Roach et al. (7) demonstrate a significant relation between pretreatment PSA and outcome, if the T category and Gleason score were considered simultaneously. Based on this evidence, we conclude that the role of preradiotherapy PSA for treatment decision needs further clarification in patients of pN0 category. As many as 33 of the deceased 70 patients died of conditions other than prostate cancer, although 35% of these men had been diagnosed with relapsing prostate cancer

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during their lifetimes. This stresses the importance to differ between prostate cancer–specific and overall survival in patients with pelvis-confined prostate cancer when treatment outcomes are considered. Because the allocation of death to either prostate cancer or other conditions may be flawed by considerable interphysician variability, protocols of prospective studies should always contain clearly defined rules for the differentiation between death resulting from prostate cancer or death from events that are unrelated to this malignancy, as recently was done in the Swedish prostatectomy trial (22). The present study has applied similar criteria for the allocation of the cause of death when cancerspecific survival was evaluated. Finally, the authors admit that the target dose in the present series is low based on today’s standard. With the availability of new techniques, target ⬎70 Gy can safely be applied to achieve better local control (2, 24, 25). With the limitation of an observation time of only 7 years (median), we conclude that long-term androgen deprivation can probably be discontinued after pelvic lymphadenectomy in pN0 M0 patients with T1/T2 tumors and Gleason score ⱕ7A histology in whom curatively intended RT is planned. In pN0 M0 patients with ⱖT3 tumors and in those with Gleason ⱖ7B, the long-term outcome may be improved if RT is combined with long-term androgen deprivation applying target doses of ⬎70 Gy.

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