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Prostate cancer: Pelvic nodes revisited — Sites, incidence and prospects for treatment with radiotherapy
Clinical Oncology (1993) 5:309--312 © 1993 The Royal College of Radiologists
Clinical Oncology
Review Article Prostate Cancer: Pelvic Nodes Revisited - Sites, Incidence and Prospects for Treatment with Radiotherapy A . J. N e a l a n d D . P. D e a r n a l e y Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey and Royal Marsden Hospital, Sutton, Surrey, UK
The role of pelvic lymph node irradiation in the management of carcinoma of the prostate remains uncertain. There have been few randomized studies designed to address this issue. Enthusiasm for this strategy has been tempered by our inability to give high doses of radiation to the pelvis without causing significant acute and late radiation morbidity, and by observations that patients die from distant metastases rather than pelvic node relapse. However, in recent years, there has been an increasing appreciation that, in some patients, pelvic recurrence itself may be the source of subsequent distant metastases; also that increased local control should be the goal of therapy as it may in turn lead to improved quality of life and survival [1-5]. Dissemination of tumour cells to the pelvic lymph nodes is an early phenomenon in the natural history of the disease. With regard to risk factors, many series have shown a positive correlation between the incidence of lymph node metastases at lymphadenectomy and tumour variables such as stage [6-18], histological grade [7,9,13,15-19], bulk [7,8] and invasion of the seminal vesicles [7,8]. Oesterling et al. [13] have performed a statistical analysis relating stage, grade and acid phosphatase to produce several nomograms which give the probability of lymph node involvement for given values of these parameters. It is currently standard practice in many centres in the USA to include the pelvic lymph nodes in the irradiated volume. Pertinent questions include: What is the incidence of nodal metastases and which nodes need to be considered as part of the clinical target volume? There can be little dispute that surgical staging of lymph nodes is the final arbiter in determining the incidence of lymph node metastases. Autopsy studies were for some years the main source of data regarding the patterns of lymphatic spread of prostatic cancer [20-22]. However, such reports were superseded by advances in surgical techniques which facilitated surgical staging by pelvic lymphadenectomy. The results from a number of surgical series are summarized in Table 1. It is important to make the distinction between clinical and pathological staging of the prostate. Correspondence and offprint requests to: Dr A. J. Neal, Clinical Research Fellow, Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, Surrey, UK.
Meticulous pathological staging by bilateral pelvic lymphadenectomy, such as that performed by McLaughlin et al. [12] can on average be expected to yield 33 nodes, rising to up to 89 if the presacral nodes are also dissected [24]. The prostatic lymphatics were originally identified by performing contrast studies using cadavers [25,26]. Lymphatic drainage to the obturator and presacral nodes was suggested by Smith [27] who infiltrated 1 ml of patent blue V dye into the prostate immediately prior to laparotomy and then assessed staining of the lymphatics at surgery. This was confirmed by Golimbu et al. [24] who performed very detailed pelvic lymphadenectomies in patients with stage A, B and C disease, with particular emphasis on clearing the presacral area, and yielding 22 to 89 nodes with a mean of 43. Of the involved lymph node groups, the external iliac group was the most frequently involved (60%) followed by the obturator group (53%). Fifty-three per cent had presacral node involvement and 47% presciatic node involvement. The largest surgical series providing data regarding the geographical distribution of involved nodes is summarized in Table 2 [9]. Other surgical series have suggested that the obturator/hypogastric complex is the main site of node metastases [7,8,15]. There is also evidence that there is a positive correlation between the side of the palpable tumour within the prostate and the side of pelvic lymph node involvement. Harrison et al. [11] reviewed the results of 411 lymphadenectomies in stage B and C carcinoma. Of 35 patients with Positive nodes and palpable disease confined to one 10be, 83% had ipsilateral nodes (57% to ipsilateral nodes or~!yand 26% to bilateral nodes), and 17% contralfiteral nodes only. This data is of value when considering less invasive means of pathologically staging the pelvic lymph nodes. In some centres technological advances in endoscopic instrumentation have made a closed procedure the method of choice, it having the advantage of providing an equivalent number of nodes to an open procedure [28] while being associated with less morbidity and a postoperative hospital stay of less than 48 hours [29, 30]. The data from the open lymphadenectomy series suggest that, when the cancer is clinically localized to one lobe of the prostate, endoscopic sampling of the
310
A . J . Neal and D. P. Dearnaley
Table 1. Summary of incidence of pelvic lymph node metastases at lymphadenectomy by stage: percentages (no. evaluable patients)
\uthor
Total no. patients
Clocks (1959) [8] )onohue (1981) [19] "owler (1981) [9] ;mith (1983) [18] ~enson (1984) [23] )esterling (1987) [13] 3ervasi (1989) [10] 'etros (1992) [14] tarrison (1992) [11] ~ean 1
411 c 215 c 300 c 452 c 519 ° 275 c 511 c 521 c 411 c -
~incke (1982)[17]
469 p
Stage A 1
Stage A 2
Stage B~
Stage C 1
Stage B 2
38 (382)
7 (29) 0 (9)
23 (44)
0 (41)
24 (33)
0 (10)
9 (23) 22 (130) 3.3 (61)
0 (32)
19 (104) 50 (58) 7 (75) 43 (129) 12 (156) 28 (154) 12:5 (519) 4 (178) 33 (64) 21 (165) 37 (100) 5.3 (189) 9.7 (236) 16 (210) 28 (106) 18 (2734)
0 (92) 0 (5)
0 (9)
Stage C2
0.5 (183)
60 (96)
53 (68)
44 (116) 38 (93) 50 (2) 43 (757)
10 (124)
36 (148)
c Equal staging. P Pathological staging. 1Flocks data excluded for stages A1 to B 2. Table 2. Summary of sites of lymph node metastases in 119 node positive patients (adapted from Fowler et al. (1981) (n = 300) Stage
% N+ (no.)
Unilateral (%)
Bilateral (%)
Solitary (%)
> 3 nodes (%)
Ob/Hypo (%)
Ext iliac (%)
Ob/hypo and ext iliac (%)
B1 B2 C
7 (5) 43 (56) 60 (58)
100 63 43
0 37 57
80 34 21
20 32 59
75 43 35
25 30 18
0 28 47
N+, node positive; OB, obturator group; Hypo, hypogastnc group.
ipsilateral external iliac, obturator and hypogastric nodes will be a sensitive means of identifying lymph node metastases with a lower risk of surgical complications than when bilateral sampling or an open lymphadenectomy is performed. Approximately 13% of patients will have the lateral sacral and/or presacral nodes as the sole site of nodal metastases [24] but these patients are unlikely to be staged correctly with the type of open lymphadenectomy currently practised. To date it has not been possible to administer sufficiently high doses of radiation to eradicate malignant cells (particularly when macroscopic disease is present) without considerable acute and late normal tissue morbidity. The dose complication effect for pelvic radiotherapy is well documented [31-33]. The risk of pelvic complications is also related to the volume irradiated [34,35]. Conventional treatment techniques lead to excessive bowel complications when high doses of radiation are administered. An early prospective randomized trial of extended field irradiation for prostatic cancer giving 55 Gy to the whole pelvis in 2 Gy fractions had to be modified due to excessive small bowel morbidity [15]. The most robust study to date has been that of the RTOG 77-06 [36] in which patients with prostatic cancer clinically limited to the gland (stages A2 and B) after surgical staging or lymphangiography were randomized to either a minimum of 65 Gy to the prostate and paraprostatic tissues, or 45 Gy to the whole pelvis and a 20 Gy boost to the prostate. In the 445 evaluable patients, there was no significant difference between the two arms after a median follow-up
of 7 years in terms of local control, time to distant metastases or overall survival. These results contrast with an earlier non-randomized report by McGowan et al. [37] in which patients with stages B 2 and C disease had a statistically significant advantage after pelvic node irradiation of 50-60 Gy, with a 63% 5-year survival versus 35% for prostatic irradiation alone. Similar findings have recently been presented by Ploysongsang et al. [38] using pelvic radiotherapy to a dose of 46-50 Gy. Patients with stage C disease had a 3-year disease free survival of 63% and a local control rate of 84% when pelvic radiotherapy was given, compared with 30% and 66% respectively for a historical cohort who had received radiotherapy to the prostate alone. Paulson et al. [39] randomized 77 patients with histologically confirmed pelvic lymph node metastases to either hormonal therapy delayed until relapse or elective irradiation of 45-50 Gy to the pelvic nodes. They demonstrated a statistically significant increase in the median disease free survival for pelvic irradiation (23.9 months versus 12.2 months, P=0.02) and a suggestion of an increase in overall survival. Bagshaw [6] has reported a similar benefit after long term follow-up of patients who received 50 Gy as a split course over 7 weeks, but this did not reach statistical significance. Similarly, multivariate analysis of patients with T2-T4 prostatic cancer treated at The Royal Marsden Hospital [40] showed a small but statistically significant advantage for additional radiotherapy to the pelvis. One hundred and fortynine previously untreated patients without radio-
Prostate Cancer: Pelvic Nodes Revisited
logical evidence of lymphadenopathy, who received radiotherapy to the prostate alone, attained 82% local control and 53 % 5-year survival versus 88% and 66% respectively for 36 comparable patients who received radiotherapy to the whole pelvis. The R T O G 75-06 study [41] randomized 607 patients with stage A2-C carcinoma to pelvic radiotherapy alone or combined pelvic and para-aortic irradiation. Although this does not add to our knowledge regarding whether pelvic node irradiation is beneficial, after a median follow-up of 4.25 years there was no advantage for added para-aortic irradiation in terms of disease free survival and overall survival. Conformal treatment techniques and threedimensional treatment planning mean that it is possible to reduce the clinical target volume and thereby reduce unnecessary irradiation of the surrounding small bowel, large bowel and bladder, so increasing the therapeutic gain [42]. Threedimensional planning has already been shown to be of benefit in para-aortic lymph node irradiation where analogous constraints on radiation dose are present [43]. Reduced acute morbidity compared with conventional treatment has already been demonstrated in early reports from non-randomized studies of conformal radiotherapy to the prostate [44--46]. Conformal radiotherapy therefore seems to be the tool for the delivery of high doses of radiation to the pelvis. However, before it can be implemented, it is necessary to have a precise definition of the lymph node groups at risk. We are therefore currently undertaking a study using multimodality imaging, comprising bipedal lymphangiography followed by computed tomographic scanning and magnetic resonance imaging (MRI) of the pelvis in order to define accurately the clinical target volume for threedimensional treatment planning and conformal radiotherapy. Lymphangiography (LAG) is a reliable means of delineating the anatomical distribution of the common iliac, external iliac and lower para-aortic lymph nodes. This has led to it being accepted as a valuable aid to a surgeon performing pelvic lymphadenectomy [47], and to the radiotherapist, as it yields data in a form that permits direct planning of the radiation treatment portals. It has also been used to provide precise anatomical information to localize pelvic lymph nodes for fine needle aspiration [48-50]. The obturator nodes are an important site of metastases from carcinoma of the prostate. For many years it was thought that these nodes did not opacify on LAG [51], although there is much evidence to the contrary [52-54]. LAG performed prior to a CT scan does not appear to be detrimental to the quality of the CT image obtained [55]. Indeed, lipiodol helps to identify the nodes due to its high iodine content giving rise to an area of high attenuation [56]. Computed tomography is of value to show lymph nodes that have not been opacified by LAG [49], particularly the internal iliac nodes [57]. In addition to giving useful anatomical information for treatment planning, a CT scan will provide the three-dimensional map of linear attenuation coefficients necessary to perform radiation dose calculations. In terms
311
of localizing the pelvic lymph nodes, MRI has the advantage over computed tomography of increased soft tissue contrast with more detailed and superior multiplanar reconstruction capabilities. It also has the advantage of allowing modulation of the signal from flowing blood by varying the pulse sequences, thus increasing the contrast between lymph nodes and the blood vessels. As with CT, lipiodol from the L A G will also contribute to node localization on T2 and proton density images [56]. These images will form the basis of devising new treatment techniques employing the versatility of a linear accelerator with multileaf collimation and planning systems, with the facility to use non-coplanar field arrangements. There may be analogies between the results of treatment of prostatic and breast cancer. The effect of radical treatment of the axillary lymph nodes in breast cancer has been a source of controversy for some years, but a recent large randomized study indicated a survival advantage for aggressive local treatment of axillary node positive disease [58]. Advances in treatment planning and radiotherapy techniques should therefore be used to address this issue in the pelvis.
Acknowledgements. Dr Neal is funded by the EEC
as part of the COVIRA (Computer Vision in Radiology) project. Dr Dearnaley is funded by The Cancer Research Campaign and The Bob Champion Cancer Trust.
References 1. Anderson P, Dische S. Local tumour control and the subsequent incidence of distant metastatic disease. Int J Radiat Oncol Biol Phys 1981;7:1645-8. 2. Kuban DA, El-Mahdi AM, Schellhammer PF. Effect of local tumour control on distant metastasis and survival in prostatic adenocarcinoma. Urology 1987;30:420-6. 3. Ramsay J, Suit HD, Sedlacek R. Experimental studies on the incidence of metastases after failure of radiation treatment and the effect of salvage surgery. Int. J. Radiat Oncol Biol Phys 1988;14:1165-8. 4. Suit HD, Westgate SJ. Impact of improved local control on survival. Int J Radiat Biol Phys 1986;12:453-8. 5. Zagars GK, von Eschenbach AC, Ayala AG, et al. The influence of local control on metastatic dissemination of prostate cancer treated by external beam megavoltage radiation therapy. Cancer 1991;68:2370-7. 6. BagshawMA. Radiotherapeutictreatment ofprostaticcarcinoma with pelvic node involvement. Urol Clin North Am 1984;11:297-304. 7. BarzellW, B e a n M A , HilarisBS, et al. Prostatic adenocarcinoma: Relationship of grade and local extent to the pattern of metastases. J Urol 1977;118:278-82. 8. Flocks Rt-I, Culp D, P0rto R. Lymphatic spread from prostatic cancer. J Urol 1959;81:194-45. 9. Fowler JE, Whitmore WF. The incidence and extent of pelvic lymph node metastases in apparently localised prostatic cancer. Cancer 1981;47:2941-5. 10. Gervasi LA, Mata J, Easley JD, et al. Prognostic significance of lymph node metastases in prostate cancer. J Urol 1989;142:332-6. 11. Harrison SH, Seale-Hawkins C, Schum CW, et al. Correlation between side of palpable tumour and side of pelvic lymph node metastasis in clinically localised prostate cancer. Cancer 1992;69:750-4. 12. McLaughlin AP, Saltzstein SL, McCullough DL, et al. Prostatic carcinoma: Incidence and location of unsuspected lymphatic metastases. J Urol 1976;115:89-94. 13. Oesterling JE, Brendler CB, Epstein JI, et al. Correlation of clinical stage, serum prostatic acid phosphatase and preoperative Gleason grade with final pathological stage in 275 patients
312 with clinically localised adenocarcinoma of the prostate. J Urol 1987;138:92-7. 14. Petros JA, Catalona WJ. Lower incidence of unsuspected lymph node metastases in 521 consecutive patients with clinically localised prostate cancer. J Urol 1992;147:1574-5. 15. Pistenma DA, Bagshaw MA, Freiha FS. Extended field radiation therapy for prostatic adenocarcinoma: Status report of a limited prospective trial. In: Johnso~ DE, Samuels ML, editors. Cancer of the Genitourinary tract. New York: Raven, 1979:229-47. 16. Prout GR, Heaney JA, Griffin PP, et al. Nodal involvement as a prognostic indicator in patients with prostatic carcinoma. J Urol 1980;124:226-31. 17. Zincke H, Farrow GM, Myers RP, et al. Relationship between grade and stage of adenocarcinoma of the prostate and regional pelvic lymph node metastases. J Urol 1982;128:498-501. 18. Smith JA, Seaman JP, Gleidman JB, et al. Pelvic lymph node metastasis from prostatic cancer: Influence of tumour grade and stage in 452 consecutive patients. J Urol 1983;130:290-2. 19. Donohue RE, Fauver HE, Whitesel JA, et al. Prostatic carcinoma: Influence of tumour grade on results of pelvic lymphadenectomy. Urology 1981;17:435-40. 20. Arnheim FK. Carcinoma of the prostate: A study of the postmortem findings in one hundred and seventy-six cases. J Urol 1948;60:599-603. 21. Elkin M, Mueller HP, Metastases from cancer of the prostate: Autopsy and roentgenological findings. Cancer 1954;6:12468. 22. Mintz ER, Smith GG. Autopsy findings in 100 cases of prostatic cancer. N Engl J Med 1934;211:479-87. 23. Benson RC, Tomera KM, Zincke H, et al. Bilateral pelvic lymphadenectomy and radical retropubic prostatectomy for adenocarcinoma confined to the prostate. J Urol 1984; 131:1103-6. 24. Golimbu M, Morales P, AI-Askari S, et al. Extended pelvic lymphadenectomy for prostatic cancer. J Urol 1979;121:61720. 25. Sappey PC. Anatomie, physiologie, pathologie des vaisseaux lymphatiques consider6s chez l'homme et les vert6br6s. Paris: A. Delahaye, 1874. 26. Poirier P, Cuneo B, Delamere G. The lymphatics. (Translation Leaf CH) Chicago: W. T. Keener, 1904. 27. Smith MJV. The lymphatics of the prostate. Invest Urol 1966;3:439-47. 28. Parra RO, Andrus C, Boullier J. Staging laparoscopic pelvic lymph node dissection: Comparison of results with open pelvic lymphadenectomy. J Urol 1992;147:875-8. 29. Schuessler WW, Vancaillie TG, Reich H, et al. Transperitoneal endosurgical lymphadenectomy in patients with localised prostate cancer. J Urol 1991;145:988--91. 30. Boullier JA, Parra RO. The current status of endoscopic (laparoscopic) pelvic lymphadenectomy in the staging of prostate cancer: Experience, indications and future directions. Semin Urol 1992;10:232-8. 31. Orton CG, Wolf-Rosenblum S. Dose dependence of complication rates in cervix cancer radiotherapy. Int J Radiat Oncol Biol Phys 1986;12:37-44. 32. Montana GS, Fowler WC. Carcinoma of the cervix: Analysis of bladder and rectal radiation dose and complications. Int J Radiat Oncol Biol Phys 1989;16:95-100. 33. Smit WGJM, Helle PA, van Putten WLJ, et al. Late radiation damage in prostate cancer patients treated by high dose external radiotherapy in relation to rectal dose. Int J Radiat Oncol Biol Phys 1990;18:23-9. 34. Rosen E, Cassady JR, Connolly J, et al. Radiotherapy for prostate carcinoma: The JCRT experience (1968-1978). Factors related to tumour control and complications (JCRT Harvard). Int J Radiat Oncol Biol Phys 1985;11:725-30. 35. Mameghan H, Fisher R, Mameghan J, et al. Bowel complications after radiotherapy for carcinoma of the prostate: The volume effect. Int J Radiat Oncol Biol Phys 1990;18:315-20. 36. Asbell SO, Krall JM, Pilepich M, et al. Elective pelvic irradiation in stage A2, B carcinoma of the prostate: Analysis of RTOG 77-06. Int J Radiat Oncol Biol Phys 1988;15:130716.
A . J . Neal and D. P. Dearnaley 37. McGowan DE. The value of extended field radiation therapy in carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1981 ;7:1333-9. 38. Ploysongsang SS, Aron BS, Shehata WM. Radiation therapy in prostate cancer: Whole pelvis with prostate boost or small field to pelvis. Urology 1992;40:18--26. 39. Paulson DF, Cline WA, K0efoot RB, et al. and the Urooncology Research Group. Extended field radiation therapy versus delayed hormonal therapy in node positive prostatic adenocarcinoma. J Urol 1982;127:935-6. 40. Dearnaley DP, Eeles R, Syndikus I, et al. External beam radiotherapy for localised prostate cancer: Long term follow up [abstract]. Radiother Oncol 1992;24 suppl 1:$80 41. Pilepich MV, Krall JM, Johnson RJ, et al. Extended field (periaortic) irradiation in carcinoma of the prostate: Analysis of RTOG 75-06. Int J Radiat Oncol Biol Phys 1986;12:34551. 42. Tait D, Nahum A, Southall C, et al. Benefits expected from simple conformal radiotherapy in the treatment of pelvic tumours. Radiother Oncol 1988;132:23-30. 43. Munzenrider JE, Doppke K, Brown AP, et al. Three dimensional treatment planning for para-aortic node irradiation in patients with cervical cancer. Int J Radiat Oncol Biol Phys 1991;21:229-42. 44. Soften EM, Hanks GE, Hunt MA, et al. Conformal static field radiation therapy treatment of early prostate cancer versus non-conformal techniques: A reduction in acute morbidity. Int J Radiat Oncol Biol Phys 1992;24:485-8. 45. Sandier HM, Perez-Tomayo C, Ten Haken RK, et al. Dose escalation for stage C (T3) prostate cancer: Minimal rectal toxicity observed using conformal therapy. Radiother Oncol 1992;23:53-4. 46. Vijayakumar S, Awan A, Karrison T, et al, Acute toxicity during external beam radiotherapy for localised prostate cancer: Comparison of different techniques. Int J Radiat Oncol Biol Phys 1993;25:359-71. 47. Kajanoja P, Raisanen I, Lehtovirta P. Wertheim radical hysterectomy: Surgical complications, accuracy of clinical staging and value of lymphangiography in cervical carcinoma. Ann Chir Gynaecol 1985;74:94-7. 48. Cochand-Priollet B, Roger B, Boccon-Gibod I, et al. Retroperitoneal lymph node aspiration biopsy in staging of pelvic cancer: A cytological study of 228 consecutive cases. Diagn Cytopathol 1987;3:102-7. 49. Khan O, Pearse E, Bowley N, et al. Combined bipedal lymphangiography, CT scanning and transabdominal lymph node aspiration cytology for node staging in carcinoma of the prostate. Br J Urol 1983;55:538-41. 50. Scappini P, Piscioli F, Pusiol T, et al. Penile cancer: Aspiration biopsy cytology for staging. Cancer 1986;58:1526-33. 51. Cerny JC, Farah R, Rian R, et al. An evaluation of lymphangiography in staging carcinoma of the prostate. J Urol 1975 ;113:367-70. 52. Komatsu HH, Hayashi S, Tanabe N, et al. Ex vivo comparison of radiological and histological evaluation of early metastatic lesions of pelvic lymph nodes from carcinoma of the bladder or prostate. J Urol 1987;138:341-3. 53. Merrin C, Wajsman Z, Baumgarmer G, et al. The clinical value of lymphangiography: Are the nodes surrounding the obturator nerve visualised? J Urol 1977;117:762. 54. Zoretic SN, Wajsman Z, Beckley A, et al. Filling of the obturator nodes in pedal lymphangiography: Fact or fiction. J Urol 1983;129:533-5. 55. Hodson NJ, Husband JE, Macdonald JS. The role of computed tomography in the staging of bladder cancer. Clin Radiol 1979;30:389-95. 56. Havard AC, Collins D J, Guy RL, et al. Magnetic resonance behaviour of lipiodol. Clin Radiol 1992;45:198-200. 57. Feigen M, Crocker EF, Read J, et al. The value of lymphoscintigraphy, lymphangiography and computer tomography scanning in the preoperative assessment of lymph nodes involved by pelvic malignant conditions. Surg Gynecol Obstet 1987; 165:107-10. 58. Cabanes PA, Salmon RJ, Vilcoq JR, et al. Value of axillary dissection in addition to lumpectomy and radiotherapy in early breast cancer. Lancet 1992;339:1245-8.
Clinical Oncology
Review Article Prostate Cancer: Pelvic Nodes Revisited - Sites, Incidence and Prospects for Treatment with Radiotherapy A . J. N e a l a n d D . P. D e a r n a l e y Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey and Royal Marsden Hospital, Sutton, Surrey, UK
The role of pelvic lymph node irradiation in the management of carcinoma of the prostate remains uncertain. There have been few randomized studies designed to address this issue. Enthusiasm for this strategy has been tempered by our inability to give high doses of radiation to the pelvis without causing significant acute and late radiation morbidity, and by observations that patients die from distant metastases rather than pelvic node relapse. However, in recent years, there has been an increasing appreciation that, in some patients, pelvic recurrence itself may be the source of subsequent distant metastases; also that increased local control should be the goal of therapy as it may in turn lead to improved quality of life and survival [1-5]. Dissemination of tumour cells to the pelvic lymph nodes is an early phenomenon in the natural history of the disease. With regard to risk factors, many series have shown a positive correlation between the incidence of lymph node metastases at lymphadenectomy and tumour variables such as stage [6-18], histological grade [7,9,13,15-19], bulk [7,8] and invasion of the seminal vesicles [7,8]. Oesterling et al. [13] have performed a statistical analysis relating stage, grade and acid phosphatase to produce several nomograms which give the probability of lymph node involvement for given values of these parameters. It is currently standard practice in many centres in the USA to include the pelvic lymph nodes in the irradiated volume. Pertinent questions include: What is the incidence of nodal metastases and which nodes need to be considered as part of the clinical target volume? There can be little dispute that surgical staging of lymph nodes is the final arbiter in determining the incidence of lymph node metastases. Autopsy studies were for some years the main source of data regarding the patterns of lymphatic spread of prostatic cancer [20-22]. However, such reports were superseded by advances in surgical techniques which facilitated surgical staging by pelvic lymphadenectomy. The results from a number of surgical series are summarized in Table 1. It is important to make the distinction between clinical and pathological staging of the prostate. Correspondence and offprint requests to: Dr A. J. Neal, Clinical Research Fellow, Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, Surrey, UK.
Meticulous pathological staging by bilateral pelvic lymphadenectomy, such as that performed by McLaughlin et al. [12] can on average be expected to yield 33 nodes, rising to up to 89 if the presacral nodes are also dissected [24]. The prostatic lymphatics were originally identified by performing contrast studies using cadavers [25,26]. Lymphatic drainage to the obturator and presacral nodes was suggested by Smith [27] who infiltrated 1 ml of patent blue V dye into the prostate immediately prior to laparotomy and then assessed staining of the lymphatics at surgery. This was confirmed by Golimbu et al. [24] who performed very detailed pelvic lymphadenectomies in patients with stage A, B and C disease, with particular emphasis on clearing the presacral area, and yielding 22 to 89 nodes with a mean of 43. Of the involved lymph node groups, the external iliac group was the most frequently involved (60%) followed by the obturator group (53%). Fifty-three per cent had presacral node involvement and 47% presciatic node involvement. The largest surgical series providing data regarding the geographical distribution of involved nodes is summarized in Table 2 [9]. Other surgical series have suggested that the obturator/hypogastric complex is the main site of node metastases [7,8,15]. There is also evidence that there is a positive correlation between the side of the palpable tumour within the prostate and the side of pelvic lymph node involvement. Harrison et al. [11] reviewed the results of 411 lymphadenectomies in stage B and C carcinoma. Of 35 patients with Positive nodes and palpable disease confined to one 10be, 83% had ipsilateral nodes (57% to ipsilateral nodes or~!yand 26% to bilateral nodes), and 17% contralfiteral nodes only. This data is of value when considering less invasive means of pathologically staging the pelvic lymph nodes. In some centres technological advances in endoscopic instrumentation have made a closed procedure the method of choice, it having the advantage of providing an equivalent number of nodes to an open procedure [28] while being associated with less morbidity and a postoperative hospital stay of less than 48 hours [29, 30]. The data from the open lymphadenectomy series suggest that, when the cancer is clinically localized to one lobe of the prostate, endoscopic sampling of the
310
A . J . Neal and D. P. Dearnaley
Table 1. Summary of incidence of pelvic lymph node metastases at lymphadenectomy by stage: percentages (no. evaluable patients)
\uthor
Total no. patients
Clocks (1959) [8] )onohue (1981) [19] "owler (1981) [9] ;mith (1983) [18] ~enson (1984) [23] )esterling (1987) [13] 3ervasi (1989) [10] 'etros (1992) [14] tarrison (1992) [11] ~ean 1
411 c 215 c 300 c 452 c 519 ° 275 c 511 c 521 c 411 c -
~incke (1982)[17]
469 p
Stage A 1
Stage A 2
Stage B~
Stage C 1
Stage B 2
38 (382)
7 (29) 0 (9)
23 (44)
0 (41)
24 (33)
0 (10)
9 (23) 22 (130) 3.3 (61)
0 (32)
19 (104) 50 (58) 7 (75) 43 (129) 12 (156) 28 (154) 12:5 (519) 4 (178) 33 (64) 21 (165) 37 (100) 5.3 (189) 9.7 (236) 16 (210) 28 (106) 18 (2734)
0 (92) 0 (5)
0 (9)
Stage C2
0.5 (183)
60 (96)
53 (68)
44 (116) 38 (93) 50 (2) 43 (757)
10 (124)
36 (148)
c Equal staging. P Pathological staging. 1Flocks data excluded for stages A1 to B 2. Table 2. Summary of sites of lymph node metastases in 119 node positive patients (adapted from Fowler et al. (1981) (n = 300) Stage
% N+ (no.)
Unilateral (%)
Bilateral (%)
Solitary (%)
> 3 nodes (%)
Ob/Hypo (%)
Ext iliac (%)
Ob/hypo and ext iliac (%)
B1 B2 C
7 (5) 43 (56) 60 (58)
100 63 43
0 37 57
80 34 21
20 32 59
75 43 35
25 30 18
0 28 47
N+, node positive; OB, obturator group; Hypo, hypogastnc group.
ipsilateral external iliac, obturator and hypogastric nodes will be a sensitive means of identifying lymph node metastases with a lower risk of surgical complications than when bilateral sampling or an open lymphadenectomy is performed. Approximately 13% of patients will have the lateral sacral and/or presacral nodes as the sole site of nodal metastases [24] but these patients are unlikely to be staged correctly with the type of open lymphadenectomy currently practised. To date it has not been possible to administer sufficiently high doses of radiation to eradicate malignant cells (particularly when macroscopic disease is present) without considerable acute and late normal tissue morbidity. The dose complication effect for pelvic radiotherapy is well documented [31-33]. The risk of pelvic complications is also related to the volume irradiated [34,35]. Conventional treatment techniques lead to excessive bowel complications when high doses of radiation are administered. An early prospective randomized trial of extended field irradiation for prostatic cancer giving 55 Gy to the whole pelvis in 2 Gy fractions had to be modified due to excessive small bowel morbidity [15]. The most robust study to date has been that of the RTOG 77-06 [36] in which patients with prostatic cancer clinically limited to the gland (stages A2 and B) after surgical staging or lymphangiography were randomized to either a minimum of 65 Gy to the prostate and paraprostatic tissues, or 45 Gy to the whole pelvis and a 20 Gy boost to the prostate. In the 445 evaluable patients, there was no significant difference between the two arms after a median follow-up
of 7 years in terms of local control, time to distant metastases or overall survival. These results contrast with an earlier non-randomized report by McGowan et al. [37] in which patients with stages B 2 and C disease had a statistically significant advantage after pelvic node irradiation of 50-60 Gy, with a 63% 5-year survival versus 35% for prostatic irradiation alone. Similar findings have recently been presented by Ploysongsang et al. [38] using pelvic radiotherapy to a dose of 46-50 Gy. Patients with stage C disease had a 3-year disease free survival of 63% and a local control rate of 84% when pelvic radiotherapy was given, compared with 30% and 66% respectively for a historical cohort who had received radiotherapy to the prostate alone. Paulson et al. [39] randomized 77 patients with histologically confirmed pelvic lymph node metastases to either hormonal therapy delayed until relapse or elective irradiation of 45-50 Gy to the pelvic nodes. They demonstrated a statistically significant increase in the median disease free survival for pelvic irradiation (23.9 months versus 12.2 months, P=0.02) and a suggestion of an increase in overall survival. Bagshaw [6] has reported a similar benefit after long term follow-up of patients who received 50 Gy as a split course over 7 weeks, but this did not reach statistical significance. Similarly, multivariate analysis of patients with T2-T4 prostatic cancer treated at The Royal Marsden Hospital [40] showed a small but statistically significant advantage for additional radiotherapy to the pelvis. One hundred and fortynine previously untreated patients without radio-
Prostate Cancer: Pelvic Nodes Revisited
logical evidence of lymphadenopathy, who received radiotherapy to the prostate alone, attained 82% local control and 53 % 5-year survival versus 88% and 66% respectively for 36 comparable patients who received radiotherapy to the whole pelvis. The R T O G 75-06 study [41] randomized 607 patients with stage A2-C carcinoma to pelvic radiotherapy alone or combined pelvic and para-aortic irradiation. Although this does not add to our knowledge regarding whether pelvic node irradiation is beneficial, after a median follow-up of 4.25 years there was no advantage for added para-aortic irradiation in terms of disease free survival and overall survival. Conformal treatment techniques and threedimensional treatment planning mean that it is possible to reduce the clinical target volume and thereby reduce unnecessary irradiation of the surrounding small bowel, large bowel and bladder, so increasing the therapeutic gain [42]. Threedimensional planning has already been shown to be of benefit in para-aortic lymph node irradiation where analogous constraints on radiation dose are present [43]. Reduced acute morbidity compared with conventional treatment has already been demonstrated in early reports from non-randomized studies of conformal radiotherapy to the prostate [44--46]. Conformal radiotherapy therefore seems to be the tool for the delivery of high doses of radiation to the pelvis. However, before it can be implemented, it is necessary to have a precise definition of the lymph node groups at risk. We are therefore currently undertaking a study using multimodality imaging, comprising bipedal lymphangiography followed by computed tomographic scanning and magnetic resonance imaging (MRI) of the pelvis in order to define accurately the clinical target volume for threedimensional treatment planning and conformal radiotherapy. Lymphangiography (LAG) is a reliable means of delineating the anatomical distribution of the common iliac, external iliac and lower para-aortic lymph nodes. This has led to it being accepted as a valuable aid to a surgeon performing pelvic lymphadenectomy [47], and to the radiotherapist, as it yields data in a form that permits direct planning of the radiation treatment portals. It has also been used to provide precise anatomical information to localize pelvic lymph nodes for fine needle aspiration [48-50]. The obturator nodes are an important site of metastases from carcinoma of the prostate. For many years it was thought that these nodes did not opacify on LAG [51], although there is much evidence to the contrary [52-54]. LAG performed prior to a CT scan does not appear to be detrimental to the quality of the CT image obtained [55]. Indeed, lipiodol helps to identify the nodes due to its high iodine content giving rise to an area of high attenuation [56]. Computed tomography is of value to show lymph nodes that have not been opacified by LAG [49], particularly the internal iliac nodes [57]. In addition to giving useful anatomical information for treatment planning, a CT scan will provide the three-dimensional map of linear attenuation coefficients necessary to perform radiation dose calculations. In terms
311
of localizing the pelvic lymph nodes, MRI has the advantage over computed tomography of increased soft tissue contrast with more detailed and superior multiplanar reconstruction capabilities. It also has the advantage of allowing modulation of the signal from flowing blood by varying the pulse sequences, thus increasing the contrast between lymph nodes and the blood vessels. As with CT, lipiodol from the L A G will also contribute to node localization on T2 and proton density images [56]. These images will form the basis of devising new treatment techniques employing the versatility of a linear accelerator with multileaf collimation and planning systems, with the facility to use non-coplanar field arrangements. There may be analogies between the results of treatment of prostatic and breast cancer. The effect of radical treatment of the axillary lymph nodes in breast cancer has been a source of controversy for some years, but a recent large randomized study indicated a survival advantage for aggressive local treatment of axillary node positive disease [58]. Advances in treatment planning and radiotherapy techniques should therefore be used to address this issue in the pelvis.
Acknowledgements. Dr Neal is funded by the EEC
as part of the COVIRA (Computer Vision in Radiology) project. Dr Dearnaley is funded by The Cancer Research Campaign and The Bob Champion Cancer Trust.
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